Improved Patient Safety and Quality Outcomes With Amiodarone Infusions.

BACKGROUND: Amiodarone is a common intravenous medication and a known irritant to the vessel wall when administered peripherally. LOCAL PROBLEM: Nurses identified an increase in phlebitis associated with peripheral amiodarone leading to multiple catheter replacements and interruptions in drug therapy. Central venous access is recommended by the manufacturer but not practical for a short-term infusion based on the risk to the patient, time, and cost. METHODS: A 4-phased approach was used to identify a more suitable peripheral intravenous catheter. INTERVENTIONS: A collaborative effort between bedside nurses and the vascular access team evolved to look at alternative products for peripheral intravenous catheters. RESULTS: The extended dwell peripheral catheter decreased phlebitis from 54% to 5%. It also decreased interruptions in drug therapy and improved patient comfort and satisfaction. CONCLUSIONS: A practice change was implemented utilizing extended dwell peripheral catheters for intravenous amiodarone and disseminated to other units.

Peripheral Nerve Microscopic Changes Related to Study Procedures: Two Nonclinical Case Studies.

Peripheral nerves are routinely examined microscopically during the nonclinical safety assessment of therapeutics. In addition to test article-related on- or off-target changes, microscopic changes in peripheral nerves may also be caused by study procedures, such as parenteral test article administration and blood or tissue sampling. We present 2 nonclinical case studies in which nonstandard peripheral nerves had study procedure-related histologic changes. The first case study describes mouse trigeminal nerve changes as a result of blood sampling via retro-orbital sinus puncture. These changes included minimal-to-mild nerve fiber (axonal) degeneration associated with macrophage infiltration. The second case study presents rat brachial plexus changes associated with animal handling and blood sampling. Brachial plexus changes included minimal-to-moderate inflammation, focal hemorrhage, and nerve fiber degeneration. In both cases, the histological changes were morphologically indistinguishable from those that might be due to test article. Therefore, careful consideration of the incidence and severity across groups and a review of study procedures to rule out handling-related nerve damage are essential before identifying a test article-related effect on peripheral nerves. Study design considerations to avoid such procedure-related changes will be discussed, as well as sampling strategies to help distinguish these from test article-related effects.

New Method of Destroying Waste Anesthetic Gases Using Gas-Phase Photochemistry.

BACKGROUND: The inhalation anesthetics are potent greenhouse gases. To reduce the global environmental impact of the health care sector, technologies are sought to limit the release of waste anesthetic gas into the atmosphere. METHODS: Using a photochemical exhaust gas destruction system, removal efficiencies for nitrous oxide, desflurane, and sevoflurane were measured at various inlet concentrations (25% and 50%; 1.5%, 3.0%, and 6.0%; and 0.5%, 1.0%, and 2.0%, respectively) with flow rates ranging from 0.25 to 2.0 L/min. To evaluate the economic competitiveness of the anesthetic waste gas destruction system, its price per ton of carbon dioxide equivalent was calculated and compared to other greenhouse gas abatement technologies and current market prices. RESULTS: All inhaled anesthetics evaluated demonstrate enhanced removal efficiencies with decreasing flow rates (P < .0001). Depending on the anesthetic and its concentration, the photochemical exhaust gas destruction system exhibits a constant first-order removal rate, k. However, there was not a simple relation between the removal rate k and the species concentration. The costs for removing a ton of carbon dioxide equivalents are <$0.005 for desflurane, <$0.114 for sevoflurane, and <$49 for nitrous oxide. CONCLUSIONS: Based on this prototype study, destroying sevoflurane and desflurane with this photochemical anesthetic waste gas destruction system design is efficient and cost-effective. This is likely also true for other halogenated inhalational anesthetics such as isoflurane. Due to differing chemistry of nitrous oxide, modifications of this prototype photochemical reactor system are necessary to improve its removal efficiency for this gas.

Progress in cancer survival, mortality, and incidence in seven high-income countries 1995-2014 (ICBP SURVMARK-2): a population-based study.

