Understanding primary care transformation and implications for ageing populations and health inequalities: a systematic scoping review of new models of primary health care in OECD countries and China.

BACKGROUND: Many countries have introduced reforms with the aim of primary care transformation (PCT). Common objectives include meeting service delivery challenges associated with ageing populations and health inequalities. To date, there has been little research comparing PCT internationally. Our aim was to examine PCT and new models of primary care by conducting a systematic scoping review of international literature in order to describe major policy changes including key 'components', impacts of new models of care, and barriers and facilitators to PCT implementation. METHODS: We undertook a systematic scoping review of international literature on PCT in OECD countries and China (published protocol: https://osf.io/2afym ). Ovid [MEDLINE/Embase/Global Health], CINAHL Plus, and Global Index Medicus were searched (01/01/10 to 28/08/21). Two reviewers independently screened the titles and abstracts with data extraction by a single reviewer. A narrative synthesis of findings followed. RESULTS: A total of 107 studies from 15 countries were included. The most frequently employed component of PCT was the expansion of multidisciplinary teams (MDT) (46% of studies). The most frequently measured outcome was GP views (27%), with < 20% measuring patient views or satisfaction. Only three studies evaluated the effects of PCT on ageing populations and 34 (32%) on health inequalities with ambiguous results. For the latter, PCT involving increased primary care access showed positive impacts whilst no benefits were reported for other components. Analysis of 41 studies citing barriers or facilitators to PCT implementation identified leadership, change, resources, and targets as key themes. CONCLUSIONS: Countries identified in this review have used a range of approaches to PCT with marked heterogeneity in methods of evaluation and mixed findings on impacts. Only a minority of studies described the impacts of PCT on ageing populations, health inequalities, or from the patient perspective. The facilitators and barriers identified may be useful in planning and evaluating future developments in PCT.

Longitudinal Lung Function Assessment of Patients Hospitalized With COVID-19 Using 1H and 129Xe Lung MRI.

BACKGROUND: Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear. RESEARCH QUESTION: Do patients hospitalized with COVID-19 without evidence of architectural distortion on structural imaging exhibit longitudinal improvements in lung function measured by using 1H and 129Xe MRI between 6 and 52 weeks following hospitalization? STUDY DESIGN AND METHODS: Patients who were hospitalized with COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25, and 51 weeks following hospital admission in a prospective cohort study between November 2020 and February 2022. The imaging protocol was as follows: 1H ultra-short echo time, contrast-enhanced lung perfusion, 129Xe ventilation, 129Xe diffusion-weighted, and 129Xe spectroscopic imaging of gas exchange. RESULTS: Nine patients were recruited (age 57 ± 14 [median ± interquartile range] years; six of nine patients were male). Patients underwent MRI at 6 (n = 9), 12 (n = 9), 25 (n = 6), and 51 (n = 8) weeks following hospital admission. Patients with signs of interstitial lung damage were excluded. At 6 weeks, patients exhibited impaired 129Xe gas transfer (RBC to membrane fraction), but lung microstructure was not increased (apparent diffusion coefficient and mean acinar airway dimensions). Minor ventilation abnormalities present in four patients were largely resolved in the 6- to 25-week period. At 12 weeks, all patients with lung perfusion data (n = 6) showed an increase in both pulmonary blood volume and flow compared with 6 weeks, although this was not statistically significant. At 12 weeks, significant improvements in 129Xe gas transfer were observed compared with 6-week examinations; however, 129Xe gas transfer remained abnormally low at weeks 12, 25, and 51. INTERPRETATION: 129Xe gas transfer was impaired up to 1 year following hospitalization in patients who were hospitalized with COVID-19 pneumonia, without evidence of architectural distortion on structural imaging, whereas lung ventilation was normal at 52 weeks.

An online parenting intervention to prevent affective disorders in high-risk adolescents: the PIPA trial protocol.

