Search

Background: Familial Hypercholesterolaemia (FH) is a monogenic disorder that causes high levels of low-density lipoprotein (LDL) cholesterol. Cascade testing, where relatives of known individuals with FH ('index') are genetically tested, is effective and cost-effective, but implementation in the UK varies., Objective: This study aims to provide evidence on current UK FH cascade yields and to identify common obstacles cascade services face and individual- and service-level predictors of success., Methods: Electronic health records from 875 index families and 5,958 linked relatives in the UK's Welsh and Wessex FH services (2019) were used to explore causes for non-testing and to estimate testing rates, detection yields, and how relative characteristics and contact methods relate to the probability of relatives being tested (using logistic regression)., Results: In Wales (Wessex), families included 7.35 (7.01) members on average, with 2.41 (1.66) relatives tested and 1.35 (0.96) diagnosed with FH per index. Cascade testing is limited by individualised circumstances (too young, not at-risk, etc.) and FH services' reach, with approximately one in four relatives out-of-area. In Wales, first-degree relatives (odds ratio (OR):1.55 [95 % confidence interval (CI):1.28,1.88]) and directly contacted relatives (OR:2.11 [CI:1.66,2.69]) were more likely to be tested. In Wales and Wessex, women were more likely to be tested than men (ORs:1.53 [CI:1.28,1.85] and 1.74 [CI:1.32,2.27])., Conclusion: In Wales and Wessex less than a third of relatives of an index are tested for FH. Improvements are likely possible by integrating geographically dispersed families into cascade testing, services directly contacting relatives where possible, and finding new ways to encourage participation, particularly amongst men., Competing Interests: Declaration of competing interest BW sits on the board of directors for the York Health Economics Consortium (unremunerated role). Since this work was completed, RF has become an employee of Astellas Pharma Europe Ltd. All authors declare no other competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Determine if herniation morphology based on the Michigan State University Classification is associated with differences in (1) patient-reported outcome measures (or (2) surgical outcomes after a microdiscectomy., Methods: Adult patients undergoing single-level microdiscectomy between 2014 and 2021 were identified. Demographics and surgical characteristics were collected through a query search and manual chart review. The Michigan State University classification, which assesses disc herniation laterality (zone A was central, zone B/C was lateral) and degree of extrusion into the central canal (grade 1 was up to 50% of the distance to the intra-facet line, grade >1 was beyond this line), was identified on preoperative MRIs. patient-reported outcome measures were collected at preoperative, 3-month, and 1-year postoperative time points., Results: Of 233 patients, 84 had zone A versus 149 zone B/C herniations while 76 had grade 1 disc extrusion and 157 had >1 grade. There was no difference in surgical outcomes between groups (P > 0.05). Patients with extrusion grade >1 were found to have lower Physical Component Score at baseline. On bivariate and multivariable logistic regression analysis, extrusion grade >1 was a significant independent predictor of greater improvement in Physical Component Score at three months (estimate = 7.957; CI: 4.443-11.471, P < 0.001), but not at 1 year., Conclusions: Although all patients were found to improve after microdiscectomy, patients with disc herniations extending further posteriorly reported lower preoperative physical function but experienced significantly greater improvement three months after surgery. However, improvement in Visual Analog Scale Leg and back, ODI, and MCS at three and twelve months was unrelated to laterality or depth of disc herniation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The 2022 wildfires in New Mexico, United States, were unparalleled compared to past wildfires in the state in both their scale and intensity, resulting in poor air quality and a catastrophic loss of habitat and livelihood. Among all wildfires in New Mexico in 2022, six wildfires were selected for our study based on the size of the burn area and their proximity to populated areas. These fires accounted for approximately 90 % of the total burn area in New Mexico in 2022. We used a regional chemical transport model and data-fusion technique to quantify the contribution of these six wildfires (April 6 to August 22) on particulate matter (PM 2.5 : diameter ≤ 2.5 μm) and ozone (O 3 ) concentrations, as well as the associated health impacts from short-term exposure. We estimated that these six wildfires emitted 152 thousand tons of PM 2.5 and 287 thousand tons of volatile organic compounds to the atmosphere. We estimated that the average daily wildfire smoke PM 2.5 across New Mexico was 0.3 μg/m 3 , though 1 h maximum exceeded 120 μg/m 3 near Santa Fe. Average wildfire smoke maximum daily average 8-h O 3 (MDA8-O 3 ) contribution was 0.2 ppb during the study period over New Mexico. However, over the state 1 h maximum smoke O 3 exceeded 60 ppb in some locations near Santa Fe. Estimated all-cause excess mortality attributable to short term exposure to wildfire PM 2.5 and MDA8-O 3 from these six wildfires were 18 (95 % Confidence Interval (CI), 15-21) and 4 (95 % CI: 3-6) deaths. Additionally, we estimate that wildfire PM 2.5 was responsible for 171 (95 %: 124-217) excess cases of asthma emergency department visits. Our findings underscore the impact of wildfires on air quality and human health risks, which are anticipated to intensify with global warming, even as local anthropogenic emissions decline., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Study Objectives: To measure the incidence of intraoperative hypotension (IOH) during surgery in ambulatory surgery centers (ASCs) and describe associated characteristics of patients and procedures., Design: Retrospective analysis., Setting: 20 ASCs., Patients: 16,750 patients having non-emergent, non-cardiac surgery; ASA physical status 2 through 4., Interventions: None., Measurements: We assessed incidence of IOH using the definition from the Centers for Medicare & Medicaid Services (CMS) Merit-based Incentive Payment System (MIPS)-mean arterial pressure (MAP) < 65 mmHg for at least 15 cumulative minutes-and three secondary definitions: minutes of MAP <65 mmHg, area under MAP of 65 mmHg, and time-weighted average MAP <65 mmHg., Main Results: 30.9% of ASC cases had a MAP <65 mmHg for at least 15 min. The incidence of IOH varied significantly, and was higher among younger adults (age 18-39; 36.2%), females (35.2%), and patients with ASA physical status 2 (32.8%). IOH increased with increasing surgery length, even when time-weighted, and was higher among low complexity (30.6%) than moderate complexity (28.8%) procedures, and highest among high complexity procedures (44.1%)., Conclusions: There was substantial occurrence of IOH in ASCs, similar to that described in academic hospital settings in previous literature. We hypothesize that this may reflect clinician preference not to intervene in perceived healthy patients or assumptions about ability to tolerate lower blood pressures on behalf of these patients. Future research will determine whether IOH in ACSs is associated with adverse outcomes to the same extent as described in more complex hospital-based surgeries., Competing Interests: Declaration of Competing Interest, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: This study aimed to ascertain how the long-term benefits and costs of diagnosis and treatment of familial hypercholesterolaemia (FH) vary by prognostic factors and 'cholesterol burden', which is the effect of long-term exposure to low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) risk., Methods: A new cost-effectiveness model was developed from the perspective of the UK National Health Service (NHS), informed by routine data from individuals with FH. The primary outcome was net health gain (i.e., health benefits net of the losses due to costs), expressed in quality-adjusted life years (QALYs) at the £15,000/QALY threshold. Prognostic factors included pre-treatment LDL-C, age, gender, and CVD history., Results: If cholesterol burden is considered, diagnosis resulted in positive net health gain (i.e., it is cost-effective) in all individuals with pre-treatment LDL-C ≥ 4 mmol/L, and in those with pre-treatment LDL-C ≥ 2 mmol/L aged ≥50 years or who have CVD history. If cholesterol burden is not considered, diagnosis resulted in lower net health gain, but still positive in children aged 10 years with pre-treatment LDL-C ≥ 6 mmol/L and adults aged 30 years with pre-treatment LDL-C ≥ 4 mmol/L., Conclusions: Diagnosis and treatment of most people with FH results in large net health gains, particularly in those with higher pre-treatment LDL-C. Economic evaluations of FH interventions should consider the sensitivity of the study conclusions to cholesterol burden, particularly where interventions target younger patients, and explicitly consider prognostic factors such as pre-treatment LDL-C, age, and CVD history., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rita Faria declares that, since the research was completed, she has become an employee of Astellas Pharma Europe Ltd. Stephen Weng was part of an institution that received grants from the NIHR SPCR for research related to Familial Hypercholesterolaemia, consulting fees from his Academic Advisory Committee for Road to Health Ltd, Honoraria and travel fees from Amgen for lectures on familial hypercholesterolaemia, was previously a committee member for the MHRA CPRD Independent Scientific Advisory Committee and is currently employed by Janssen R&D. Steve Humphries has received Support from the British Heart Foundation (PG 008/08) and is the director of the UK Paediatric FH Register which has received support from a grant from the International Atherosclerosis Society (Pfizer number 24052829) and a medical director and minor share holder of a UCL Spin-out company StoreGene which offers DNA testing for individuals with FH. Nadeem Qureshi has received grants from NIHR SPCR and MRC (NUOF), Honoraria from Amgen for lectures on familial hypercholesterolaemia, is a Member of the Board for the NIHR School for Primary Care Research (2021-) and a Member of Medical, Scientific & Research Committee of HeartUK. Edward Cox, Pedro Saramago Goncalves, Ralph Akyea, Barbara Iyen and Beth Woods have no conflicts of interest to declare., (Copyright © 2022. Published by Elsevier B.V.)

