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Medicines routinely funded for use in Wales undergo health technology appraisal by the All Wales Medicines Strategy Group (AWMSG) or the National Institute for Health and Care Excellence (NICE). This includes pediatric license extensions (PLE) notwithstanding any existing advice in adults. A review of the PLE process was conducted with the aim of providing faster access to children’s medicines in Wales.
Methods
Data were collected for PLE appraisals of medicines previously approved for adults by the AWMSG or NICE that subsequently went through the original PLE process between January 2010 and December 2020, or a simplified PLE process between January 2021 and March 2023. Data were analyzed using descriptive statistics and a two-tailed t-test (unequal variance) to test the null hypothesis that the difference between the two means was zero. An alpha of less than 0.05 was considered significant. Feedback was obtained from relevant stakeholders including the Association of the British Pharmaceutical Industry (Wales) and the Royal College of Paediatrics and Child Health.
Results
The AWMSG issued positive recommendations for all PLE appraisals included in the data collected, and these were endorsed by the Welsh Government. Appraisals that went through the original PLE process (n=56) took a mean 229.8 days (standard deviation 55.6), whereas those that went through the simplified PLE process (n=15) took a mean 102.6 days (standard deviation 48.1; p < 0.0001). The rapid access to children’s medicines was welcomed by the Association of the British Pharmaceutical Industry and the Royal College of Paediatrics and Child Health.
Conclusions
Review of the 2020 and 2023 PLE processes facilitated faster access to clinically effective and cost-effective medicines for children in Wales. In March 2023, the AWMSG and the Welsh Government reviewed these results and agreed that because all PLE medicines were approved for use within Wales irrespective of the process used, the AWMSG would no longer be required to routinely appraise PLEs.
For many years, some lawmakers, scholars, and activists have argued that firms located in each developing country (or each regional set of developing countries) should produce more of the drugs that the residents there need. They contend that local production would benefit the residents of those countries in two ways. The chapter first discusses some recent developments that have altered the relative strength of these competing considerations, sharply increasing the likelihood that fostering local production in developing countries would be socially beneficial.It then proposes five legal reforms and economic initiatives that could help build local pharmaceutical production capacity and thereby save lives.
We developed automated ablation stakes to measure colocated in situ changes in relative glacier-surface elevation and climatological drivers of ablation. The designs, refined over 10 years of development and deployments, implement open-source hardware and common building materials. The ablation stakes record distance to the snow/ice surface, air temperature and relative humidity every 1–15 min. Using these high-frequency data, we demonstrate that melt factors calculated using standard melt-rate vs temperature regressions converge over averaging windows of approximately 12 h or greater. Furthermore, we evaluate an integral approach to estimating temperature-index melt factors for ablation. In a test case on Glaciar Perito Moreno, Argentina, this integral approach reveals an overall positive-degree-day melt factor of 7.5 mm w.e. $^\circ$C−1 d−1. We describe four deployments with iteratively improved designs and provide a list of materials required to construct an automated ablation stake.
Continuous-time Markov chains are frequently used to model the stochastic dynamics of (bio)chemical reaction networks. However, except in very special cases, they cannot be analyzed exactly. Additionally, simulation can be computationally intensive. An approach to address these challenges is to consider a more tractable diffusion approximation. Leite and Williams (Ann. Appl. Prob.29, 2019) proposed a reflected diffusion as an approximation for (bio)chemical reaction networks, which they called the constrained Langevin approximation (CLA) as it extends the usual Langevin approximation beyond the first time some chemical species becomes zero in number. Further explanation and examples of the CLA can be found in Anderson et al. (SIAM Multiscale Modeling Simul.17, 2019).
In this paper, we extend the approximation of Leite and Williams to (nearly) density-dependent Markov chains, as a first step to obtaining error estimates for the CLA when the diffusion state space is one-dimensional, and we provide a bound for the error in a strong approximation. We discuss some applications for chemical reaction networks and epidemic models, and illustrate these with examples. Our method of proof is designed to generalize to higher dimensions, provided there is a Lipschitz Skorokhod map defining the reflected diffusion process. The existence of such a Lipschitz map is an open problem in dimensions more than one.
Children with CHD or born very preterm are at risk for brain dysmaturation and poor neurodevelopmental outcomes. Yet, studies have primarily investigated neurodevelopmental outcomes of these groups separately.
Objective:
To compare neurodevelopmental outcomes and parent behaviour ratings of children born term with CHD to children born very preterm.
Methods:
A clinical research sample of 181 children (CHD [n = 81]; very preterm [≤32 weeks; n = 100]) was assessed at 18 months.