BACKGROUND: Population-based cancer survival estimates provide valuable insights into the effectiveness of cancer services and can reflect the prospects of cure. As part of the second phase of the International Cancer Benchmarking Partnership (ICBP), the Cancer Survival in High-Income Countries (SURVMARK-2) project aims to provide a comprehensive overview of cancer survival across seven high-income countries and a comparative assessment of corresponding incidence and mortality trends. METHODS: In this longitudinal, population-based study, we collected patient-level data on 3·9 million patients with cancer from population-based cancer registries in 21 jurisdictions in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the UK) for seven sites of cancer (oesophagus, stomach, colon, rectum, pancreas, lung, and ovary) diagnosed between 1995 and 2014, and followed up until Dec 31, 2015. We calculated age-standardised net survival at 1 year and 5 years after diagnosis by site, age group, and period of diagnosis. We mapped changes in incidence and mortality to changes in survival to assess progress in cancer control. FINDINGS: In 19 eligible jurisdictions, 3 764 543 cases of cancer were eligible for inclusion in the study. In the 19 included jurisdictions, over 1995-2014, 1-year and 5-year net survival increased in each country across almost all cancer types, with, for example, 5-year rectal cancer survival increasing more than 13 percentage points in Denmark, Ireland, and the UK. For 2010-14, survival was generally higher in Australia, Canada, and Norway than in New Zealand, Denmark, Ireland, and the UK. Over the study period, larger survival improvements were observed for patients younger than 75 years at diagnosis than those aged 75 years and older, and notably for cancers with a poor prognosis (ie, oesophagus, stomach, pancreas, and lung). Progress in cancer control (ie, increased survival, decreased mortality and incidence) over the study period was evident for stomach, colon, lung (in males), and ovarian cancer. INTERPRETATION: The joint evaluation of trends in incidence, mortality, and survival indicated progress in four of the seven studied cancers. Cancer survival continues to increase across high-income countries; however, international disparities persist. While truly valid comparisons require differences in registration practice, classification, and coding to be minimal, stage of disease at diagnosis, timely access to effective treatment, and the extent of comorbidity are likely the main determinants of patient outcomes. Future studies are needed to assess the impact of these factors to further our understanding of international disparities in cancer survival. FUNDING: Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; The Scottish Government; Western Australia Department of Health; and Wales Cancer Network.

An exploratory study into the application of psychological theories and therapies in Australian mental health occupational therapy practice: Challenges to occupation-based practice.

BACKGROUND: While legitimate practice tools have been the subject of debate within the profession, little attention has been paid to psychological frames of reference (PFsOR). Hence, this article explores the ways psychological theories and therapies shape occupation-based practice in mental health settings. METHODOLOGY: Narrative inquiry methods and thematic analysis were used to explore the career stories of nine occupational therapists who had worked in mental health practice for more than five years. FINDINGS: Respondents found it difficult to hold onto their occupational focus in the psychology-dominated world of mental health practice. The main themes to emerge were (i) tension between occupation and psychology; (ii) overwhelming pressures to adopt PFsOR; (iii) resistance to PFsOR; and (iv) using PFsOR to enhance professional repertoires. Findings pointed to the need to ensure PFsOR include occupational considerations for occupation-based practice in mental health. CONCLUSION: A occupation-based perspective means balancing PFsOR with occupation-based considerations, so service-user issues are holistically addressed. There is a need to critically review occupational therapists' use of PFsOR lest their most visible practical actions appear psychologically based rather than occupation based.

Occupational therapy students' technological skills: Are 'generation Y' ready for 21st century practice?

BACKGROUND/AIM: Technology is becoming increasingly integral to the practice of occupational therapists and part of the everyday lives of clients. 'Generation Y' are purported to be naturally technologically skilled as they have grown up in the digital age. The aim of this study was to explore one cohort of 'Generation Y' occupational therapy students' skills and confidence in the use of technologies relevant to contemporary practice. METHODS: A cross-sectional survey design was used to collect data from a cohort of 274 students enrolled in an Australian undergraduate occupational therapy programme. RESULTS: A total of 173 (63%) students returned the survey. Those born prior to 1982 were removed from the data. This left 155 (56%) 'Generation Y' participants. Not all participants reported to be skilled in everyday technologies although most reported to be skilled in word, Internet and mobile technologies. Many reported a lack of skills in Web 2.0 (collaboration and sharing) technologies, creating and using media and gaming, as well as a lack of confidence in technologies relevant to practice, including assistive technology, specialist devices, specialist software and gaming. CONCLUSIONS: Overall, the results suggested that this group of 'Generation Y' students were not universally skilled in all areas of technology relevant to practice but appear to be skilled in technologies they use regularly. Recommendations are therefore made with view to integrating social networking, gaming, media sharing and assistive technology into undergraduate programmes to ensure that graduates have the requisite skills and confidence required for current and future practice.