Objective: To determine the influence of preoperative workers' compensation (WC) status on patient-reported outcome measures following lumbar decompression with or without fusion., Methods: All patients undergoing lumbar decompression with or without fusion at a single academic institution between 2013 and 2017 were identified. Patients were split into groups based on WC status: no workers' compensation (NWC), WC), or retired. Intragroup analysis used paired t tests. Outcomes between groups were compared using Kruskal-Wallis H test. Multiple linear regression analysis determined if WC status was a predictor of change in patient-reported outcome measures. Subgroup analysis was conducted for WC patients who returned to work., Results: Of 571 included patients, 242 (43.4%) had NWC, 83 (14.5%) had WC, and 246 (43.1%) were retired. Comparing within groups, WC patients showed significant improvement in Short Form-12 Health Survey Physical Component Score, Oswestry Disability Index, visual analog scale (VAS) back pain, and VAS leg pain (all P < 0.001) after surgery. However, WC patients improved less than NWC or retired patients in Short Form-12 Health Survey Physical Component Score (P = 0.010), VAS back pain (P = 0.028), and VAS leg pain (P = 0.015). WC was an independent predictor of decreased improvement in Short Form-12 Health Survey Physical Component Score (β = -4.31, P = 0.001), VAS back pain (β = 0.90, P = 0.034), and VAS leg pain (β = 1.50, P = 0.002) on multivariate analysis. WC patients who did not return to work was an independent predictor of decreased improvement in VAS back pain (β = 1.39, P = 0.016) and VAS leg pain (β = 2.11, P = 0.001)., Conclusions: WC patients improve less than NWC patients. However, WC patients who return to work have similar VAS back and neck pain improvements as NWC patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Antimicrobial resistance is a serious challenge to the success and sustainability of our healthcare systems. There has been increasing policy attention given to antimicrobial resistance in the last few years, and increased amounts of funding have been channeled into funding for research and development of antimicrobial agents. Nevertheless, manufacturers doubt whether there will be a market for new antimicrobial technologies sufficient to enable them to recoup their investment. Health technology assessment (HTA) has a critical role in creating confidence that if valuable technologies can be developed they will be reimbursed at a level that captures their true value. We identify 3 deficiencies of current HTA processes for appraising antimicrobial agents: a methods-centric approach rather than problem-centric approach for dealing with new challenges, a lack of tools for thinking about changing patterns of infection, and the absence of an approach to epidemiological risks. We argue that, to play their role more effectively, HTA agencies need to broaden their methodological tool kit, design and communicate their analysis to a wider set of users, and incorporate long-term policy goals, such as containing resistance, as part of their evaluation criteria alongside immediate health gains., (Copyright © 2021 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Acute spinal cord injuries in athletes are rare. However, on-field management of such injuries requires a well-planned approach from a team of well-trained medical staff. Athletes wearing protective gear should be handled with care; a primary survey should be conducted to rule out life-threatening injury while concomitantly immobilizing the spine. Treatment with steroids or hypothermia have not been shown to be beneficial, ultimately time to surgery provides the athlete with the best chance of a good outcome., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: This exploratory study aimed at investigating profiles of care needs in people with mild to moderate dementia and examined variables associated with these profiles., Design: A longitudinal international cohort study., Setting and Participants: The baseline data of 447 community-dwelling dyads of people with dementia and their caregivers from the Access to Timely Formal Care (Actifcare) Study were included for analysis., Methods: A latent class analysis was applied to identify profiles of needs, measured with the Camberwell Assessment of Need for the Elderly as rated by the caregiver. We examined sociodemographic (eg, relative stress scale) and clinical characteristics (eg, neuropsychiatric inventory) associated with these profiles., Results: Four distinct need profiles were identified through latent class analysis. These comprised a "no need" profile (41% of the sample), a "met psychological needs" profile (25%), a "met social needs" profile (19%), and an "unmet social needs" profile (15%). A larger impact of caregiving on the caregiver's life as indicated by a higher relative stress scale score was associated with the "unmet social needs" profile., Conclusions and Implications: In this large European sample, there was a subgroup of persons with dementia with high "unmet social needs" whose caregivers simultaneously perceived high stress in their caregiving tasks. Identification of these profiles may help provision of appropriate support for these people., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Recently, 3-dimensional supramolecular coordination complexes of the metallacage type have been shown to hold promise as drug delivery systems for different cytotoxic agents, including the anticancer drug cisplatin. However, so far only limited information is available on their uptake and sub-cellular localisation in cancer cells. With the aim of understanding the fate of metallacages in cells by fluorescence microscopy, three fluorescent Pd 2 L 4 metallacages were designed and synthesised by self-assembly of two types of bispyridyl ligands (L), exo-functionalised with boron dipyrromethene (BODIPY) moieties, with Pd(II) ions. The cages show high quantum yields and are moderately stable in the presence of physiologically relevant concentration of glutathione. Furthermore, the cages are able to encapsulate the anticancer drug cisplatin, as demonstrated by NMR spectroscopy. Preliminary cytotoxicity studies in a small panel of human cancer cells showed that the metallacages are scarcely toxic in vitro. The marked fluorescence due to BODIPY allowed us to visualise the cages' uptake and sub-cellular localisation inside melanoma cells using fluorescence microscopy, highlighting uptake via active transport mechanisms and accumulation in cytoplasmic vesicles., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Cost-effectiveness analysis can guide policymakers in resource allocation decisions. It assesses whether the health gains offered by an intervention are large enough relative to any additional costs to warrant adoption. When there are constraints on the health care system's budget or ability to increase expenditures, additional costs imposed by interventions have an "opportunity cost" in terms of the health foregone because other interventions cannot be provided. Cost-effectiveness thresholds (CETs) are typically used to assess whether an intervention is worthwhile and should reflect health opportunity cost. Nevertheless, CETs used by some decision makers-such as the World Health Organization that suggested CETs of 1 to 3 times the gross domestic product (GDP) per capita-do not., Objectives: To estimate CETs based on opportunity cost for a wide range of countries., Methods: We estimated CETs based on recent empirical estimates of opportunity cost (from the English National Health Service), estimates of the relationship between country GDP per capita and the value of a statistical life, and a series of explicit assumptions., Results: CETs for Malawi (the country with the lowest income in the world), Cambodia (with borderline low/low-middle income), El Salvador (with borderline low-middle/upper-middle income), and Kazakhstan (with borderline high-middle/high income) were estimated to be $3 to $116 (1%-51% GDP per capita), $44 to $518 (4%-51%), $422 to $1967 (11%-51%), and $4485 to $8018 (32%-59%), respectively., Conclusions: To date, opportunity-cost-based CETs for low-/middle-income countries have not been available. Although uncertainty exists in the underlying assumptions, these estimates can provide a useful input to inform resource allocation decisions and suggest that routinely used CETs have been too high., (Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Unlabelled: Natural biomaterials such as collagen show promise in tissue engineering applications due to their inherent bioactivity. The main limitation of collagen is its low mechanical strength and somewhat unpredictable and rapid degradation rate; however, combining collagen with another material, such as chitosan, can reinforce the scaffold mechanically and may improve the rate of degradation. Additionally, the high cost and the risk of prion transmission associated with mammal-derived collagen has prompted research into alternative sources such as marine-origin collagen. In this context, the overall goal of this study was to determine if the incorporation of chitosan into collagen scaffolds could improve the mechanical and biological properties of the scaffold. In addition the study assessed if collagen, derived from salmon skin (marine), can provide an alternative to collagen derived from bovine tendon (mammal) for tissue engineering applications. Scaffold architecture and mechanical properties were assessed as well as their ability to support mesenchymal stem cell growth and differentiation. Overall, the addition of chitosan to bovine and salmon skin-derived collagen scaffolds improved the mechanical properties, increasing the compressive strength, swelling ratio and prolonged the degradation rate. Mesenchymal stem cell (MSC) attachment and proliferation was most improved on the bovine-derived collagen scaffold containing a 75:25 ratio of collagen:chitosan, and when MSC osteogenic and chondrogenic potential on the scaffold was assessed, a significant increase in calcium production (p<0.001) and sulfated glycosaminoglycan (sGAG) production (p<0.001) was observed respectively. Regardless of chitosan content, the bovine-derived collagen scaffolds out-performed the salmon skin-derived collagen scaffolds, displaying a larger pore size and higher percentage porosity, more regular architecture, higher compressive modulus, a greater capacity for water uptake and allowed for more MSC proliferation and differentiation. This versatile scaffold incorporating the marine biomaterial