Results:
Children with CHD and born very preterm did not differ on Bayley-III cognitive, language, or motor composite scores, or on expressive or receptive language, or on fine motor scaled scores. Children with CHD had lower ross motor scaled scores compared to children born very preterm (p = 0.047). More children with CHD had impaired scores (<70 SS) on language composite (17%), expressive language (16%), and gross motor (14%) indices compared to children born very preterm (6%; 7%; 3%; ps < 0.05). No group differences were found on behaviours rated by parents on the Child Behaviour Checklist (1.5–5 years) or the proportion of children with scores above the clinical cutoff. English as a first language was associated with higher cognitive (p = 0.004) and language composite scores (p < 0.001). Lower median household income and English as a second language were associated with higher total behaviour problems (ps < 0.05).
Conclusions:
Children with CHD were more likely to display language and motor impairment compared to children born very preterm at 18 months. Outcomes were associated with language spoken in the home and household income.
US forces used Agent Orange (AO) during the Vietnam War and continued to store/test it at other locations after the war. AO is a powerful herbicide including dioxin, a highly toxic ingredient classified as a human carcinogen. The National Academies of Sciences, Engineering, and Medicine periodically review the literature on the health effects of AO exposure (AOE) and concluded in 2018 that there is sufficient evidence linking AO with a wide range of adverse health outcomes, including neurologic disorders (e.g., Parkinson’s disease). The VA has a list of medical disorders considered presumptive conditions related to AOE. More recently, AOE has been linked to a nearly double risk compared to those without AOE for receiving a dementia diagnosis. To our knowledge, no one has investigated the association of AOE to mild cognitive impairment (MCI), a condition thought to precede dementia.
Participants and Methods:
We examined men in three waves of the Vietnam Era Twin Study of Aging (VETSA). In wave 3, participants self-reported yes/no to the question of whether they ever had prolonged or serious AOE. MCI was diagnosed by the Jak-Bondi approach. Impairment was defined as 2+ tests within a cognitive domain that were more than 1.5 standard deviations below normative means after adjusting for premorbid cognitive ability. In mixed effects models, we tested the effect of AOE on MCI status. Models were adjusted for age, ethnicity, and non-independence within twin pairs.
Results:
In wave 3, 12.6% (230) of 1167 participants reported AOE. Those with AOE data had mean ages of 51.1 (wave 1), 56.0 (wave 2), and 61.4 (wave 3). Those with data on both AOE and MCI numbered 861 (wave 1), 900 (wave 2), 1121 (wave 3), and 766 had AOE and MCI at all waves. AOE was significantly related to wave 2 MCI (p < .001), but not to waves 1 and 3 MCI. AOE was significantly associated with the number of time points at which someone met criteria for MCI (p = .011). Analyses were conducted on six cognitive domains used to diagnose MCI, using available participants per wave. At all 3 waves, AOE was significantly associated with lower scores in processing speed (p = .003, p = .004, p = .005, respectively), working memory (p < .001, p = .002, p = .008) and nearly significant at all waves for executive dysfunction (p < .001, p < .001, p = .050). There were two other significant associations [wave 2 memory (p = .038), wave 3 fluency (p = .024)]. The semantic fluency cognitive domain was unrelated to AOE in all waves.
Conclusions:
AOE was consistently associated with lower processing speed, working memory, and executive dysfunction in males ages 51-61. It was also associated with the number of time points at which one met criteria for MCI in that age range, and with MCI in the mid-fifties. Findings support the idea of a risk for greater cognitive decline in those exposed to AO earlier in their lives, and with a risk for developing MCI.
We demonstrate a fast adjoint-based method to optimise tokamak and stellarator equilibria against a pressure-driven instability known as the infinite-$n$ ideal ballooning mode. We present three finite-$\beta$ (the ratio of thermal to magnetic pressure) equilibria: one tokamak equilibrium and two stellarator equilibria that are unstable against the ballooning mode. Using the self-adjoint property of ideal magnetohydrodynamics, we construct a technique to rapidly calculate the change in the eigenvalue, a measure of ideal ballooning instability. Using the SIMSOPT optimisation framework, we then implement our fast adjoint gradient-based optimiser to minimise the eigenvalue and find stable equilibria for each of the three originally unstable equilibria.