BACKGROUND: Adolescent depression can place a young person at high risk of recurrence and a range of psychosocial and vocational impairments in adult life, highlighting the importance of early recognition and prevention. Parents/carers are well placed to notice changes in their child's emotional wellbeing which may indicate risk, and there is increasing evidence that modifiable factors exist within the family system that may help reduce the risk of depression and anxiety in an adolescent. A randomised controlled trial (RCT) of the online personalised 'Partners in Parenting' programme developed in Australia, focused on improving parenting skills, knowledge and awareness, showed that it helped reduce depressive symptoms in adolescents who had elevated symptom levels at baseline. We have adapted this programme and will conduct an RCT in a UK setting. METHODS: In total, 433 family dyads (parents/carers and children aged 11-15) will be recruited through schools, social media and parenting/family groups in the UK. Following completion of screening measures of their adolescent's depressive symptoms, parents/carers of those with elevated scores will be randomised to receive either the online personalised parenting programme or a series of online factsheets about adolescent development and wellbeing. The primary objective will be to test whether the personalised parenting intervention reduces depressive symptoms in adolescents deemed at high risk, using the parent-reported Short Mood & Feelings Questionnaire. Follow-up assessments will be undertaken at 6 and 15 months and a process evaluation will examine context, implementation and impact of the intervention. An economic evaluation will also be incorporated with cost-effectiveness of the parenting intervention expressed in terms of incremental cost per quality-adjusted life year gained. DISCUSSION: Half of mental health problems emerge before mid-adolescence and approximately three-quarters by mid-20s, highlighting the need for effective preventative strategies. However, few early interventions are family focused and delivered online. We aim to conduct a National Institute for Health and Care Research (NIHR) funded RCT of the online personalised 'Partners in Parenting' programme, proven effective in Australia, targeting adolescents at risk of depression to evaluate its effectiveness, cost-effectiveness and usability in a UK setting. TRIAL REGISTRATION {2A}: ISRCTN63358736 . Registered 18 September 2019.

Imaging and Risk Stratification in Pulmonary Arterial Hypertension: Time to Include Right Ventricular Assessment.

Background: Current European Society of Cardiology and European Respiratory Society guidelines recommend regular risk stratification with an aim of treating patients with pulmonary arterial hypertension (PAH) to improve or maintain low-risk status (<5% 1-year mortality). Methods: Consecutive patients with PAH who underwent cardiac magnetic resonance imaging (cMRI) were identified from the Assessing the Spectrum of Pulmonary hypertension Identified at a Referral centre (ASPIRE) registry. Kaplan-Meier survival curves, locally weighted scatterplot smoothing regression and multi-variable logistic regression analysis were performed. Results: In 311 consecutive, treatment-naïve patients with PAH undergoing cMRI including 121 undergoing follow-up cMRI, measures of right ventricular (RV) function including right ventricular ejection fraction (RVEF) and RV end systolic volume and right atrial (RA) area had prognostic value. However, only RV metrics were able to identify a low-risk status. Age (p < 0.01) and RVEF (p < 0.01) but not RA area were independent predictors of 1-year mortality. Conclusion: This study highlights the need for guidelines to include measures of RV function rather than RA area alone to aid the risk stratification of patients with PAH.

Worldwide prevalence, genotype distribution and management of hepatitis C.

Hepatitis C virus (HCV) is one of the leading causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma, resulting in major global public health concerns. The HCV infection is unevenly distributed worldwide, with variations in prevalence across and within countries. The studies on molecular epidemiology conducted in several countries provide an essential supplement for a comprehensive knowledge of HCV epidemiology, genotypes, and subtypes, along with providing information on the impact of current and earlier migratory flows. HCV is phylogenetically classified into 8 major genotypes and 57 subtypes. HCV genotype and subtype distribution differ according to geographic origin and transmission risk category. Unless people with HCV infection are detected and treated appropriately, the number of deaths due to the disease will continue to increase. In 2015, 1.75 million new viral infections were mostly due to unsafe healthcare procedures and drug use injections. In the same year, access to direct-acting antivirals was challenging and varied in developing and developed countries, affecting HCV cure rates based on their availability. The World Health Assembly, in 2016, approved a global strategy to achieve the elimination of the HCV public health threat by 2030 (by reducing new infections by 90% and deaths by 65%). Globally, countries are implementing policies and measures to eliminate HCV risk based on their distribution of genotypes and prevalence.

Tonsillitis, tonsillectomy, and deep neck space infections in England: the case for a new guideline for surgical and non-surgical management.

