Informing evidence-based policy during the COVID-19 pandemic and recovery period: learning from a national evidence centre.

BACKGROUND: The COVID-19 pandemic demonstrated the vital need for research to inform policy decision-making and save lives. The Wales COVID-19 Evidence Centre (WCEC) was established in March 2021 and funded for two years, to make evidence about the impact of the pandemic and ongoing research priorities for Wales available and actionable to policy decision-makers, service leads and the public. OBJECTIVES: We describe the approaches we developed and our experiences, challenges and future vision. PROGRAM IMPLEMENTATION: The centre operated with a core team, including a public partnership group, and six experienced research groups as collaborating partners. Our rapid evidence delivery process had five stages: 1. Stakeholder engagement (continued throughout all stages); 2. Research question prioritisation; 3. Bespoke rapid evidence review methodology in a phased approach; 4. Rapid primary research; and 5. Knowledge Mobilisation to ensure the evidence was available for decision-makers. MAIN ACHIEVEMENTS: Between March 2021-23 we engaged with 44 stakeholder groups, completed 35 Rapid Evidence Reviews, six Rapid Evidence Maps and 10 Rapid Evidence Summaries. We completed four primary research studies, with three published in peer reviewed journals, and seven ongoing. Our evidence informed policy decision-making and was cited in 19 Welsh Government papers. These included pandemic infection control measures, the Action Plan to tackle gender inequalities, and Education Renew and Reform policy. We conducted 24 Welsh Government evidence briefings and three public facing symposia. POLICY IMPLICATIONS: Strong engagement with stakeholder groups, a phased rapid evidence review approach, and primary research to address key gaps in current knowledge enabled high-quality efficient, evidence outputs to be delivered to help inform Welsh policy decision-making during the pandemic. We learn from these processes to continue to deliver evidence from March 2023 as the Health and Care Research Wales Evidence Centre, with a broader remit of health and social care, to help inform policy and practice decisions during the recovery phase and beyond.

Tensions in primary care cancer detection: An embedded qualitative intervention development study.

BACKGROUND: UK cancer mortality is worse than many other high-income countries, partly due to diagnostic delays in primary care. AIM: To understand beliefs and behaviour of GPs, and systems of general practice teams, to inform the Think Cancer! intervention development. DESIGN AND SETTING: An embedded qualitative study guided by behaviour change models (COM-B and TDF) in primary care in Wales, UK. METHOD: Twenty qualitative, semi-structured telephone interviews with GPs and four face-to-face focus groups with practice teams. Analysis used Framework, results were mapped to multiple, overlapping components of COM-B and TDF. RESULTS: Three themes illustrate (1) complex, multi-level referral considerations facing GPs and practice teams, (2) external influences and constraints, (3) the role of practice systems and culture. Tensions emerged between individual considerations of GPs (Capability, Motivation) and context-dependent external pressures (Opportunity). Detecting cancer was guided not only by external requirements, but also by motivational factors GPs described as part of their cancer diagnostics process. External influences on the diagnosis process often resulted from the primary-secondary care interface and social pressures. GPs adapted their behaviour to deal with this disconnect. Positive practice culture and supportive practice-based systems ameliorated these tensions and complexity. CONCLUSION: By exploring individual GP behaviours together with practice systems and culture we contribute new understandings on how cancer diagnosis operates in primary care and how delays can be improved. We highlight commonly overlooked dynamics and tensions, experienced by GPs as a tension between individual decision-making (Capability, Motivation) and external considerations such as pressures in secondary care (Opportunity).

Transdermal Blood Sampling for C-Peptide Is a Minimally Invasive, Reliable Alternative to Venous Sampling in Children and Adults With Type 1 Diabetes.