chitosan show great potential as appropriate platforms for promoting orthopaedic tissue repair while the use of salmon skin-derived collagen may be more suitable in the repair of soft tissues such as skin., Statement of Significance: Collagen is commonly used in tissue engineering due to its biocompatibility; however, it has low mechanical strength and an unpredictable degradation rate. In addition, high cost and risk of prion transmission associated with mammalian-derived collagen has prompted research into alternative collagen sources, namely, marine-derived collagen. In this study, scaffolds made from salmon-skin collagen were compared to the more commonly used bovine-derived collagen with a focus on orthopaedic applications. To improve the mechanical properties of these scaffolds, another marine biomaterial, chitosan, was added to produce scaffolds with increased mechanical stability. The collagen-chitosan composites were also shown to support mesenchymal stem cell differentiation towards both bone and cartilage tissue. This multi-functional scaffold therefore has potential in both bone and cartilage regeneration applications., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: Apathy is common, impactful, and difficult to manage in people with dementia. We evaluated the efficacy of nonpharmacological interventions, exercise, and social interaction, in combination with antipsychotic review, to reduce apathy in people with dementia living in nursing homes in a cluster randomized controlled trial (RCT)., Methods: Well-being and health for people with dementia (WHELD) program included a 2 × 2 × 2 factorial cluster RCT involving people with dementia living in 16 nursing homes in the United Kingdom. All homes received training in person-centered care, and were randomized to receive antipsychotic review, social interaction, and exercise, either alone or in combinations. Apathy was one of the secondary outcomes of the WHELD trial, and it was measured by the Neuropsychiatric Inventory-nursing home version at baseline and 9 months (n = 273). We used multilevel mixed effects linear regression models to assess the impact of the interventions on apathy., Results: Prevalence of apathy was 44.0% (n = 120; 95% confidence interval [CI] 38.1%-49.9%) at baseline. Severity of apathy had significant positive correlations with dementia severity, neuropsychiatric symptoms, depressive symptoms, agitation, and the needs of the people with dementia (P < .001). Antipsychotic review reduced antipsychotic use, but it significantly increased apathy (β = 5.37; SE = 0.91; P < .001). However, antipsychotic review in combination with either social interaction (β = -5.84; SE = 1.15; P < .001) or exercise (β = -7.54; SE = 0.93; P < .001) significantly reduced apathy., Conclusions: Antipsychotic review can play a significant role in improving apathy in people with dementia living in nursing homes, when combined with psychosocial interventions such as social interaction and exercise. Guidance must be adapted to reflect this subtlety in care., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the cost-effectiveness of eltrombopag compared with romiplostim to be used in the treatment of chronic immune thrombocytopenia in patients in England and Wales who are splenectomized or ineligible for splenectomy and are refractory to other treatments., Methods: A Markov cohort model in which patients were administered a sequence of treatments was used to predict long-term outcomes associated with each treatment. The model was informed by data from the eltrombopag clinical trial program and the available literature. The analysis was conducted from the perspective of the UK National Health Service, and a lifetime time horizon was used. Deterministic and probabilistic sensitivity analyses were performed., Results: Eltrombopag dominated romiplostim (i.e., eltrombopag was as effective as but less costly than romiplostim) in both splenectomized and nonsplenectomized patients, assuming a class effect for the two treatments. Eltrombopag also dominated romiplostim in most deterministic sensitivity analyses with the exception of when indirect efficacy estimates were incorporated into the model. In this analysis, eltrombopag no longer dominated romiplostim but remained cost-effective versus romiplostim at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Probabilistic sensitivity analysis demonstrated that there was a 99% and 92% chance of eltrombopag being cost-effective at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year in splenectomized and nonsplenectomized patients, respectively., Conclusions: Results of this study demonstrate that eltrombopag is cost-effective when compared with romiplostim to be used in the treatment of chronic immune thrombocytopenia, representing good value for the UK National Health Service., (Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Context: Although pain is frequent in people with dementia (PwD), evidence on the prevalence and factors influencing ratings of pain in dementia is limited. Carer variables are often associated with bias in proxy ratings of pain, but few studies have examined the role of caregiver pain in influencing these ratings., Objectives: This study explored the prevalence of pain in PwD in a large U.K., Sample: A secondary aim was to identify factors influencing ratings of pain in people with mild to moderate dementia and whether carer pain systematically influences proxy ratings., Methods: This was a cross-sectional study of 488 caregiving dyads living in the community. Self- and carer-rated pain was assessed as part of the EuroQoL-5D (EQ-5D). Depression and anxiety for the PwD were measured by the Cornell Scale for Depression in Dementia and the Rating of Anxiety in Dementia Scale. The Hospital Anxiety and Depression Scale was used to measure anxiety and depressive symptoms in carers. Using logistic regression modeling, we examined the relationship between self- and carer-rated (proxy) pain in PwD and psychological distress, functional ability, and health status. Carer variables included self-rated health, strain, anxiety, depression, and caregiver pain., Results: A total of 45% of PwD reported pain, whereas carer-rated pain was higher (59%). Self-rated pain was more frequent in those with lower self-rated health (adjusted odds ratio [AOR] 0.97; 95% CI 0.96-0.99, P ≤ 0.001) and higher anxiety (AOR 1.07; 95% CI 1.01-1.12, P = 0.013). Carer-rated (proxy) pain was additionally predicted by poor proxy-rated health in the PwD (AOR 0.98; 95% CI 0.96-0.99, P = 0.006) and carers' own experience of pain (AOR 0.36; 95% CI 0.21-0.63, P ≤ 0.001)., Conclusion: Our results indicate that pain is very frequently reported in PwD and that the presence of pain is associated with high levels of anxiety. Caregiver pain affects carers' perceptions of pain in PwD., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the cost-effectiveness of bendamustine compared with chlorambucil as first-line treatment for patients with chronic lymphocytic leukemia who would be considered unsuitable for treatment with fludarabine combination chemotherapy regimens., Methods: A semi-Markov approach was used to estimate time in each health state. The model was parameterized primarily by using data from a phase III randomized, open-label trial comparing bendamustine with chlorambucil. It captured the increased progression-free survival and improved response rates with bendamustine, and the cost and quality of life impacts of postprogression treatments. The analysis was conducted from the perspective of the National Health Service in England and Wales. A lifetime (35-year) time horizon was used. Deterministic sensitivity analyses, probabilistic sensitivity analyses, and subgroup analyses in older patients and patients with poor performance status were carried out., Results: The estimated incremental cost-effectiveness ratio was £ 11,960 per quality-adjusted life-year. None of the deterministic sensitivity analyses increased the incremental cost-effectiveness ratio by more than £ 2000. Subgroup analyses showed that bendamustine remained cost-effective across different patient groups. Probabilistic sensitivity analysis showed that at the £ 20,000 threshold, bendamustine has a 90% probability of being cost-effective., Conclusions: Bendamustine represents good value for first-line treatment of patients with chronic lymphocytic leukemia who are unsuitable for treatment with fludarabine combination chemotherapy. The incremental cost-effectiveness ratio is below the thresholds commonly applied in England and Wales (£ 20,000-£ 30,000 per quality-adjusted life-year)., (Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Objectives: To demonstrate how value of information (VOI) analysis can be used to establish research priorities regarding the use of pharmacogenetic tests using CYP2D6 testing to select adjuvant hormonal therapy in early stage breast cancer as a case study., Methods: The following four treatment pathways are compared in a Markov model: tamoxifen treatment; CYP2D6 test and treat homozygous and heterozygous wild type patients (wt/wt; wt/*4) with tamoxifen and *4/*4 patients with anastrozole (HetTam); CYP2D6 test and treat homozygous wild type patients with tamoxifen and others with anastrozole (HomTam); and anastrozole treatment. Pharmacogenetic testing efficacy is estimated by synthesizing randomized controlled trial data comparing tamoxifen to anastrozole with observational data linking CYP2D6 genotype to tamoxifen outcomes., Results: In order of increasing effectiveness the comparators are tamoxifen, HetTam, HomTam, anastrozole. Health outcomes for test and treatment strategies are highly uncertain. Differences in comparator costs depend on assumptions made regarding anastrozole patent expiry. The expected value of a decision taken with perfect information is £69 to £106 million (pound sterling) for the United Kingdom depending on patent expiry assumptions and the acceptable cost-effectiveness threshold. The most valuable research (VOI £53-£82 million) elucidates the relationship between CYP2D6 genotype and tamoxifen effectiveness. It is uncertain whether values of other research designs would exceed their costs., Conclusions: Retrospective analysis of one of the large adjuvant aromatase inhibitor trials is warranted to better understand any association between CYP2D6 genotype and tamoxifen outcomes. VOI approaches may be helpful for prioritising evidence needs and structuring coverage with evidence development agreements for pharmacogenetics., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