Background: Previous analyses describing the relationship between SARS-CoV-2 infection and Staphylococcus aureus have focused on hospital-onset S. aureus infections occurring during COVID-19 hospitalizations. Because most invasive S. aureus (iSA) infections are community-onset (CO), we characterized CO iSA cases with a recent positive SARS-CoV-2 test (coinfection). Methods: We analyzed CDC Emerging Infections Program active, population- and laboratory-based iSA surveillance data among adults during March 1–December 31, 2020, from 11 counties in 7 states. The iSA cases (S. aureus isolation from a normally sterile site in a surveillance area resident) were considered CO if culture was obtained <3 days after hospital admission. Coinfection was defined as first positive SARS-CoV-2 test ≤14 days before the initial iSA culture. We explored factors independently associated with SARS-CoV-2 coinfection versus no prior positive SARS-CoV-2 test among CO iSA cases through a multivariable logistic regression model (using demographic, healthcare exposure, and underlying condition variables with P<0.25 in univariate analysis) and examined differences in outcomes through descriptive analysis. Results: Overall, 3,908 CO iSA cases were reported, including 138 SARS-CoV-2 coinfections (3.5%); 58.0% of coinfections had iSA culture and the first positive SARS-CoV-2 test on the same day (Fig. 1). In univariate analysis, neither methicillin resistance (44.2% with coinfection vs 36.5% without; P = .06) nor race and ethnicity differed significantly between iSA cases with and without SARS-CoV-2 coinfection (P = .93 for any association between race and ethnicity and coinfection), although iSA cases with coinfection were older (median age, 72 vs 60 years , P<0.01) and more often female (46.7% vs 36.3%, P=0.01). In multivariable analysis, significant associations with SARS-CoV-2 coinfection included older age, female sex, previous location in a long-term care facility (LTCF) or hospital, presence of a central venous catheter (CVC), and diabetes (Figure 2). Two-thirds of co-infection cases had ≥1 of the following characteristics: age > 73 years, LTCF residence 3 days before iSA culture, and/or CVC present any time during the 2 days before iSA culture. More often, iSA cases with SARS-CoV-2 coinfection were admitted to the intensive care unit ≤2 days after iSA culture (37.7% vs 23.3%, P<0.01) and died (33.3% vs 11.3%, P<0.01). Conclusions: CO iSA patients with SARS-CoV-2 coinfection represent a small proportion of CO iSA cases and mostly involve a limited number of factors related to likelihood of acquiring SARS-CoV-2 and iSA. Although CO iSA patients with SARS-CoV-2 coinfection had more severe outcomes, additional research is needed to understand how much of this difference is related to differences in patient characteristics.
Changes in abundance and distribution of marine top predators can indicate environmental change or anthropogenic pressure requiring management response. Here, we used an extensive dataset (21 years) to conduct a spatial and temporal analysis of grey seal strandings in Cornwall and the Isles of Scilly, close to the southern edge of the breeding range of the species. A total of 2007 strandings were reported from 2000 to 2020, increasing by 474% from 35 to 201 individuals per year during this period. The continued rise in strandings was consistent across all life stages and timeframes (5, 10 and 20 years), underpinning the suggestion of increasing abundance in the region. The observed seasonality differed by life stage, coinciding with the increased presence of animals near the coast for key life phases such as breeding, moulting and pupping. Strandings are widely distributed across the coast of Cornwall and the Isles of Scilly; however, most strandings were recorded on the north coast of Cornwall (70%) where major pupping and haul out sites are found. Despite hosting several pupping and haul out sites, a small proportion was recorded on the Isles of Scilly (5%) where it is thought that strandings are particularly underreported. Describing baselines in magnitude of strandings and life-stage compositions across space and time allows future deviations in frequency, demographic composition or spatial distribution to be detected and investigated. We demonstrate the utility of long-term citizen science data to provide valuable and cost-effective information on the distribution and abundance of a highly mobile marine mammal.
Individuals living with severe mental illness can have significant emotional, physical and social challenges. Collaborative care combines clinical and organisational components.
Aims
We tested whether a primary care-based collaborative care model (PARTNERS) would improve quality of life for people with diagnoses of schizophrenia, bipolar disorder or other psychoses, compared with usual care.
Method
We conducted a general practice-based, cluster randomised controlled superiority trial. Practices were recruited from four English regions and allocated (1:1) to intervention or control. Individuals receiving limited input in secondary care or who were under primary care only were eligible. The 12-month PARTNERS intervention incorporated person-centred coaching support and liaison work. The primary outcome was quality of life as measured by the Manchester Short Assessment of Quality of Life (MANSA).