OBJECTIVE: C-peptide and islet autoantibodies are key type 1 diabetes biomarkers, typically requiring venous sampling, which limits their utility. We assessed transdermal capillary blood (TCB) collection as a practical alternative. RESEARCH DESIGN AND METHODS: Ninety-one individuals (71 with type 1 diabetes, 20 control; individuals with type 1 diabetes: aged median 14.8 years [interquartile range (IQR) 9.1-17.1], diabetes duration 4.0 years [1.5-7.7]; control individuals: 42.2 years [38.0-52.1]) underwent contemporaneous venous and TCB sampling for measurement of plasma C-peptide. Participants with type 1 diabetes also provided venous serum and plasma, and TCB plasma for measurement of autoantibodies to glutamate decarboxylase, islet antigen-2, and zinc transporter 8. The ability of TCB plasma to detect significant endogenous insulin secretion (venous C-peptide ≥200 pmol/L) was compared along with agreement in levels, using Bland-Altman. Venous serum was compared with venous and TCB plasma for detection of autoantibodies, using established thresholds. Acceptability was assessed by age-appropriate questionnaire. RESULTS: Transdermal sampling took a mean of 2.35 min (SD 1.49). Median sample volume was 50 µL (IQR 40-50) with 3 of 91 (3.3%) failures, and 13 of 88 (14.7%) <35 µL. TCB C-peptide showed good agreement with venous plasma (mean venous ln[C-peptide] - TCB ln[C-peptide] = 0.008, 95% CI [-0.23, 0.29], with 100% [36 of 36] sensitivity/100% [50 of 50] specificity to detect venous C-peptide ≥200 pmol/L). Where venous serum in multiple autoantibody positive TCB plasma agreed in 22 of 32 (sensitivity 69%), comparative specificity was 35 of 36 (97%). TCB was preferred to venous sampling (type 1 diabetes: 63% vs. 7%; 30% undecided). CONCLUSIONS: Transdermal capillary testing for C-peptide is a sensitive, specific, and acceptable alternative to venous sampling; TCB sampling for islet autoantibodies needs further assessment.

Exploring the perceived influence of social media use on disordered eating in nutrition and dietetics students.

BACKGROUND: Social media use (SMU) is increasingly widespread. More recently, SMU has been associated with increases in disordered eating; however, few qualitative studies have explored this issue in nutrition and dietetics students specifically, where susceptibility to disordered eating may be particularly high. The present study therefore aimed to investigate the perceived impact of SMU on disordered eating in nutrition and dietetics students. METHODS: One-to-one, in-depth, semi-structured interviews were conducted with nutrition and dietetics students from universities across the UK. Interviews explored students' views on the potential influence of SMU on their eating-related thoughts, feelings and behaviours. Data were thematically analysed to identify key themes. RESULTS: The findings suggested that SMU may provide students with a useful tool for the exploration of new recipes, ingredients and health-related information, thus enabling them to improve their eating behaviour and diet quality. However, students also showed high levels of objective awareness regarding the problems associated with SMU, including the presence of misinformation, body image dissatisfaction, social pressures and disordered eating. Interestingly, despite enabling them to detect sources of misinformation, students also discussed the negative impact that their course had on their eating habits, suggesting course content may be an additional risk factor for the development of disordered eating for this particular group. CONCLUSIONS: Future research should investigate ways to mitigate the negative impact of SMU and course content on disordered eating in nutrition and dietetics students.

Single nucleotide polymorphisms in C-reactive protein (CRP) predict response to adjunctive celecoxib treatment of resistant bipolar depression.

