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Background: Opioids are frequently prescribed for persistent non-cancer pain despite limited evidence of long-term effectiveness and risk of harm. Evidence-based interventions to address inappropriate opioid prescribing are lacking. Aim: To explore perspectives of people living with persistent pain to understand barriers and facilitators in reducing opioids in the context of a pharmacist-led primary care review, and identify review components and features for optimal delivery. Design & setting: A multi-method qualitative study undertaken in the primary care setting in the UK. Method: Adults with experience of persistent pain and taking opioids participated in semi-structured interviews (n = 15, 73% female) and an online discussion forum (n = 31). The Theoretical Domains Framework (TDF) provided a framework for data collection and thematic analysis, involving deductive analysis to TDF domains, inductive analysis within domains to generate sub-themes, and sub-theme comparison to form across-domain overarching themes. The behaviour change technique taxonomy (v1) and motivational behaviour change technique classification system were used to systematically map themes to behaviour change techniques to identify potential review components and delivery features. Results: Thirty-two facilitator and barrier sub-themes for patients reducing opioids were identified across 13 TDF domains. These combined into the following six overarching themes: learning to live with pain; opioid reduction expectations; assuming a medical model; pharmacist-delivered reviews; pharmacist–patient relationship; and patient engagement. Sub-themes mapped to 21 unique behaviour change techniques, yielding 17 components and five delivery features for the proposed PROMPPT review. Conclusion: This study generated theoretically informed evidence for design of a practice pharmacist-led PROMPPT review. Future research will test the feasibility and acceptability of the PROMPPT review and pharmacist training.

ABSTRACT Tupanviruses, members of the family Mimiviridae, infect phagocytic cells. Particle uncoating begins inside the phagosome, with capsid opening via the stargate. The mechanism through which this opening takes place is unknown. Once phagocytized, metal ion flux control and ROS are induced to inactivate foreign particles, including viruses. Here, we studied the effect of iron ions, copper ions, and H2O2 on Tupanvirus particles. Such treatments induced stargate opening in vitro, as observed by different microscopy techniques. Metal-treated viruses were found to be non-infectious, leading to the hypothesis that stargate opening likely resulted in the release of the viral seed, which is required for infection initiation. To the best of our knowledge, this is the first description of a giant virus capsid morphological change induced by transition metals and H2O2, which may be important to describe new virulence factors and capsid uncoating mechanisms.