The incidence of asthma is increasing worldwide, but morbidity and mortality are decreasing because of improvements in medical care. Although the incidence of severe perioperative bronchospasm is relatively low in asthmatics undergoing anaesthesia, when it does occur it may be life-threatening. The keys to an uncomplicated perioperative course are assiduous attention to detail in preoperative assessment, and maintenance of the anti-inflammatory and bronchodilatory regimens through the perioperative period. Potential trigger agents should be identified and avoided. Many routinely used anaesthetic agents have an ameliorative effect on airway constriction. Nonetheless, acute bronchospasm can still occur, especially at induction and emergence, and should be promptly and methodically managed.

Objective: To document the smoking practices of Aboriginal mothers living in Perth during pregnancy and during the subsequent year while feeding their infants., Method: A cohort of mothers was followed from the time of delivery for 12 months to obtain details of infant feeding practices. A total of 455 mothers delivered between May 2000 and July 2001 and 425 completed the baseline questionnaire., Results: Prior to and during pregnancy, 67% of the mothers smoked regularly. While the rate appeared to decline slightly with the length of breastfeeding, the trend was not significant. The rate of smoking of Aboriginal mothers was significantly greater than for an earlier study of non-Aboriginal mothers in Perth, where the rate was 28.4%. Among Aboriginal women there was no difference in the percentage of smokers and non-smokers who initiated breastfeeding. While fewer women who smoked were still breastfeeding at 24 weeks postpartum, compared with non-smokers (58% vs. 64%), this difference was not significant., Conclusions: The percentage of women smoking in this study is consistent with rates reported in the 2001 National Drug Strategy Household Survey. In other studies, smoking is associated with lower rates of breastfeeding initiation and duration, but this was not the case in the Aboriginal mothers., Implications: Although the high prevalence of smoking identified in this study did not appear to adversely affect breastfeeding, smoking during and after pregnancy does contribute to increased rates of low birth weight and other health problems in early childhood. Targeted antenatal smoking cessation programs are needed for Aboriginal mothers.