Npt2b deletion attenuates hyperphosphatemia associated with CKD.

The incidence of cardiovascular events and mortality strongly correlates with serum phosphate in individuals with CKD. The Npt2b transporter contributes to maintaining phosphate homeostasis in the setting of normal renal function, but its role in CKD-associated hyperphosphatemia is not well understood. Here, we used adenine to induce uremia in both Npt2b-deficient and wild-type mice. Compared with wild-type uremic mice, Npt2b-deficient uremic mice had significantly lower levels of serum phosphate and attenuation of FGF23. Treating Npt2b-deficient mice with the phosphate binder sevelamer carbonate further reduced serum phosphate levels. Uremic mice exhibited high turnover renal osteodystrophy; treatment with sevelamer significantly decreased the number of osteoclasts and the rate of mineral apposition in Npt2b-deficient mice, but sevelamer did not affect bone formation and rate of mineral apposition in wild-type mice. Taken together, these data suggest that targeting Npt2b in addition to using dietary phosphorus binders may be a therapeutic approach to modulate serum phosphate in CKD.

Survey of sensitive information written in patient notes by psychiatry trainees.

OBJECTIVE: Allowing psychiatric patients access to their electronic medical record (EMR) may cause difficulty related to the sensitivity of the note content. The authors investigated whether notes written by psychiatry trainees were ready for release to patients. METHODS: Authors conducted a review of 128 PGY-3 to PGY-5 outpatient notes not explicitly marked as "highly confidential." One psychiatrist and one non-psychiatrist read each note from the patient's perspective. Reviewers assigned a score of 0-2 (0: No Concern; 1: Some Concern; 2: Major Concern) for each note. RESULTS: Eighty-nine notes (70%) were assessed as "No Concern" by both reviewers; 30 (23%) were of "Some Concern;" and 9 (7%) were of "Major Concern;" 92 (72%) were deemed of "No Concern" by a psychiatrist, as compared with 120 (94%) by the non-psychiatrist. CONCLUSIONS: Trainee EMR outpatient notes are not likely to cause major concerns for patients who read them. Psychiatrist-reviewers identified more concerns than non-psychiatrist-reviewers.

Occupational therapy and obesity: an integrative literature review.

BACKGROUND/AIM: Obesity is a significant public health concern globally. It is associated with poor physical health, mental health and subjective well-being and limitations on occupational participation. With its focus on the relationship between occupation, health and well-being, occupational therapy would appear to be well placed to address both the causes and consequences of obesity. The aim of this review was to explore the scope of the role of occupational therapy practice in this field and the supporting evidence base. METHODS: Searches were conducted in four online databases and nine occupational therapy journals. Articles were included if they were theoretical, quantitative or qualitative research, explicitly related to occupational therapy and obesity, published in peer-reviewed journals, in English between 2002 and 2012. All research articles were critically reviewed and thematic analysis was conducted across all of the articles in the review. RESULTS: Eight theoretical articles, 12 quantitative and two qualitative research studies were included. Only three were outcome studies. Thematic analysis identified four categories of focus of occupational therapy intervention: health promotion and prevention, increasing physical activity participation, modifying dietary intake and reducing the impact of obesity. Four categories of intervention strategies were also identified; assessment, modifying the environment, education and introducing and adapting occupations. CONCLUSION AND SIGNIFICANCE: The findings of this review suggest a comprehensive role for occupational therapy in addressing obesity. However, the paucity of outcome studies mean that significantly more research is required to further define and provide a strong evidence base for occupational therapy practice in this emerging field.

Factors that influence the professional resilience of occupational therapists in mental health practice.