INTRODUCTION: Tonsillectomy is a common surgical procedure performed chiefly for recurrent tonsillitis. The Scottish Intercollegiate Guidance Network (SIGN) introduced guidelines in 1998 to improve patient selection for tonsillectomy and reduce the potential harm to patients from surgical complications such as haemorrhage. Since the introduction of the guidance, the number of admissions for tonsillitis and its complications has increased. National Hospital Episode Statistics over a 20-year period were analysed to assess the trends in tonsillectomy, post-tonsillectomy haemorrhage, tonsillitis and its complications with reference to the guidance, procedures of limited clinical value and the associated costs and benefits. MATERIALS AND METHODS: A literature search was conducted via PubMed and the Cochrane Library to identify relevant research. Hospital Episode Statistics data were interrogated and relevant data compared over time to assess trends related to the implementation of national guidance. RESULTS: Over the period analysed, the incidence of deep neck space infections has increased almost five-fold, mediastinitis ten-fold and peritonsillar abscess by 1.7-fold compared with prior to SIGN guidance. Following procedures of limited clinical value implementation, the incidence of deep neck space infections has increased 2.4-fold, mediastinitis 4.1-fold and peritonsillar abscess 1.4-fold compared with immediately prior to clinical commissioning group rationing. The rate of tonsillectomy and associated haemorrhage (1-2%) has remained relatively constant at 46,299 (1999) compared with 49,447 (2009) and 49,141 (2016), despite an increase in the population of England by seven million over the 20-year period. DISCUSSION: The rise in admissions for tonsillitis and its complications appears to correspond closely to the date of SIGN guidance and clinical commissioning group rationing of tonsillectomy and is on the background of a rise in the population of the UK. The move towards daycase tonsillectomy has reduced bed occupancy after surgery but this has been counteracted by an increase in admissions for tonsillitis and deep neck space infections, sometimes requiring lengthy intensive care stays and a protracted course of rehabilitation. The total cost of treating the complications of tonsillitis in England in 2017 is estimated to be around £73 million. The cost of tonsillectomy and treating post-tonsillectomy haemorrhage is £56 million by comparison. The total cost per annum for tonsillectomy prior to the introduction of SIGN guidance was estimated at £71 million with tonsillitis and its complications accounting for a further £8 million.

Outcomes from a Male-to-Male Promotores Intervention in an Emerging Latino Community.

Emerging Latino communities experience social isolation and lack services tailored to their culture. Few male-to-male promotores (community health workers in Spanish) interventions exist. This 6-month participatory study aimed to improve social support, healthcare access, depressive symptoms, and decrease alcohol consumption among Latino immigrant men. Promotores delivered non-directive social support to participants recruited from community venues. We analyzed baseline and 6-month questionnaires data (n = 89) using paired chi square tests. All participants were immigrants; 47% had not finished high school, 29% had depression symptoms, 35% reported past month binge drinking and 93% were uninsured. The intervention significantly improved having a usual source of care (24 to 43%), doctor's visits (41 to 62%) and dentist's visits (27 to 42%) in the past year. Other outcomes did not improve. Male promotores increased healthcare access among vulnerable Latino men. Addressing drinking behavior and depression may require longer interventions or specialized providers.

Multidisciplinary Intraoperative Assessment of Breast Specimens Reduces Number of Positive Margins.

BACKGROUND: Successful breast-conserving surgery requires achieving negative margins. At our institution, the whole surgical specimen is imaged and then serially sectioned with repeat imaging. A multidisciplinary discussion then determines need for excision of additional margins. The goal of this study was to determine the benefit of each component of this approach in reducing the number of positive margin. METHODS: This single-institution, prospective study included ten breast surgical oncologists who were surveyed to ascertain whether they would have taken additional margins based their review of whole specimen images (WSI) and review of serially sectioned images (SSI). These results were compared with the multidisciplinary decisions (MDD) and pathology results. Margin status was defined using consensus guidelines. RESULTS: One hundred surveys were completed. Margins on the original specimen were positive or close in 21%. After WSI, surgeons reported that they would have taken additional margins in 26 cases, reducing the number of positive/close margins from 21 to 13% (p < 0.001). After SSI, 52 would have taken additional margins; however, the number of positive/close margins remained 13%. MDD resulted in additional margins taken in 56 cases, reducing the number of positive/close margins to 7% (p < 0.001 compared with SSI). CONCLUSIONS: While surgeon review of specimen radiographs can decrease the number of positive or close margins from 21 to 13%, more rigorous multidisciplinary, intraoperative margin assessment reduces the number of close or positive margins to 7%.