Ovarian follicular dynamics and steroid secretion patterns were monitored in postpartum beef cows that were synchronized for estrus with melengestrol acetate (MGA) or prostaglandin F(2alpha) (PGF) prior to superovulation. Twenty-four muhiparous Angus cows were stratified by number of days postpartum to an MGA or PGF treatment prior to superovulation. Cows in the MGA group were fed 0.5 mg MGA/d for 14 d in a grain carrier. Superstitnulatory treatments began 14 d after withdrawal of MGA from feed or 11 d after administering a single injection of 500 microg cloprostenol (PGF). Supersthnulatory treatments (FSH) were administered twice daily in decreasing doses (7.5, 5, 5, 2.5 mg) over 4 d. Sixty and 72 h after initiating the superstimulatory treatments, all cows were treated with 750 microg and 500 microg PGF, respectively Cows were inseminated at 0, 12, and 24 h from the onset of standing estrus with semen from 2 proven sires. Cows within treatment were inseminated with 1, 2 and 1 (single) or 2, 4 and 2 units (double) of semen at the designated insemination times. Blood sampling and transrectal ultrasonography of ovaries were performed daily beginning 2 d prior to the initiation of FSH treatment and were continued through embryo recovery. Ovaries were examined daily to determine the number and size of follicles. Plasma samples were analyzed for progesterone and estradiol. Follicles were counted and categorized based on a 5 to 9 mm range or >/= 10 mm. At the end of superovulatory treatment there were more (P /= 10 mm among cows that were estrus synchronized with MGA (75 +/- 1.2) than with PGF (3.9 +/- 1.2) These differences were reflected in higher (P