Results
We allocated 39 general practices, with 198 participants, to the PARTNERS intervention (20 practices, 116 participants) or control (19 practices, 82 participants). Primary outcome data were available for 99 (85.3%) intervention and 71 (86.6%) control participants. Mean change in overall MANSA score did not differ between the groups (intervention: 0.25, s.d. 0.73; control: 0.21, s.d. 0.86; estimated fully adjusted between-group difference 0.03, 95% CI −0.25 to 0.31; P = 0.819). Acute mental health episodes (safety outcome) included three crises in the intervention group and four in the control group.
Conclusions
There was no evidence of a difference in quality of life, as measured with the MANSA, between those receiving the PARTNERS intervention and usual care. Shifting care to primary care was not associated with increased adverse outcomes.
This cross-national study explores a key concept in contemporary European political, policy and academic debates and demonstrates the value of a multi-level conceptualisation of citizenship.
Responding to calls for more knowledge about the motivations (and changing motivations) of self-initiated expatriates (SIEs), this qualitative research examines 58 Australian SIEs working in culturally (dis)similar host contexts, to address the question: Why are Australian SIEs motivated to expatriate to South Korea or the United Kingdom? The findings demonstrate that, although personal/lifestyle considerations are important to SIEs, career-related considerations are either primary or become more prevalent following expatriation. The findings reveal that, while SIEs expatriate with particular motivations, over time their motivations may change as other factors determine desire to stay/leave a host country. Drawing on self-determination theory (SDT), the research highlights variations in extrinsic and intrinsic motivations of SIEs including those who intended to utilise their expatriation as part of a boundaryless career and those who unintentionally found themselves focused on career. Knowledge of (changing) motivations is salient to organisations' selection decisions and support for international employees.
Background: Incidence of methicillin-sensitive Staphylococcus aureus (MSSA) bloodstream infections (BSIs) in the United States during 2012–2017 has been reported to have been stable for hospital-onset BSIs and to have increased 3.9% per year for community-onset BSIs. We sought to determine whether these trends continued in more recent years and whether there were further differences within subgroups of community-onset BSIs. Methods: We analyzed CDC Emerging Infections Program active, population- and laboratory-based surveillance data during 2016–2019 for MSSA BSIs from 8 counties in 5 states. BSI cases were defined as isolation of MSSA from blood in a surveillance area resident. Cases were considered hospital onset (HO) if culture was obtained >3 days after hospital admission and healthcare-associated community-onset (HACO) if culture was obtained on or after day 3 of hospitalization and was associated with dialysis, hospitalization, surgery, or long-term care facility residence within 1 year prior or if a central venous catheter was present ≤2 days prior. Cases were otherwise considered community-associated (CA). Annual rates per 100,000 census population were calculated for each epidemiologic classification; rates of HACO cases among chronic dialysis patients per 100,000 dialysis patients were calculated using US Renal Data System data. Annual increases were modeled using negative binomial or Poisson regression and accounting for changes in the overall population age group, and sex. Descriptive analyses were performed. Results: Overall, 8,344 MSSA BSI cases were reported. From 2016–2019 total MSSA BSI rates increased from 23.9 per 100,000 to 28.5 per 100,000 (6.6% per year; P < .01). MSSA BSI rates also increased significantly among all epidemiologic classes. HO cases increased from 2.5 per 100,000 to 3.2 per 100,000 (7.9% per year; P = .01). HACO cases increased from 12.7 per 100,000 to 14.7 per 100,000 (7.0% per year; P = .01). CA cases increased from 8.4 per 100,000 to 10.4 per 100,000 (6.7% per year; P < .01) (Fig. 1). Significant increases in MSSA BSI rates were also observed for nondialysis HACO cases (9.3 per 100,000 to 11.1 per 100,000; 7.8% per year; P < .01) but not dialysis HACO cases (1,823.2 per 100,000 to 1,857.4 per 100,000; 1.4% per year; P = .59). Healthcare risk factors for HACO cases were hospitalization in the previous year (82%), surgery (31%), dialysis (27%), and long-term care facility residence (19%). Conclusions: MSSA BSI rates increased from 2016–2019 overall, among all epidemiologic classes, and among nondialysis HACO cases. Efforts to prevent MSSA BSIs among individuals with healthcare risk factors, particularly those related to hospitalization, might have an impact on MSSA BSI rates.
To determine associations of alcohol use with cognitive aging among middle-aged men.
Method:
1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003–2007 to 2016–2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, former drinkers, very light (1–4 drinks in past 14 days), light (5–14 drinks), moderate (15–28 drinks), and at-risk drinkers (>28 drinks in past 14 days). Linear mixed-effects regressions modeled cognitive trajectories by alcohol group, with time-based models evaluating rate of decline as a function of baseline alcohol use, and age-based models evaluating age-related differences in performance by current alcohol use. Analyses used standardized cognitive domain factor scores and adjusted for sociodemographic and health-related factors.