Background: Affective illness has been associated with a proinflammatory state, and it is generally accepted that the immune system plays a key role in the pathophysiology of mood disorders. Since inflammatory biomarkers are elevated in bipolar disorder, anti-inflammatory combination therapies may enhance response and reverse treatment resistance. Purpose: In the present study we investigated the possible impact of single nucleotide polymorphisms (SNPs) within the CRP gene on CRP blood levels, treatment response and level-of-stress perception in our cohort of treatment-resistant bipolar-depressed patients receiving escitalopram and celecoxib, or escitalopram and placebo, as previously reported (Halaris et al., 2020). Methods: Study design, clinical findings, and CRP blood levels have been reported previously (Halaris et al., 2020; Edberg et al., 2018). In this follow-up study we extracted DNA from blood cells collected at baseline. Genome-wide genotyping was performed for all subjects using the Infinium Multi-Ethnic Global-8 v1.0 Kit. Based on reports in the literature indicating possible associations with psychiatric conditions, ten previously reported CRP gene polymorphisms were evaluated in a preliminary analysis. We focused on rs3093059 and rs3093077 were in complete LD. Carriers were defined as those possessing at least one C allele for rs3093059, or at least one G allele for rs3093077. Additionally, we determined blood levels of the medications administered. Results: Non-carriers of rs3093059 and rs3093077 had significantly lower baseline CRP blood levels than carriers (p = 0.03). Increased rates of HAM-D17 response (p = 0.21) and remission (p = 0.13) and lower PSS-14 scores (p = 0.13) were observed in non-carriers among subjects receiving celecoxib but they did not reach statistical significance. When examining all subjects, nominally significant associations between carrier-status and remission (p = 0.04) and PSS-14 scores (p = 0.04) were observed after correcting for treatment arm. Non-carriers receiving celecoxib had the highest rates of response and remission, and the lowest stress scores. Conclusions: Carriers of the CRP SNPs may have higher baseline CRP levels, although non-carriers appear to benefit more from celecoxib co-therapy. Determination of the carrier status in conjunction with pretreatment blood CRP level measurement may contribute to personalized psychiatric practice, but replication of the present findings is needed.

Impact of COVID-19 pandemic on incidence of long-term conditions in Wales: a population data linkage study using primary and secondary care health records.

BACKGROUND: The COVID-19 pandemic has directly and indirectly had an impact on health service provision owing to surges and sustained pressures on the system. The effects of these pressures on the management of long-term or chronic conditions are not fully understood. AIM: To explore the effects of COVID-19 on the recorded incidence of 17 long-term conditions. DESIGN AND SETTING: This was an observational retrospective population data linkage study on the population of Wales using primary and secondary care data within the Secure Anonymised Information Linkage (SAIL) Databank. METHOD: Monthly rates of new diagnosis between 2000 and 2021 are presented for each long-term condition. Incidence rates post-2020 were compared with expected rates predicted using time series modelling of pre-2020 trends. The proportion of annual incidence is presented by sociodemographic factors: age, sex, social deprivation, ethnicity, frailty, and learning disability. RESULTS: A total of 5 476 012 diagnoses from 2 257 992 individuals are included. Incidence rates from 2020 to 2021 were lower than mean expected rates across all conditions. The largest relative deficit in incidence was in chronic obstructive pulmonary disease corresponding to 343 (95% confidence interval = 230 to 456) undiagnosed patients per 100 000 population, followed by depression, type 2 diabetes, hypertension, anxiety disorders, and asthma. A GP practice of 10 000 patients might have over 400 undiagnosed long-term conditions. No notable differences between sociodemographic profiles of post- and pre-2020 incidences were observed. CONCLUSION: There is a potential backlog of undiagnosed patients with multiple long-term conditions. Resources are required to tackle anticipated workload as part of COVID-19 recovery, particularly in primary care.

Diagnostic pathways for breast cancer in 10 International Cancer Benchmarking Partnership (ICBP) jurisdictions: an international comparative cohort study based on questionnaire and registry data.

OBJECTIVES: A growing body of evidence suggests longer time between symptom onset and start of treatment affects breast cancer prognosis. To explore this association, the International Cancer Benchmarking Partnership Module 4 examined differences in breast cancer diagnostic pathways in 10 jurisdictions across Australia, Canada, Denmark, Norway, Sweden and the UK. SETTING: Primary care in 10 jurisdictions. PARTICIPANT: Data were collated from 3471 women aged >40 diagnosed for the first time with breast cancer and surveyed between 2013 and 2015. Data were supplemented by feedback from their primary care physicians (PCPs), cancer treatment specialists and available registry data. PRIMARY AND SECONDARY OUTCOME MEASURES: Patient, primary care, diagnostic and treatment intervals. RESULTS: Overall, 56% of women reported symptoms to primary care, with 66% first noticing lumps or breast changes. PCPs reported 77% presented with symptoms, of whom 81% were urgently referred with suspicion of cancer (ranging from 62% to 92%; Norway and Victoria). Ranges for median patient, primary care and diagnostic intervals (days) for symptomatic patients were 3-29 (Denmark and Sweden), 0-20 (seven jurisdictions and Ontario) and 8-29 (Denmark and Wales). Ranges for median treatment and total intervals (days) for all patients were 15-39 (Norway, Victoria and Manitoba) and 4-78 days (Sweden, Victoria and Ontario). The 10% longest waits ranged between 101 and 209 days (Sweden and Ontario). CONCLUSIONS: Large international differences in breast cancer diagnostic pathways exist, suggesting some jurisdictions develop more effective strategies to optimise pathways and reduce time intervals. Targeted awareness interventions could also facilitate more timely diagnosis of breast cancer.