It has been suggested that schizophrenia is primarily a prefrontal-temporal-limbic circuitry disorder. Further, it has been argued that primary neurologic vulnerability to the illness is established only during early stages of brain development and is not progressive. We tested the hypothesis of whether brain volume losses in prefrontal and temporal-limbic regions have occurred either before or after brain growth was hypothesized to be complete in schizophrenia. Nineteen chronic schizophrenic patients and 19 age- and sex-matched normal controls underwent magnetic resonance imaging (MRI). All scans were segmented into gray and white matter and cerebrospinal fluid (CSF) compartments for the frontal and temporal lobes and posterior cerebral hemispheres. Multivariate analysis of variance was used to analyze absolute intracranial cerebrum and subregion volumes, i.e., gray, white and CSF, absolute tissue (i.e., gray plus white) volumes, and tissue to intracranial volume (TCV) ratios. Patients showed significant intracranial volume reductions only in the frontal lobes but highly significantly lower TCV ratios (i.e., greater relative tissue loss) in all three major regions. It is suggested that the observed decreases in frontal intracranial volumes reflect a pathologic process in schizophrenia that impacted the frontal regions before brain growth was complete. We hypothesize that the generalized lower patient TCV ratios are attributable to a process that affected the whole cerebrum over a time period after brain volume had reached its maximum levels.

In a group of schizophrenic patients, magnetic resonance imaging (MRI) measures of relative frontal brain volume (total frontal volume/total cerebral volume) correlated highly with the capacity to use context as an aid to recall in a verbal memory task. The dorsolateral area of the prefrontal cortex appears to have contributed most to this effect. Recall of simple word lists without contextual features revealed no correlation with relative frontal volume. With increasing contextual organization of the material, correlations between frontal volume and recall scores increased significantly. These findings are consistent with the general proposition that impairment in the use of informational redundancy is a significant component of schizophrenic pathology.