BACKGROUND/AIM: Mental health practice can create challenging environments for occupational therapists. This study explores the dynamic processes involved in the development and maintenance of professional resilience of experienced mental health occupational therapy practitioners. It presents the PRIOrity model that summarises the dynamic relationship between professional resilience, professional identity and occupation-based practice. METHODS: A narrative inquiry methodology with two phases of interviews was used to collect the data from nine experienced mental health practitioners. Narrative thematic analysis was used to interpret the data. RESULTS: Professional resilience was linked to: (i) professional identity which tended to be negatively influenced in contexts dominated by biomedical models and psychological theories; (ii) expectations on occupational therapists to work outside their professional domains and use generic knowledge; and (iii) lack of validation of occupation-focussed practice. Professional resilience was sustained by strategies that maintained participants' professional identity. These strategies included seeking 'good' supervision, establishing support networks and finding a job that allowed a match between valued knowledge and opportunities to use it in practice. CONCLUSION: For occupational therapists professional resilience is sustained and enhanced by a strong professional identity and valuing an occupational perspective of health. Strategies that encourage reflection on the theoretical knowledge underpinning practice can sustain resilience. These include supervision, in-service meetings and informal socialisation. Further research is required into the role discipline-specific theories play in sustaining professional values and identity. The development of strategies to enhance occupational therapists' professional resilience may assist in the retention of occupational therapists in the mental health workforce.

Managing 'Generation Y' occupational therapists: optimising their potential.

BACKGROUND/AIM: 'Generation Y' is a descriptor of those therapists born between 1982 and 2000. According to generational theory, each generation have unique characteristics due to the social and historical factors they have experienced during their formative years. Occupational therapy educators have reported on 'Generation Y' characteristics observed in occupational therapy students. This study aimed to investigate if managers considered there was a 'Generation Y' therapist and their observed characteristics in practice, as well as successful management strategies used to maximise their potential in the workplace. METHODS: A hard copy survey based on the 'Generation Y' literature was sent to all managers listed on an Australian University database. RESULTS: Almost all respondents considered there was a 'Generation Y' therapist. Overall, managers reported characteristics of this staff group as being hard working, confident with technology, needing positive feedback and demanding professional development opportunities. Managers also reported that this group may be a challenge to retain in work positions. Managers also viewed 'Generation Y' staff as a positive energy and considered that in the future they will be of benefit to the profession. CONCLUSION: While there may be generational differences between therapists in the workplace, inclusive management styles may be the most appropriate management approach. Career guidance, facilitating creativity, increasing work responsibility and integrating new technologies like social networking into practice may be appropriate strategies for this staff group, to facilitate both their professional development and to retain them in the profession.

The impact of 'Generation Y' occupational therapy students on practice education.

BACKGROUND/AIM: Many occupational therapy students can be classified as 'Generation Y', a group whose characteristics are perceived as being confident, optimistic and 'techno-savvy'. This study aimed to explore practice educator perceptions of 'Generation Y' students. METHODS: A questionnaire survey was sent to all practice educators affiliated with the university. The survey contained fixed choice questions on demographics and educators' knowledge of the term 'Generation Y', followed by open-ended questions on practice educator perceptions of occupational therapy 'Generation Y' students and the educational strategies used in practice education. RESULTS: Anonymous responses were analysed using descriptive statistics, attribute coding and content analysis. Most educators considered that there was, in fact, a 'Generation Y student', describing them as confident with technology, over confident in their skill level and easily bored. Practice educators raised concerns regarding students' casual communication, poor professional behaviour, shallow professional reasoning and difficulty when receiving negative feedback. CONCLUSIONS: Overall, the results of this study suggest that 'Generation Y' students are having both a negative and a positive impact on practice education in occupational therapy. For educators, management of the overconfident student and professional reasoning development should be addressed in university practice education workshops. For students, the need for clarification of placement expectations on professional behaviour and communication was indicated. Students may also require 'listening to feedback' skill development prior to practice education. Universities and practice educators should consider the development of technological resources for practice education, including simulation, to meet the needs of the, now recognised 'Generation Y' student.

Improvement of quality of life in hospitalized depressed elderly.