Review and Meta-analysis on the Impact of the ADRA2A Variant rs1800544 on Methylphenidate Outcomes in Attention-Deficit/Hyperactivity Disorder.

Background: Methylphenidate is among the most prescribed medications for treating attention-deficit/hyperactivity disorder (ADHD). However, nearly half of pediatric patients with ADHD do not respond to methylphenidate treatment. Pharmacogenetic testing can aid in identifying patients for whom methylphenidate is unlikely to be safe or effective, leading to improved methylphenidate outcomes and increased use of alternative treatment options for ADHD. This article aimed to summarize findings from studies of the ADRA2A gene variant, rs1800544, and its association with methylphenidate outcomes in ADHD. Methods: We systematically reviewed and meta-analyzed available literature on the impact of rs1800544 on methylphenidate outcomes in ADHD. Results: Fourteen studies met inclusion criteria for review, 9 of which were eligible for meta-analysis. The included studies compared methylphenidate outcomes in patients with ADHD categorized by rs1800544 genotype. G-allele carriers experienced significantly greater improvements in ADHD symptom scores (Swanson, Nolan, and Pelham Version-IV Scale or ADHD Rating Scale-IV) relative to noncarriers (odds ratio 3.08, 95% confidence interval 1.71-5.56, p = .0002) and greater response rates as measured by a ≥50% improvement in symptom scores (odds ratio 2.68, 95% confidence interval 1.23-5.82, p = .01); no significant difference in response rate as measured by Clinical Global Impressions score ≤2 was found. Stouffer's z-score method showed significant improvement across all methylphenidate outcomes in G-allele carriers relative to noncarriers (z = 3.03, p = .002). Conclusions: These findings suggest that carriers of rs1800544 may have improved ADHD outcomes following methylphenidate treatment. However, the extent to which these improvements are clinically impactful remain unclear. Additional studies are required to determine if rs1800544 carrier status should influence clinical recommendations for treatment of ADHD symptoms.

Characterisation of seven medications approved for attention-deficit/hyperactivity disorder using in vitro models of hepatic metabolism.

The metabolism of most medications approved for the treatment of attention deficit/hyperactivity disorder (ADHD) is not fully understood.In vitro studies using cryopreserved, plated human hepatocytes (cPHHs) and pooled human liver microsomes (HLMs) were performed to more thoroughly characterise the metabolism of several ADHD medications.The use of enzyme-specific chemical inhibitors indicated a role for CYP2D6 in atomoxetine (ATX) metabolism, and roles for CYP3A4/5 in guanfacine (GUA) metabolism.The 4-hydroxy-atomoxetine and N-desmethyl-atomoxetine pathways represented 98.4% and 1.5% of ATX metabolism in cPHHs, respectively. The 3-OH-guanfacine pathway represented at least 2.6% of GUA metabolism in cPHHs, and 71% in HLMs.The major metabolising enzyme for methylphenidate (MPH) and dexmethylphenidate (dMPH) could not be identified using these methods because these compounds were too unstable. Hydrolysis of these medications was spontaneous and did not require the presence of protein to occur.Clonidine (CLD), amphetamine (AMPH), and dextroamphetamine (dAMPH) did not deplete substantially in cPHHs nor HLMs, suggesting that these compounds may not undergo considerable hepatic metabolism. The major circulating metabolites of AMPH and dAMPH (benzoic acid and hippuric acid) were not observed in either system, and therefore could not be characterised. Additionally, inhibition experiments suggested a very minimal role for CYP2D6 in CLD and AMPH metabolism.