This preliminary study focused on the relationship between prefrontal and temporal lobe MRI measures and neuropsychological performance in chronic schizophrenia. Seventeen schizophrenic inpatients received an MRI and a neuropsychological test battery after clinical stabilization, on average 2 months after admission. The central finding was a significant inverse correlation between neurocognitive measures of prefrontal function and dorsolateral prefrontal cortex (DLPFC) area, strongest in the left hemisphere. Neurocognitive performance did not correlate significantly with orbital frontal area or total temporal lobe volume. The correlations of neuropsychological performance with total frontal volume and whole brain volume were generally not significant, although the pattern was similar to that associated with the DLPFC. Because a number of executive-attention and abstraction measures were significantly associated with the DLPFC, dysfunctions of this region may underlie a syndrome of cognitive dysfunctions. Long-term memory functions were also significantly correlated with the DLPFC, raising the possibility that recall memory defects in schizophrenia are, in part, associated with prefrontal contributions of attention, abstract reasoning, and executive function. This study needs replication with a larger sample of patients and more comprehensive volumetric morphometric analyses.

Brain alcohol was measured in rhesus monkeys (Macaca mulatta) by proton magnetic resonance spectroscopy (MRS) following acute nasogastric alcohol administration (0.8 g/kg). Monkeys were anesthetized with ketamine and xylazine. A 1.5 T whole body imager and a 3-inch surface coil were used to acquire TE 30 and 270 ms spectra from a 7.5 cc voxel localized with a stimulated echo (STEAM) sequence. Venous blood samples were collected during spectral acquisitions for gas chromatographic determination of temporally concordant blood alcohol levels (BALs). Acute alcohol administration did not alter the resonance areas of N-acetylaspartate/N-acetyl containing compounds (NAA), choline containing compounds, or total creatine. The NAA resonance was used as an internal standard to calculate approximate brain alcohol concentrations, which averaged 27 +/- 3% and 27 +/- 8% of temporally concordant BALs (T2-corrected TE 30 and TE 270 ms spectra, respectively). In addition to reconfirming results from prior studies finding incomplete detection of brain alcohol with MRS, these results demonstrate the feasibility of measuring brain alcohol in anesthetized nonhuman primates to examine relationships between alcohol exposure history and MRS-visibility of brain alcohol.

A nonferrous joystick device was developed to permit subjects to continuously report ethanol-induced alterations in subjective mood states while undergoing a magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) procedure. The device utilizes air pressure (supplied by a small compressor) that is directed to a series of tubes that terminate in a hand-held unit. The hand-held unit easily fits inside the magnet and resembles a standard computer game joystick except that the ends of the air hoses replace the buttons. The control unit contains three pressure transducers, which are triggered when the tubes are occluded by the subject, activating different pens on an event marker located 6 m from the whole body imager. The unit is safe to use inside a 1.5-Tesla magnetic field and does not disrupt the MRI and MRS recording procedures. Subjective reports of ethanol-induced euphoria and intoxication paralleled the MRS detection of ethanol in the brain. This device could prove to be useful in numerous behavioral studies involving whole-body MRI and MRS.

Using magnetic resonance imaging (MRI), we studied brain morphometric differences between patients with first-episode mania (n = 17) and normal control subjects (n = 16). Patients were admitted for their first psychiatric hospitalization and met DSM-III-R criteria for bipolar disorder, manic or mixed. Diagnoses were made using the Structured Clinical Interview for DSM-III-R. Patients and control subjects were matched for age, gender, height, past history of substance abuse, and handedness, although control subjects had attained higher levels of education. MRI inversion recovery coronal scans were used for measurements. Volumetric measurements were obtained for cerebral hemispheres, lateral and third ventricles, caudate, thalamus, and cingulate gyrus. Patients with first-episode mania demonstrated significantly larger third-ventricular volumes, possibly increased lateral ventricular volumes, and differences in gray/white matter distribution compared with normal control subjects. The possible pathophysiological meaning of these findings is discussed.

Previous research found schizophrenics to have significantly more neurological signs than normal controls, even when signs were screened to exclude possible artifacts, and limited to "hard" signs of localizing significance. Schizophrenics with a family history of psychosis also tended to have more neurological signs than those without such a history. The present study examined whether these findings could be confirmed in new samples of schizophrenics and controls, using interview-based DSM-III and DSM-III-R diagnoses. Schizophrenics had significantly more hard signs than controls, and schizophrenics with a family history for psychosis again had more signs than those without this history. When present study data were analyzed alone, as well as when pooled with data from previous research using similar methods, hard signs were significantly greater in both (a) schizophrenics versus controls and (b) schizophrenics with versus without a family history of psychosis, supporting the hypothesis that neurological signs reflect a significant etiologic factor in schizophrenia.

Balloon angioplasty is being used with increasing frequency in the management of patients with peripheral vascular disease. Balloon angioplasty is useful alone and as an adjunct to conventional surgery. Angioplasty is relatively inexpensive, is performed under local anesthesia, and is associated with few complications. Technical success depends on the morphologic characteristics of a lesion and on the skill and experience of the operator. Long-term patency is more likely with larger vessels and short-segment stenosis. Careful selection of patients is vital and depends on cooperation between the vascular consultant and radiologist. PCTA is most often used at the extremes of clinical severity. Most complications are minor and do not require surgical treatment. The main disadvantage is the high incidence of restenosis. Angioplasty can be repeated easily, however, and its use does not preclude later surgery.