BACKGROUND: Quality of life is important for all individuals, but is frequently overlooked in psychiatric populations. Our purpose was to assess the quality of life (QOL) of depressed psychiatrically hospitalized elderly patients, examine the association of QOL and depression, and explore any QOL differences related to electroconvulsive therapy (ECT). METHODS: This Institutional Review Board (IRB)-approved prospective study recruited geropsychiatric inpatients aged 65 years and older who were depressed, had Mini-mental State Examination (MMSE) scores >18/30, and adequate communication skills. Surveys were completed upon admission and discharge to measure depression (Hamilton Depression Rating Scale (HDRS)), quality of life (Linear Analogue Scales of Assessment (LASA); Medical Outcomes Short Form-36 Health Survey (SF-36)), cognitive function (MMSE; Executive Interview (EXIT 25)), and coping (Brief COPE Inventory (COPE)). Spearman correlations and Wilcoxon signed rank tests were used to assess changes in measures during hospitalization and relationships among variables. RESULTS: The 45 study participants who completed the study had a mean age of 74 years. The majority were female (67%), married (58%), Protestant (60%), with at least high school education (78%). Admission scores demonstrated severe depression (HDRS 24.88 ± 10.14) and poor QOL (LASA overall QOL 4.4 ± 2.79, and SF-36 mental [27.68 ± 9.63] and physical [46.93 ± 10.41] component scores). At discharge, there was a significant improvement of depression (HDRS 24.88v12.04, p < 0.0001) and QOL (LASA overall QOL 4.4v6.66, p < 0.0001; and SF-36 mental [27.68v39.10, p < 0.0001] and physical [46.93v50.98, p = 0.003] component scores). Not surprisingly, depression was negatively correlated with overall QOL, mental well-being, physical well-being, and emotional well-being at both admission and discharge. For the group who received ECT, there was a greater magnitude of improvement in SF-36 vitality (p = 0.002) and general health perception (p = 0.04), but also a reduction in EXIT 25 scores at discharge (p = 0.008). CONCLUSIONS: There was improvement of both QOL and depression during the course of hospitalization. Additionally, improvement of QOL was associated with improvement of depression. Perhaps future studies could develop interventions to improve both mood and QOL in elderly depressed inpatients.

Spiritual well-being and spiritual practices in elderly depressed psychiatric inpatients.

This study's aims were to describe the spirituality of depressed elderly psychiatric inpatients and to examine associations among spirituality, depression, and quality of life (QOL). Forty-five persons participated. Most reported frequent, stable spiritual practices and experiencing spiritual comfort and guidance. Some reported spiritual distress and changes in spirituality. During hospitalization, participants demonstrated increased spiritual well-being (SWB) and peacefulness, and reduced hopelessness, worthlessness, and guilt. Positive associations were found between SWB and QOL and negative associations between SWB and depression.

Nontraditional Small House Nursing Homes Have Fewer COVID-19 Cases and Deaths.

OBJECTIVES: Green House and other small nursing home (NH) models are considered "nontraditional" due to their size (10-12 beds), universal caregivers, and other home-like features. They have garnered great interest regarding their potential benefit to limit Coronavirus Disease 2019 (COVID-19) infections due to fewer people living, working, visiting, and being admitted to Green House/small NHs, and private rooms and bathrooms, but this assumption has not been tested. If they prove advantageous compared with other NHs, they may constitute an especially promising model as policy makers and providers reinvent NHs post-COVID. DESIGN: This cohort study compared rates of COVID-19 infections, COVID-19 admissions/readmissions, and COVID-19 mortality, among Green House/small NHs with rates in other NHs between January 20, 2020 and July 31, 2020. SETTING AND PARTICIPANTS: All Green House homes that held a skilled nursing license and received Medicaid or Medicare payment were invited to participate; other small NHs that replicate Green House physical design and operational practices were eligible if they had the same licensure and payer sources. Of 57 organizations, 43 (75%) provided complete data, which included 219 NHs. Comparison NHs (referred to as "traditional NHs") were up to 5 most geographically proximate NHs within 100 miles that had <50 beds and ≥50 beds for which data were available from the Centers for Medicare and Medicaid Services (CMS). Because Department of Veterans Affairs organizations are not required to report to CMS, they were not included. METHODS: Rates per 1000 resident days were derived for COVID-19 cases and admissions, and per 100 COVID-19 positive cases for mortality. A log-rank test compared rates between Green House/small NHs and traditional NHs with <50 beds and ≥50 beds. RESULTS: Rates of all outcomes were significantly lower in Green House/small NHs than in traditional NHs that had <50 beds and ≥50 beds (log-rank test P < .025 for all comparisons). The median (middle value) rates of COVID-19 cases per 1000 resident days were 0 in both Green House/small NHs and NHs <50 beds, while they were 0.06 in NHs ≥50 beds; in terms of COVID-19 mortality, the median rates per 100 positive residents were 0 (Green House/small NHs), 10 (<50 beds), and 12.5 (≥50 beds). Differences were most marked in the highest quartile: 25% of Green House/small NHs had COVID-19 case rates per 1000 resident days higher than 0.08, with the corresponding figures for other NHs being 0.15 (<50 beds) and 0.74 (≥50 beds). CONCLUSIONS AND IMPLICATIONS: COVID-19 incidence and mortality rates are less in Green House/small NHs than rates in traditional NHs with <50 and ≥50 beds, especially among the higher and extreme values. Green House/small NHs are a promising model of care as NHs are reinvented post-COVID.