Pharmacogenomics of Clozapine-induced agranulocytosis: a systematic review and meta-analysis.

Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20-15.80, pcorrected = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation.

Diagnostic routes and time intervals for ovarian cancer in nine international jurisdictions; findings from the International Cancer Benchmarking Partnership (ICBP).

BACKGROUND: International Cancer Benchmarking Partnership Module 4 reports the first international comparison of ovarian cancer (OC) diagnosis routes and intervals (symptom onset to treatment start), which may inform previously reported variations in survival and stage. METHODS: Data were collated from 1110 newly diagnosed OC patients aged >40 surveyed between 2013 and 2015 across five countries (51-272 per jurisdiction), their primary-care physicians (PCPs) and cancer treatment specialists, supplement by treatment records or clinical databases. Diagnosis routes and time interval differences using quantile regression with reference to Denmark (largest survey response) were calculated. RESULTS: There were no significant jurisdictional differences in the proportion diagnosed with symptoms on the Goff Symptom Index (53%; P = 0.179) or National Institute for Health and Care Excellence NG12 guidelines (62%; P = 0.946). Though the main diagnosis route consistently involved primary-care presentation (63-86%; P = 0.068), onward urgent referral rates varied significantly (29-79%; P < 0.001). In most jurisdictions, diagnostic intervals were generally shorter and other intervals, in particular, treatment longer compared to Denmark. CONCLUSION: This study highlights key intervals in the diagnostic pathway where improvements could be made. It provides the opportunity to consider the systems and approaches across different jurisdictions that might allow for more timely ovarian cancer diagnosis and treatment.

Dose response effect of chemical surface concentration on percutaneous penetration in human: In vivo + in vitro.

The concentration of a formulation, defined as the mass of applied chemical per unit of skin surface area, is a key variable of skin absorption. Often only one concentration is available in the literature, hence a general evidence-based theory could allow prediction of how altering the concentration would produce a linear, increased, or decreased relative permeation. Here, we group topical chemicals into groups of how they permeate the skin when we increase or decrease their concentrations per unit area and discuss why we would like to predict their permeability in ranges of studied concentrations. PURPOSE: Our research question is: How, if at all, do changes in surface chemical concentration affect percutaneous penetration/absorption in man? Specifically, as the drug concentration is relatively increased, is the rate or extent of absorption proportionally affected? And if so, how? METHODS: We searched PubMed, Google Scholar, the United States Food and Drug Administration, Scientific Committee on Consumer Safety, and the European Food Safety Authority for approved transdermal delivery systems from January 1965 to October 2020. Search terms included combinations of the following words: topical + [absorption/penetration] + cm + [human/man]. RESULTS: Of the nineteen chemicals identified, five (testosterone, hydrocortisone, benzoic acid, fluazifop-butyl and lindane) showed decreased percent absorbed with increased dose, one (2-butoxyethanol) showed decreased flux with increased concentration, and thirteen (Basic Brown 17, benzene in gasoline, benzophenone-3, benzoyl peroxide, boric acid, caffeine, climbazole, diclofenac, ethanolamines, ibuprofen, N-octylamine, 2-phenoxyethanol, 2-pyrrolidone) showed increased flux with increasing concentrations. CONCLUSION: Dermal absorption depends on the interaction between the characteristics of the substance, the vehicle, and the skin. Without experiments investigating these characteristics, we cannot accurately predict the percent absorbed or flux of a formulation without in vitro or in vivo data. More experimental data, especially in vivo, is mandated before a highly efficient prediction model will be reached for validation.

Combinatorial pharmacogenomic algorithm is predictive of sertraline metabolism in patients with major depressive disorder.