Progressive MS Alliance Industry Forum: Maximizing Collective Impact To Enable Drug Development.

The Progressive MS Alliance Industry Forum describes a new approach to address barriers to developing treatments for progressive multiple sclerosis (MS). This innovative model promises to facilitate robust collaboration between industry, academia, and patient organizations and accelerate research towards the overarching goal of developing safe and effective treatments for progressive MS.

Viewpoint: Availability of oestrogen receptor and HER2 status for the breast multidisciplinary meeting discussion; time to get it right.

The efficacy and pivotal role of the multidisciplinary meeting (MDM) in informed decision making is well established. It aims to provide a forum in which clinical evidence combines with individual patient data to create a personalized treatment plan. It does not fulfil this role adequately when undertaken without the full results of the patient's investigations being available. Neither doctor nor patient can make an informed decision about treatment options without knowledge of the tumour receptor status. Both targeted therapies and the aim to treat a majority of patients within clinical trials must now drive MDM decision making to be based on accuracy and best available treatment choices. A fully informed decision on treatment delayed by 1-2 weeks is clearly preferable to rushed time target-driven decisions made without the patient being offered a fully informed choice as ratified by a multidisciplinary team. Whilst the early anxiety of waiting for all relevant information to be available may be stressful for patients, not being sure that they have been offered fully informed treatment choices is also stressful and could cause longer lasting anxiety both during and after treatment. MDMs need to develop (along with targeted therapies) to retain their role as a forum whereby patients receive a correct, but specifically a full diagnosis and allow a fully informed discussion of all treatment options, including pre-operative clinical trials.

Analgesic opioid use in a health-insured epilepsy population during 2012.

RATIONALE: Analgesic opioid use has increased dramatically in the general population. Although opioid analgesics are not indicated for the treatment of epilepsy, frequent opioid use has been reported in the epilepsy population. It is not clear whether comorbid disorders and/or epilepsy-associated injuries due to seizures foster opioid use. Our primary objective was to compare the prevalence of analgesic opioid use in an insured patient population with epilepsy to a matched control population without epilepsy. After observing increased frequency of opioid use in people with epilepsy compared with matched controls, we assessed the contribution of age, gender, pain diagnosis, and psychiatric illness as possible drivers regarding the use of opioids. METHODS: Health insurance claims and membership data from nine United States (U.S.) health plans for the year 2012 were analyzed. Individuals with epilepsy (n=10,271) were match-paired at a 1:2 ratio to individuals without epilepsy (n=20,542) within each health plan using propensity scores derived from age group, gender, and insurance type. Matched comparison groups had 53% females and 47% males with an average age of 34 years for the group with epilepsy and 33 years for controls. Each matched comparison group included 66% of individuals with commercial insurance, 30% with Medicaid insurance, and 4% with Medicare coverage. Based on prescriptions filled at least once during 2012, prevalence of analgesic opioid use was determined. The percentages of individuals with diagnosis for specific pain conditions and those with psychiatric diagnoses were also determined for the two comparison groups. RESULTS: Analgesic opioids were used by 26% of individuals in the group with epilepsy vs. 18% of matched controls (p<0.001). Compared with matched controls, the group with epilepsy had a significantly higher percentage of individuals with all 16 pain conditions examined: joint pain or stiffness (16% vs. 11%), abdominal pain (14% vs. 9%), headache (14% vs. 5%), pain in limb (12% vs. 7%), chest pain (11% vs. 6%), sprain of different parts (9% vs. 7%), sinusitis (9% vs. 7%), migraine (8% vs. 2%), lumbago (8% vs. 6%), backache (6% vs. 4%), cervicalgia (6% vs. 3%), fracture (5% vs. 3%), fibromyalgia (4% vs. 3%), chronic pain (3% vs. 1%), sciatica (1.4% vs. 1%), and jaw pain (0.4% vs. 0.1%) (all p<0.001). The prevalence of pain diagnosis was 51% in the group with epilepsy and 39% in the matched control group (p<0.0001). The prevalence of 'psychiatric diagnoses' was 27% in the group with epilepsy and 12% in the matched control group (p<0.0001). CONCLUSION: The prevalences of analgesic opioid use, psychiatric diagnoses, and 16 pain conditions were significantly higher in the patient population with epilepsy than in the control population without epilepsy. Our study also showed how opioid use rate varied by gender, age category, and depression. The reasons for the greater prevalence of opioid use in people with epilepsy are unclear. It seems that increased pain prevalence is an important driver for the higher frequency of opioid use in people with epilepsy. Psychiatric illness and other factors also appear to contribute. Further analysis including more detailed clinical information that cannot be obtained through claims data alone will be required to provide more insight into opioid use in people with epilepsy. If opioid use is higher in people with epilepsy as our results suggest, physicians managing patients with epilepsy need to pay special attention to safe opioid prescribing habits in order to prevent adverse outcomes such as abuse, addiction, diversion, misuse, and overdose.