Inhibition of TGF-ß Increases Bone Volume and Strength in a Mouse Model of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI), is a genetic disorder of bone fragility caused by mutations in collagen I or proteins involved in collagen processing. Previous studies in mice and human OI bones have shown that excessive activation of TGF-ß signaling plays an important role in dominant and recessive OI disease progression. Inhibition of TGF-ß signaling with a murine pan-specific TGF-ß neutralizing antibody (1D11) was shown to significantly increase trabecular bone volume and long bone strength in mouse models of OI. To investigate the frequency of dosing and dose options of TGF-ß neutralizing antibody therapy, we assessed the effect of 1D11 on disease progression in a dominant OI mouse model (col1a2 gene mutation at G610C). In comparison with OI mice treated with a control antibody, we attempted to define mechanistic effects of 1D11 measured via µCT, biomechanical, dynamic histomorphometry, and serum biomarkers of bone turnover. In addition, osteoblast and osteoclast numbers in histological bone sections were assessed to better understand the mechanism of action of the 1D11 antibody in OI. Here we show that 1D11 treatment resulted in both dose and frequency dependency, increases in trabecular bone volume fraction and ultimate force in lumbar bone, and ultimate force, bending strength, yield force, and yield strength in the femur (p ≤ 0.05). Suppression of serum biomarkers of osteoblast differentiation, osteocalcin, resorption, CTx-1, and bone formation were observed after 1D11 treatment of OI mice. Immunohistochemical analysis showed dose and frequency dependent decreases in runt-related transcription factor, and increase in alkaline phosphatase in lumbar bone sections. In addition, a significant decrease in TRACP and the number of osteoclasts to bone surface area was observed with 1D11 treatment. Our results show that inhibition of the TGF-ß pathway corrects the high-turnover aspects of bone disease and improves biomechanical properties of OI mice. These results highlight the potential for a novel treatment for osteogenesis imperfecta. © 2021 Sanofi-Genzyme. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

CRISPR/Cas9 generated knockout mice lacking phenylalanine hydroxylase protein as a novel preclinical model for human phenylketonuria.

Phenylketonuria (PKU) is an autosomal recessive inborn error of L-phenylalanine (Phe) metabolism. It is caused by a partial or complete deficiency of the enzyme phenylalanine hydroxylase (PAH), which is necessary for conversion of Phe to tyrosine (Tyr). This metabolic error results in buildup of Phe and reduction of Tyr concentration in blood and in the brain, leading to neurological disease and intellectual deficits. Patients exhibit retarded body growth, hypopigmentation, hypocholesterolemia and low levels of neurotransmitters. Here we report first attempt at creating a homozygous Pah knock-out (KO) (Hom) mouse model, which was developed in the C57BL/6 J strain using CRISPR/Cas9 where codon 7 (GAG) in Pah gene was changed to a stop codon TAG. We investigated 2 to 6-month-old, male, Hom mice using comprehensive behavioral and biochemical assays, MRI and histopathology. Age and sex-matched heterozygous Pah-KO (Het) mice were used as control mice, as they exhibit enough PAH enzyme activity to provide Phe and Tyr levels comparable to the wild-type mice. Overall, our findings demonstrate that 6-month-old, male Hom mice completely lack PAH enzyme, exhibit significantly higher blood and brain Phe levels, lower levels of brain Tyr and neurotransmitters along with lower myelin content and have significant behavioral deficit. These mice exhibit phenotypes that closely resemble PKU patients such as retarded body growth, cutaneous hypopigmentation, and hypocholesterolemia when compared to the age- and sex-matched Het mice. Altogether, biochemical, behavioral, and pathologic features of this novel mouse model suggest that it can be used as a reliable translational tool for PKU preclinical research and drug development.

Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models.

Emergency use authorization of COVID vaccines has brought hope to mitigate pandemic of coronavirus disease 2019 (COVID-19). However, there remains a need for additional effective vaccines to meet the global demand and address the potential new viral variants. mRNA technologies offer an expeditious path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on the spike (S) glycoprotein of SARS-CoV-2. Several mRNA constructs of S-protein, including wild type, a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), as well as others, were tested in animal models for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques, and for efficacy in a Syrian golden hamster model. The selected 2P/GSAS vaccine formulation, designated MRT5500, elicited potent nAbs as measured in neutralization assays in all three preclinical models and more importantly, protected against SARS-CoV-2-induced weight loss and lung pathology in hamsters. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate (NHP), thus alleviating a hypothetical concern of potential vaccine-associated enhanced respiratory diseases known associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for entering clinical development.

Global warming potential of inhaled anesthetics: application to clinical use.

BACKGROUND: Inhaled anesthetics are recognized greenhouse gases. Calculating their relative impact during common clinical usage will allow comparison to each other and to carbon dioxide emissions in general. METHODS: We determined infrared absorption cross-sections for sevoflurane and isoflurane. Twenty-year global warming potential (GWP(20)) values for desflurane, sevoflurane, and isoflurane were then calculated using the present and previously published infrared results, and best estimate atmospheric lifetimes were determined. The total quantity of each anesthetic used in 1 minimal alveolar concentration (MAC)-hour was then multiplied by the calculated GWP(20) for that anesthetic, and expressed as "carbon dioxide equivalent" (CDE(20)) in grams. Common fresh gas flows and carrier gases, both air/oxygen and nitrous oxide (N2O)/oxygen, were considered in the calculations to allow these examples to represent common clinical use of inhaled anesthetics. RESULTS: GWP(20) values for the inhaled anesthetics were: sevoflurane 349, isoflurane 1401, and desflurane 3714. CDE(20) values for 1 MAC-hour at 2 L fresh gas flow were: sevoflurane 6980 g, isoflurane 15,551 g, and desflurane 187,186 g. Comparison among these anesthetics produced a ratio of sevoflurane 1, isoflurane 2.2, and desflurane 26.8. When 60% N2O/40% oxygen replaced air/oxygen as a carrier gas combination, and inhaled anesthetic delivery was adjusted to deliver 1 MAC-hour of anesthetic, sevoflurane CDE(20) values were 5.9 times higher with N2O than when carried with air/O2, isoflurane values were 2.9 times higher, and desflurane values were 0.4 times lower. On a 100-year time horizon with 60% N2O, the sevoflurane CDE(100) values were 19 times higher than when carried in air/O2, isoflurane values were 9 times higher, and desflurane values were equal with and without N2O. CONCLUSIONS: Under comparable and common clinical conditions, desflurane has a greater potential impact on global warming than either isoflurane or sevoflurane. N2O alone produces a sizable greenhouse gas contribution relative to sevoflurane or isoflurane. Additionally, 60% N2O combined with potent inhaled anesthetics to deliver 1 MAC of anesthetic substantially increases the environmental impact of sevoflurane and isoflurane, and decreases that of desflurane. N2O is destructive to the ozone layer as well as possessing GWP; it continues to have impact over a longer timeframe, and may not be an environmentally sound tradeoff for desflurane. From our calculations, avoiding N2O and unnecessarily high fresh gas flow rates can reduce the environmental impact of inhaled anesthetics.

Dementia palliative care in the acute psychiatric hospital: A feasibility study.

PURPOSE: We explored the feasibility of a clinical pathway to identify hospitalized patients with dementia who would benefit from a palliative intervention. DESIGN AND METHODS: Consecutive geropsychiatric admissions were screened for terminal dementia to be randomized to a palliative consultation vs usual care. FINDINGS: A total of 43 of the 188 patients (23%) had dementia; however, dementia stages were severe but not terminal. The pathway was not feasible because of the lack of the target population in the inpatient setting for the intervention. PRACTICE IMPLICATIONS: New clinical pathways are needed to identify patients with dementia who would benefit from palliative care.