Pharmacogenomic testing can be used to guide medication selection in patients with major depressive disorder (MDD). Currently, there is no consensus on which gene or genes to consider in medication management. Here, we assessed the clinical validity of the combinatorial pharmacogenomic algorithm to predict sertraline blood levels in a subset of patients enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial. Patients who reported taking sertraline within ≤2 weeks of the screening blood draw were included. All patients received combinatorial pharmacogenomic testing, which included a weighted assessment of individual phenotypes for multiple pharmacokinetic genes relevant for sertraline (CYP2C19, CYP2B6, and CYP3A4). Sertraline blood levels were compared between phenotypes based on: 1) the pharmacokinetic portion of the combinatorial pharmacogenomic algorithm, and 2) individual genes. When evaluated separately, individual genes (for CYP2C19 and CYP2B6) and the combinatorial algorithm were significant predictors of sertraline blood levels. However, in multivariate analyses that included individual genes and the combinatorial pharmacogenomic algorithm, only the combinatorial pharmacogenomic algorithm remained a significant predictor of sertraline blood levels. These findings support the clinical validity of the combinatorial pharmacogenomic algorithm, in that it is a superior predictor of sertraline blood levels compared to individual genes.

Efficacy of water skin decontamination in vivo in humans: A systematic review.

With the constant possibility of occupational exposures, chemical warfare, and targeted attacks, increased attention has been given to determining effective and timely dermal decontamination strategies. This systematic review summarises experimental studies reporting decontamination with water-based solutions of dermal chemical contaminants with in vivo human data. Embase, MEDLINE, PubMed, Web of Science, and Google Scholar databases were comprehensively searched using search terms ("cutaneous" or "skin" or "dermal" or "percutaneous") and ("decontamination" or "decontaminant" or "skin decontamination") to include 10 studies, representing 18 chemical contaminants, 199 participants, and 351 decontamination outcomes. Three studies included data from decontamination with water (10.8%, n = 38/351 decontamination outcomes), seven with soap and water (68.4%, n = 240/351 decontamination outcomes), and two with 10% isopropanol distilled water (20.8%, n = 73/351 decontamination outcomes). Results of dermal decontamination using water showed complete decontamination (CD) outcomes in 52.6% (n = 20/38) and partial decontamination (PD) in 47.4% (n = 18/38); using soap and water showed PD outcomes in 92.9% (n = 223/240) and minimal to no effect in 7.1% (n = 17/240); and using 10% isopropanol distilled water achieved PD outcomes in 100.0% (n = 73/73). Available data show that decontamination with water, soap and water, and 10% isopropanol distilled water is incomplete. Much remains to be learned about decontamination of the large variety of chemical contaminants including a range of molecular weights, lipid and water solubilities, melting points, volatility, and hydrogen bonds, as well as clinically relevant anatomic sites. A major void exists in data confirming or denying the completeness of decontamination by measuring absorption and excretion. The development of effective decontamination solutions is of high priority.

Effect of the COVID-19 pandemic on incidence of long-term conditions in Welsh residents: a population linkage study.

BACKGROUND: The COVID-19 pandemic had direct and indirect effects on health. Indirect effects on long term medical conditions (LTCs) are unclear. We examined trends in recorded incidences of LTCs and quantified differences between expected rates and observed rates from 2020 onwards. METHODS: This is a population data linkage study using primary and secondary care data within the Secure Anonymised Information Linkage Databank. We included data of Welsh residents diagnosed with any of 17 identified LTCs for the first time between Jan 1, 2000, and Dec 31, 2021. LTC's include mental health conditions, respiratory diseases, and heart conditions among others, generally chosen in line with the Quality and Outcomes Framework. The primary outcome was incidence rates (monthly number of new cases per 100 000 population). For each LTC, we did interrupted time series analysis of incidence rates from 2015 to 2021. Expected rates from between Jan 1, 2020, to Dec 31, 2021, were predicted using overall trends and seasonal patterns from the preceding 5 years and compared with observed rates. FINDINGS: We included 5 476 012 diagnoses from 2 257 992 individuals diagnosed with at least one LTC between Jan 1, 2000, to Dec 31, 2021. Across multiple long-term conditions, there was an abrupt reduction in observed incidence of new diagnoses from March to April 2020, followed by a general increase in incidence towards prepandemic rates. The conditions with the largest percentage difference between the observed and expected incidence rates in 2020 and 2021 were chronic obstructive pulmonary disease (38·4% lower than expected), depression (28·3% lower), hypertension (25·5% lower), and anxiety disorders (24·9% lower). The condition with the largest absolute difference between observed and expected incidence rates was anxiety disorders, with 830 per 100 000 less in 2020 and 2021 compared with observed rates. INTERPRETATION: The reduction in incidence rates of LTCs suggests an underreporting of LTCs, especially during 2020 and early 2021. The emergence of these yet undiagnosed cases could result in a surge of new patients in the near future. FUNDING: This work was supported by the Wales COVID-19 Evidence Centre, funded by Health and Care Research Wales.