Ground-based assessment of the bias and long-term stability of fourteen limb and occultation ozone profile data records.

The ozone profile records of a large number of limb and occultation satellite instruments are widely used to address several key questions in ozone research. Further progress in some domains depends on a more detailed understanding of these data sets, especially of their long-term stability and their mutual consistency. To this end, we made a systematic assessment of fourteen limb and occultation sounders that, together, provide more than three decades of global ozone profile measurements. In particular, we considered the latest operational Level-2 records by SAGE II, SAGE III, HALOE, UARS MLS, Aura MLS, POAM II, POAM III, OSIRIS, SMR, GOMOS, MIPAS, SCIAMACHY, ACE-FTS and MAESTRO. Central to our work is a consistent and robust analysis of the comparisons against the ground-based ozonesonde and stratospheric ozone lidar networks. It allowed us to investigate, from the troposphere up to the stratopause, the following main aspects of satellite data quality: long-term stability, overall bias, and short-term variability, together with their dependence on geophysical parameters and profile representation. In addition, it permitted us to quantify the overall consistency between the ozone profilers. Generally, we found that between 20-40 km the satellite ozone measurement biases are smaller than ±5 %, the short-term variabilities are less than 5-12% and the drifts are at most ±5% decade-1 (or even ±3 % decade-1 for a few records). The agreement with ground-based data degrades somewhat towards the stratopause and especially towards the tropopause where natural variability and low ozone abundances impede a more precise analysis. In part of the stratosphere a few records deviate from the preceding general conclusions; we identified biases of 10% and more (POAM II and SCIAMACHY), markedly higher single-profile variability (SMR and SCIAMACHY), and significant long-term drifts (SCIAMACHY, OSIRIS, HALOE, and possibly GOMOS and SMR as well). Furthermore, we reflected on the repercussions of our findings for the construction, analysis and interpretation of merged data records. Most notably, the discrepancies between several recent ozone profile trend assessments can be mostly explained by instrumental drift. This clearly demonstrates the need for systematic comprehensive multi-instrument comparison analyses.

Breeding objectives for sheep should be customised depending on variation in pasture growth across years.

Breeding programmes for livestock require economic weights for traits that reflect the most profitable animal in a given production system, which affect the response in each trait after selection. The profitability of sheep production systems is affected by changes in pasture growth as well as grain, meat and wool prices between seasons and across years. Annual pasture growth varies between regions within Australia's Mediterranean climate zone from low growth with long periods of drought to high growth with shorter periods of drought. Therefore, the objective of this study was to assess whether breeding objectives need to be adapted for regions, depending on how reliable the pasture growth is across years. We modelled farms with Merino sheep bred for wool and meat in 10 regions in Western Australia. Across these 10 regions, mean annual pasture growth decreased, and the CV of annual pasture growth increased as pasture growth for regions became less reliable. We calculated economic values for nine traits, optimising management across 11 years, including variation for pasture growth and wool, meat and grain prices between and within years from 2002 to 2012. These economic values were used to calculate responses to selection for each trait for the 10 regions. We identified two potential breeding objectives, one for regions with low or high reliability and the other for regions with medium reliability of pasture growth. Breeding objectives for high or low pasture growth reliability had more emphasis on live weight traits and number of lambs weaned. Breeding objectives for medium reliability of pasture growth had more emphasis on decreasing fibre diameter. Relative economic weights for fleece weight did not change across the regions. Regions with low or high pasture reliability had similar breeding objectives and response to selection, because the relationship between the economic values and CV of pasture growth were not linear for live weight traits and the number of lambs weaned. This non-linearity was caused by differences in distribution of pasture growth between regions, particularly during summer and autumn, when ewes were pregnant, with increases in energy requirements affecting the value of lambs weaned. In addition, increasing live weight increased the intake capacity of sheep, which meant that more poor quality pasture could be consumed during summer and autumn, which had more value in regions with low and high pasture reliability. We concluded that breeding values for sheep production systems should be customised depending on the reliability of pasture growth between years.