Cardiologists are becoming more interested in peripheral arterial disease with the development of sophisticated noninvasive diagnostic techniques and invasive therapeutic modalities for the symptomatic patient. The clinical diagnosis of occlusive arterial disease, which is predominantly atherosclerosis, is relatively easy and a clue to the possibility of coexistent underlying coronary disease or cerebrovascular disease or both. Occlusive arterial disease of the lower extremities is more prevalent in men than in women. Nevertheless, the lifestyle of women is increasingly similar to that of men, especially with regard to smoking and diet. Therefore, the role of primary prevention remains the cornerstone of treatment.

Previous studies of long-term serial changes in ventricular size in schizophrenia (SCZ) have yielded mixed, albeit predominantly negative results. The current study examined ventricular changes in CT scans over intervals of 1-to 4 1/2 years in chronic schizophrenic and bipolar patients. The results indicated significant progression of ventricular size from initial to final scan in the schizophrenia group but not in the bipolar or control groups; the percent increase in VBR over baseline was 25% (p less than 0.01) in the schizophrenia group as compared with 11% (n.s.) in the bipolar group. The increases in ventricular enlargement in the schizophrenic group did not correlate with duration of illness but did appear to show an irregular stepwise pattern in several patients. It is concluded that progressive ventricular enlargement after onset of illness does occur in a subgroup of schizophrenic patients characterized by a chronic or deteriorating clinical course. The etiological implications of this finding are discussed.

Plasma thromboxane A2, a vasoconstrictor, and plasma prostacyclin (epoprostenol), a vasodilator, were assessed by double-antibody radioimmunological assay of their respective stable circulating metabolites, thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha, in 9 patients with severe diffuse pulmonary fibrosis (DPF), who were known to become hypo-oxaemic during exercise, and in 9 healthy volunteers. In the 7 patients with the most severe DPF, mean arterial PO2 fell from 68 mm Hg at rest to 51 mm Hg at peak aerobic exercise, and mean TxB2 increased to twice the value at rest. The 9 controls remained oxygen saturated throughout exercise; their mean TxB2 did not change during aerobic exercise, but during anaerobic exercise increased to twice the value at rest, and increased further during recovery. There were no significant changes in 6-keto-prostaglandin F1 alpha in either group. The selective release of TxB2 during aerobic exercise in hypo-oxaemic patients suggests that thromboxane mediates hypoxic pulmonary vasoconstriction. Its release in normal man during anaerobic exercise may reflect a more general response to the metabolic changes of tissue hypoxia.

In Wilson's disease, redistribution of copper from the liver to extrahepatic tissue coincides with the development of liver disease and cirrhosis. We have considered the possibility that portasystemic shunting may be a factor determining the organ distribution of copper in patients with liver disease. Thirty-two Sprague-Dawley rats were randomized into a sham-operated group, and a group subjected to partial occlusion of the portal vein (PPVO). Half the rats in each group were fed on normal diet and the remainder had copper added to the drinking water. Rats subjected to PPVO developed large portasystemic shunts. Over a 3-month period, none of the groups showed an increase in serum copper concentrations, or copper oxidase levels. Liver and kidney copper concentrations were similarly increased in copper supplemented sham-operated and PPVO rats, but brain copper content in both groups was similar to the unsupplemented controls. In neither unsupplemented nor copper supplemented rats subjected to PPVO, was the organ distribution of copper different from sham-operated controls. This study suggests that portasystemic shunting does not alter the organ distribution, or tissue concentration of copper.

In this report, data are presented on pre- and postdexamethasone cortisol levels, neuropsychological testing, and computed tomography (CT) scan findings in 30 depressed patients (15 psychotic and 15 nonpsychotic). Particularly significant findings were observed when data from the unipolar subgroup (n = 22) were analyzed separately. Unipolar psychotic depressed patients had significantly larger (p less than 0.05) anterior pole and cella media ventricle-to-brain ratios (VBRs) and significantly greater (p less than 0.05) left and right inferior parietal brain "atrophy" than nonpsychotic depressed patients. Higher rates of Dexamethasone Suppression Test (DST) nonsuppression were observed in psychotic depressed patients and in patients with larger cella VBRs. Inferior parietal brain atrophy and large VBRs were also associated with greater cognitive impairment on psychometric testing. Implications of these findings are discussed.

Competing etiological models make opposite predictions as to the relationship between focal neurological abnormalities in schizophrenics and the prevalence of psychosis in their families. In previous studies of neurological abnormalities in schizophrenia, the authors found an increased prevalence of focal neurological signs in both patients and their nonschizophrenic relatives. The current study examines the relationship between neurological abnormalities in 24 schizophrenic patients and psychopathology in their families. A family history of psychotic psychopathology was found to be associated with an increased prevalence of focal neurological abnormalities in the schizophrenics. The results are relevant to current models of the potential role of neurological factors in the etiology of schizophrenia and illustrate how family studies of the joint distribution of psychiatric and neurological data can potentially help to distinguish between different etiological models.

The presence of mirror movements was assessed as part of the overall neurological examination of 170 inpatients in a child psychiatric unit. It was found that when patients were divided by presence or absence of problems of repetitive aggressiveness, the aggressive patients, particularly the subgroup of aggressive male patients, had significantly more mirror movements than nonaggressive patients. The results persisted after the exclusion of patients with focal neurological or electroencephalographic abnormalities. It is hypothesized that mirror movements and repetitive aggressive behavior may both result from a delay in the development of normal inhibitory mechanisms.