Efficacy of water-only or soap and water skin decontamination of chemical warfare agents or simulants using in vitro human models: A systematic review.

Water-only or water and soap are widely recommended as preferred solutions for dermal decontamination. However, limited efficacy data exist. We summarized experimental studies evaluating in vitro efficacy of water-only or soap and water in decontaminating chemical warfare agents (CWA) or their simulants from human skin models. Embase, Covidence®, MEDLINE, PubMed, Web of Science, and Google Scholar were searched for articles using water-only or soap and water decontamination methods for removal of CWA/CWA simulants in in vitro human skin models. Data extraction was completed from seven studies, yielding seven contaminants. Water-only decontamination led to partial decontamination in all skin samples (100%, n = 81/81). Soap and water decontamination led to partial decontamination in all skin samples (100%, n = 143/143). Four studies found decontamination to either paradoxically enhance absorption of contaminants or their penetration rates, known as the "wash-in" effect. Despite recommendations, water-only or water and soap decontamination were found to yield partial decontamination of CWA or their simulants in all human in vitro studies. Thus, more effective decontaminating agents are needed. Some studies demonstrated increased or faster penetration of chemicals following decontamination, which could prove deadly for agents such as VX, although these findings require in vivo validation. Heterogeneity in experimental setups limits interstudy comparison, and it remains unclear when water-only or water and soap are ideal decontaminants, which requires more studies. Pending manuscripts will summarize in vivo human and animal efficacy data. International harmonized efficacy protocol should enable more efficient public health decisions for evidence-based public health decisions.

Ability of mathematical models to predict human in vivo percutaneous penetration of steroids.

Human skin is a common route for topical steroids to enter the body. To aid with risk management of therapeutic steroid usage, the US Environmental Protection Agency estimates percutaneous penetration using mathematical models. However, it is unclear how accurate are mathematical models in estimating percutaneous penetration/absorption of steroids. In this study, accuracy of predicted flux (penetration/absorption) by the main mathematical model used by the EPA, the Potts and Guy model based on in vitro data is compared to actual human in vivo data from our laboratory of percutaneous absorption of topical steroids. We focused on steroids due to the availability of steroid in vivo human data in our laboratory. For most steroids the flux was underestimated by a factor 10-60. However, within the group itself, there was an association between the Potts and Guy model and experimental human in vivo data (Pearson Correlation = 0.8925, p = 0.000041). Additionally, some physiochemical parameters used in the Potts and Guy equation, namely log Kp (Pearson Correlation = 0.7307, p = 0.0046) and molecular weight (Pearson correlation = -0.6807, p = 0.0105) correlated significantly with in vivo flux. Current mathematical models used in estimating percutaneous penetration/absorption did not accurately predict in vivo flux of steroids. Why? Proposed limitations to mathematical models currently used include: not accounting for volatility, lipid solubility, hydrogen bond effects, drug metabolism, as well as protein binding. Further research is needed in order to increase the predictive nature of such models for in vivo flux.

Efficacy of soap and water based skin decontamination using in vivo animal models: a systematic review.