Results:
Performance decreased over time in all domains. Relative to very light drinkers, former drinkers showed worse verbal fluency performance, by –0.21 SD (95% CI –0.35, –0.07), and at-risk drinkers showed faster working memory decline, by 0.14 SD (95% CI 0.02, –0.20) per decade. There was no evidence of protective associations of light/moderate drinking on rate of decline. In age-based models, light drinkers displayed better memory performance at advanced ages than very light drinkers (+0.14 SD; 95% CI 0.02, 0.20 per 10-years older age); likely attributable to residual confounding or reverse association.
Conclusions:
Alcohol consumption showed minimal associations with cognitive aging among middle-aged men. Stronger associations of alcohol with cognitive aging may become apparent at older ages, when cognitive abilities decline more rapidly.
Newly arriving Syrian refugees can present with specific health characteristics and medical conditions when entering the United States. Given the lack of epidemiological data available for the refugee populations, our study examined the demographic features of Syrian refugees resettled in the state of Kentucky. Specifically, we examined mental and physical health clinical data in both pre-departure health screenings and domestic Refugee Health Assessments (RHA; Kentucky Office for Refugees, n.d.) performed after resettlement.
Method:
The current study adopted a cross-sectional research design. We analyzed outcome data collected from participants from 2013 and 2015. Specifically, a comparative cross-sectional analysis was performed using clinical data from Syrian refugees who underwent an RHA as part of the resettlement process between January 2015 and August 2016. Those data were compared to data derived from refugees from other countries who resettled in Kentucky between 2013 and 2015.
Results:
Mental health screenings using the Refugee Health Screener (RHS-15; Hollifield et al., 2013) found that 19.5% (n = 34) of adult Syrian refugees reported signs and symptoms from posttraumatic stress, depressive symptoms, and/or anxiety, and nearly 40% (n = 69) reported personal experiences of imprisonment or violence, and/or having witnessed someone experiencing torture or violence. Intestinal parasites and lack of immunity to varicella were the most prevalent communicable diseases among Syrian refugees. Dental abnormalities and decreased visual acuity account for the first and second most prevalent non-communicable conditions. When comparing these results to all refugees arriving during the same years, significant differences arose in demographic variables, social history, communicable diseases, and non-communicable diseases.
Conclusion:
This study provides an initial health profile of Syrian refugees resettling in Kentucky, which reflects mental health as a major healthcare concern. Posttraumatic stress and related symptoms are severe mental health conditions among Syrian refugees above and beyond other severe physical problems.
Although the potential of arts to promote social inclusion is recognised, barriers to social inclusion for disabled people in the arts is under-researched. Based on 34 semi-structured interviews with disabled people and those without disability from four arts organisations in Australia, the paper identifies barriers for social inclusion for disabled people within performing arts across four dimensions: access; participation; representation and empowerment. Findings highlight barriers are societal, being created with little awareness of needs of disabled people, supporting the social model of disability. Findings have implications beyond social inclusion of disabled people within the arts, demonstrating how the arts can empower disabled people and enable them to access, participate and represent themselves and have a voice. Our framework conceptualises these four barriers for social inclusion for disabled people for management to change.
Susceptibility to infection such as SARS-CoV-2 may be influenced by host genotype. TwinsUK volunteers (n = 3261) completing the C-19 COVID-19 symptom tracker app allowed classical twin studies of COVID-19 symptoms, including predicted COVID-19, a symptom-based algorithm to predict true infection, derived from app users tested for SARS-CoV-2. We found heritability of 49% (32−64%) for delirium; 34% (20−47%) for diarrhea; 31% (8−52%) for fatigue; 19% (0−38%) for anosmia; 46% (31−60%) for skipped meals and 31% (11−48%) for predicted COVID-19. Heritability estimates were not affected by cohabiting or by social deprivation. The results suggest the importance of host genetics in the risk of clinical manifestations of COVID-19 and provide grounds for planning genome-wide association studies to establish specific genes involved in viral infectivity and the host immune response.
Clarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems.
Methods
The study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse (‘baseline’) and the longitudinal Vietnam Era Twin Study of Aging (‘follow-up’). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)].
Results
Total depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07–1.57), erectile dysfunction (OR 1.32, 95% CI 1.10–1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04–1.53), and sleep apnea (OR 1.40, 95% CI 1.13–1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09–1.60).
Conclusions
A history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.