Diagnoses, procedures, drug utilization, comorbidities, and cost of health care for people with epilepsy in 2012.

Our objective was to identify the top MD-office, inpatient and outpatient diagnoses, procedures, drug classes, comorbidities, and cost of health care for people with epilepsy. We examined health insurance claims for 8388 persons with epilepsy (females = 52%, males = 48%; average age = 35 years; privately insured = 78%, and Medicaid-insured = 22%) from eight health insurance plans for the year 2012. All of the top three diagnoses for MD-office place of service were either for other convulsions (780.39) or for epilepsy (345.90 and 345.40). Two of the top three primary diagnosis codes from the inpatient hospital and emergency department places of service were 780.39 and 345.90 for convulsions and epilepsy, respectively, while the third code was 786.50 for chest pain. The top three procedures from the MD-office setting were for immunizations (90471 and 90658) and blood counts (85025). The top three procedure codes from the outpatient hospital setting were 85025 for complete blood count, 80053 for comprehensive metabolic panel, and 80048 for basic metabolic panel. In the emergency department, the top three procedures were electrocardiogram (93010), computed tomography (70450), and chest X-ray (71020). The top five drug classes among prescription drugs billed using an NDC code were (1) anticonvulsants, (2) analgesic-opioids, (3) antidepressants, (4) penicillins, and (5) dermatologicals. The mean monthly health plan paid cost for each patient with epilepsy in 2012 was $1028 (SD = $3181). Of this total, $761 (SD = $2988; 74%) was for medical, and $267 (SD = $760; 26%) was for prescription pharmacy claims. Fifty-eight percent (58%) of the patients had one or more of 29 prespecified comorbidities, while 42% had none. Monthly health-care costs increased markedly as the number of comorbidities increased. This information should help guide cost estimates and resource allocation in order to optimally care for people with epilepsy.

Common comorbidities in women and men with epilepsy and the relationship between number of comorbidities and health plan paid costs in 2010.

The objectives of this observational study were to determine the prevalence of the most common comorbidities in women and men with epilepsy and to demonstrate the relationship of these comorbidities to health plan paid costs. Data for 6621 members with epilepsy (52% women, 48% men) from eight commercial health plans were analyzed. The presence of comorbidities in people with epilepsy was identified by searching health insurance claims for 29 prespecified comorbidity-specific diagnosis codes. More women (50%) than men (43%) with epilepsy had one or more of the 29 comorbidities (p<0.05). The top 10 comorbidities for women and their relative prevalences were psychiatric diagnosis (16%), hypertension (12%), asthma (11%), hyperlipidemia (11%), headache (7%), diabetes (6%), urinary tract infection (5%), hypothyroidism (5%), anemia (5%), and migraine (4%). For men, the top 10 comorbidities and their relative prevalences were psychiatric diagnosis (15%), hyperlipidemia (12%), hypertension (12%), asthma (8%), diabetes (5%), headache (4%), cancer (4%), coronary artery disease (3%), anemia (3%), and gastroesophageal reflux disease (3%). Seven of the top 10 comorbidities were common to both women and men. Psychiatric diagnosis was the only comorbidity among the top five comorbidities for all age groups. The presence of one comorbidity approximately tripled the health-care cost for that member compared with the cost for members who had no comorbidities. Additional comorbidities generally further increased costs. The increase in health-care cost per member per month ($) with increase in number of comorbidities was greater for men than for women (p<0.05).