Water-only or soap and water solutions are considered a gold standard for skin decontamination. However, there is lack of conclusive data regarding their efficacy. The aim of this study was to summarize in vivo animal model data on skin decontamination using water-only, and/or soap and water. Covidence, Embase, MEDLINE, PubMed, Web of Science, and Google Scholar were searched to identify relevant articles using water-only or soap and water decontamination methods in in vivo animals. Data extraction was completed from studies, representing three animal models, and 11 contaminants. Results demonstrated water-only decontamination solutions led to complete decontamination in 3.1% (n = 16/524) protocols, incomplete decontamination in 90.6% (n = 475/524) of protocols, and mortality in 6.3% (n = 33/524) of protocols. Soap and water decontamination solutions resulted in complete decontamination in 6.9% (n = 8/116) protocols, incomplete decontamination in 92.2% (n = 107/116) of protocols, and mortality in 6.9% (n = 8/116) of protocols. Although water only, or soap and water is considered a gold standard for skin decontamination, most papers investigated found that water only, and soap and water provided incomplete decontamination. Due to the insufficient data, and limitations that hinder the applicability of available data, evidence indicates that more contemporary studies investigating skin decontamination are needed, and compared to other model species, including humans, when practical.

'Function First': how to promote physical activity and physical function in people with long-term conditions managed in primary care? A study combining realist and co-design methods.

OBJECTIVES: To develop a taxonomy of interventions and a programme theory explaining how interventions improve physical activity and function in people with long-term conditions managed in primary care. To co-design a prototype intervention informed by the programme theory. DESIGN: Realist synthesis combining evidence from a wide range of rich and relevant literature with stakeholder views. Resulting context, mechanism and outcome statements informed co-design and knowledge mobilisation workshops with stakeholders to develop a primary care service innovation. RESULTS: A taxonomy was produced, including 13 categories of physical activity interventions for people with long-term conditions. ABRIDGED REALIST PROGRAMME THEORY: Routinely addressing physical activity within consultations is dependent on a reinforcing practice culture, and targeted resources, with better coordination, will generate more opportunities to address low physical activity. The adaptation of physical activity promotion to individual needs and preferences of people with long-term conditions helps affect positive patient behaviour change. Training can improve knowledge, confidence and capability of practice staff to better promote physical activity. Engagement in any physical activity promotion programme will depend on the degree to which it makes sense to patients and professions, and is seen as trustworthy. CO-DESIGN: The programme theory informed the co-design of a prototype intervention to: improve physical literacy among practice staff; describe/develop the role of a physical activity advisor who can encourage the use of local opportunities to be more active; and provide materials to support behaviour change. CONCLUSIONS: Previous physical activity interventions in primary care have had limited effect. This may be because they have only partially addressed factors emerging in our programme theory. The co-designed prototype intervention aims to address all elements of this emergent theory, but needs further development and consideration alongside current schemes and contexts (including implications relevant to COVID-19), and testing in a future study. The integration of realist and co-design methods strengthened this study.

Efficacy of water-based skin decontamination of occupational chemicals using in vitro human skin models: a systematic review.

Percutaneous absorption of chemicals is a potential route of topical and systemic toxicity. Skin decontamination interrupts this process by removing contaminants from the skin surface. Decontamination using water-only or soap and water solutions is the current gold standard despite limited efficacy data. A summary of studies evaluating their efficacy in decontaminating occupational contaminants from in vitro human skin models is presented. Embase, MEDLINE, PubMed, Web of Science, and Google Scholar were searched for relevant articles and data extracted from 15 investigations that reported on 21 occupational contaminants, which were further classified as industrial chemicals, drugs, or pesticides. Water-only decontamination yielded no response in 4.3% (n = 6/140) and partial decontamination in 95.7% (n = 134/140) of skin samples. Soap and water decontamination yielded complete decontamination in 4.9% (n = 13/264) and partial decontamination in 95.1% (n = 251/264) of skin samples. Four studies (26.7%, n = 4/15) reported increased penetration rates or skin concentration of contaminants following decontamination, demonstrating a "wash-in" effect. Varying study methodologies hinder our ability to compare data and determine when water alone or soap and water are best used. International harmonized efficacy protocol might enhance our decontamination understanding and enable a more customized approach to decontamination clinical practice and research.