The value of high adherence to tamoxifen in women with breast cancer: a community-based cohort study.

BACKGROUND: Low adherence to adjuvant tamoxifen is associated with worse health outcomes but little is known about the cost-effectiveness of high adherence. METHODS: We conducted an economic evaluation using data for all women with incident breast cancer between 1993 and 2000 who were subsequently prescribed tamoxifen in the Tayside region of Scotland. Patient-level, lifetime Markov models evaluated the impact of high vs low adherence to tamoxifen using linked prescribing, cancer registry, clinical cancer audit, hospital discharge and death records. Direct medical costs were estimated for each patient and quality-of-life weights were assigned. Recurrence information was collected by case note review and adherence calculated from prescribing records with low adherence classed below 80%. RESULTS: A total of 354 (28%) patients had a recorded recurrence and 504 (39%) died. Four hundred and seventy-five (38%) patients had low adherence over the treatment period, which was associated with reduced time to recurrence of 52% (P<0.001). Time to other cause mortality was also reduced by 23% (P=0.055) but this was not statistically significant. For an average patient over her lifetime, low adherence was associated with a loss of 1.43 (95% CI: 1.15-1.71) discounted life years or 1.12 (95% CI: 0.91-1.34) discounted quality-adjusted life years (QALYs) and increased discounted medical costs of £5970 (95% CI: £4644-£7372). Assuming a willingness to pay threshold of £25,000 per QALY, the expected value of changing a patient from low to high adherence is £33,897 (95% CI: £28,322-£39,652). CONCLUSION: Patients with low adherence have shorter time to recurrence, increased medical costs and worse quality of life. Interventions that encourage patients to continue taking their treatment on a daily basis for the recommended 5-year period may be highly cost-effective.

A comprehensive assessment of cerebellar damage in multiple sclerosis using diffusion tractography and volumetric analysis.

BACKGROUND: White matter (WM) and grey matter (GM) brain damage in multiple sclerosis (MS) is widespread, but the extent of cerebellar involvement and impact on disability needs to be clarified. OBJECTIVE: This study aimed to assess cerebellar WM and GM atrophy and the degree of fibre coherence in the main cerebellar connections, and their contribution to disability in relapsing-remitting MS (RRMS) and primary progressive MS (PPMS). METHODS: Fourteen patients with RRMS, 12 patients with PPMS and 16 healthy controls were recruited. Cerebellar WM and GM volumes and tractography-derived measures from the middle and superior cerebellar peduncles, including fractional anisotropy (FA), mean diffusivity (MD), and directional diffusivities, were quantified from magnetic resonance imaging (MRI). Patients were assessed on clinical scores, including the MS Functional Composite score subtests. Linear regression models were used to compare imaging measures between 12 RRMS, 11 PPMS and 16 controls, and investigate their association with clinical scores. RESULTS: Patients with PPMS showed reduced FA and increased radial diffusivity in the middle cerebellar peduncle compared with controls and patients with RRMS. In PPMS, lower cerebellar WM volume was associated with worse performance on the upper limb test. In the same patient group, we found significant relationships between superior cerebellar peduncle FA and upper limb function, and between superior cerebellar peduncle FA, MD and radial diffusivity and speed of walking. CONCLUSION: These findings indicate reduced fibre coherence in the main cerebellar connections, and link damage in the whole cerebellar WM, and, in particular, in the superior cerebellar peduncle, to motor deficit in PPMS.

The challenge of follow-on biologics for treatment of multiple sclerosis.

Intellectual property protections for biologic medicinals for multiple sclerosis (MS) are beginning to expire, opening the possibility of development, regulatory approval, and marketing of so-called follow-on biologics, biosimilars, or subsequent entry biologics that might be offered at lower price to consumers and third-party payers, as has been the case for generic drugs. Determining the comparability of a follow-on biologic to its innovator product is more difficult than for small-molecule drugs because of the greater complexity of biologics and the possibility that manufacturing differences can introduce differences in biologic activity and immunogenicity that could result in unpredictable differences in safety or efficacy. We provide a perspective on issues surrounding development, regulatory approval, and potential use of follow-on biologics, with an emphasis on disease-modifying agents for MS.