Background Chronic pain is common and costly. Antidepressants are prescribed to reduce pain. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions, so effectiveness and safety for most antidepressants for pain conditions remain unknown. Objective To assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change, serious adverse events and withdrawal. Design This was a systematic review with a network meta-analysis. We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials of antidepressants for chronic pain conditions up until 4 January 2022. The review was registered in PROSPERO (CRD42020171855), and the protocol was published in the Cochrane Library (https://doi.org/10.1002/14651858.CD014682). Setting We analysed trials from all settings. Participants We included trials in which participants had chronic pain, defined as longer than 3 months, from any condition excluding headache. Interventions We included all antidepressants. Main outcome measures Our primary outcome was substantial pain relief, defined as a reduction ˃ 50%. We also measured pain intensity, mood and adverse events. Secondary measures included moderate pain relief (above 30% reduction), physical function, sleep, quality of life, Global Impression of Change, serious adverse events, and withdrawal from trial. Results We identified 176 studies with a total of 28,664 participants. Most studies were placebo-controlled (n = 83) and parallel armed (n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of randomised controlled trials was 10 weeks. Most studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. Standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that for duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Limitations The evidence for antidepressants other than duloxetine is poor. For duloxetine, it is not clear whether the effect applies to groups with both pain and low mood, since these groups were excluded from trials. There is also insufficient evidence on long-term outcomes and on adverse effects. Conclusions There is only reliable evidence for duloxetine in the treatment of chronic pain. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Data for all other antidepressants were of low certainty. However, the findings should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. Future work There is a need for large, methodologically sound trials testing the effectiveness of antidepressants for chronic pain. These trials should examine long-term outcomes (> 6 months) and include people with low mood. There should also be better reporting of adverse events, tolerance of drugs, and long-term compliance. Study registration This study is registered as PROSPERO CRD42020171855. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? Chronic pain is pain that lasts for more than 3 months. Over one-third of people across the world experience chronic pain. This often has a detrimental impact on people’s mood, disability and well-being. Antidepressants are often prescribed to reduce pain, but we are not sure which antidepressants work best for different types of pain, or whether they are safe. We wanted to find out whether antidepressants were effective and safe for management of chronic pain. What did we do? We searched for studies that had compared any antidepressant with any other treatment for any type of chronic pain (except headache). We compared all the treatments against each other using a statistical method called network meta-analysis. This method allows us to rank the treatments in order of best to worst for each outcome. What did we find? We found 176 studies that included a total of 28,664 people with chronic pain. Most of the studies (83/176) compared an antidepressant with a placebo (which looks like the real medicine but does not have any medicine in it). The evidence from our analysis suggests that: Duloxetine is the antidepressant that we have the most confidence in. It was the best antidepressant for reducing pain and improving physical function. A standard dose of duloxetine was equally as effective for reducing pain as a high dose of duloxetine. Milnacipran was also effective at reducing pain, but we are not as confident in this result as in the one for duloxetine because there were fewer studies with fewer people involved. Aside from duloxetine and milnacipran, we do not have confidence in the results from any other antidepressant included in this review, and even for duloxetine and milnacipran, we do not know the long-term effects. It is important to recognise that the lack of evidence for the majority of antidepressants in this review does not necessarily equal a lack of benefit. Rather, this means that the large, high-quality trials required for us to be certain of an antidepressant’s effectiveness have not been undertaken. Altogether, although duloxetine and milnacipran are effective, the results of this review should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. These conclusions were informed by our patient and public involvement group. Scientific summary Background Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients’ global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions. Objectives Our objective was to assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events and withdrawal. Search methods We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions up until 4 January 2022. Selection criteria We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant or the same antidepressant at different doses, then the study was required to be double-blind. RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) were included but rated as at high risk of bias. We excluded RCTs where the follow-up was < 2 weeks and those with < 10 participants in each trial arm. We included any antidepressant at any dose, for any indication but used primarily for treatment of people with chronic pain and compared to placebo or active intervention. Participants We included adults (aged 18 years or older) reporting primary or secondary pain in any part of their body (except headache) as their primary complaint, that matched the International Association for the Study of Pain definition of chronic pain (i.e. at least 3 months’ duration). We included all trials regardless of the severity of participants’ chronic pain, although we extracted whether severity was part of the inclusion criteria of the individual studies. We excluded studies where the participants’ primary pain condition was headache or migraine. Data collection and analysis Two authors separately screened, extracted data and judged risk of bias. We synthesised the data using Bayesian network meta-analysis (NMA) and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve. We primarily used the Confidence in Network Meta-Analysis (CINeMA) framework and ‘Risk Of Bias due to Missing Evidence in Network meta-analysis’ (ROB-MEN) tool to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used Grading of Recommendations, Assessment, Development and Evaluations (GRADE) to assess the certainty of the evidence. Main results This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (n = 83) and parallel-armed (n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks; seven studies provided no useable data and were omitted from the NMAs. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine trials, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes For pain relief, duloxetine standard dose showed a small to moderate effect for substantial pain relief [odds ratio 0.91, 95% confidence interval (CI) 0.56 to 0.84] and continuous pain intensity [standardised mean difference (SMD) −0.31, 95% CI −0.39 to −0.24]. For pain intensity, milnacipran standard dose also showed a small effect (SMD −0.22, 95% CI −0.39 to 0.06) with moderate-certainty evidence. For mood, mirtazapine had a moderate effect (SMD −0.5, 95% CI −0.78 to −0.22), while duloxetine showed a small effect (−0.16, 95% CI −0.22 to −0.1); however, it is important to note that most trials excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the ‘normal’ or ‘subclinical’ ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were equally as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. Authors’ conclusions Our review and NMAs show that despite studies investigating 25 different antidepressants, there is reliable evidence for only duloxetine in the treatment of chronic pain. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Data for all other antidepressants were of low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy and safety of any antidepressant. Study registration This study is registered as PROSPERO CRD42020171855. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information.

Research into sex and gender-based differences in the brain is of key importance in many arenas. As findings will be scrutinised by both specialists and non-specialists, problems of miscommunication may arise. Guidelines to identify and avoid such problems are proposed.

Abstract Background Observational studies of polypharmacy and the risk of death or stroke in individuals with atrial fibrillation (AF) have produced inconsistent findings. By using propensity score matching (PSM) and Cox regression, this study aimed to determine whether polypharmacy (five to nine medicines) in the 3 months following AF diagnosis, is associated with an increased risk of death or ischemic stroke, compared to non‐polypharmacy (one to four medicines). Methods A prospective cohort study using data from the Clinical Practice Research Datalink (2006–2019). Data from 23 629 individuals with AF were analyzed. Cox regression models were adjusted for age, gender, morbidities, obesity, alcohol, smoking, and wealth. In the PSM models, cases and controls with near identical health profiles were selected from the study pool. The risk of death and stroke were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Results 68.9% (n = 16 271) of the participants had polypharmacy. PSM showed that polypharmacy was associated with an increased risk of death during follow‐up (HR 1.32; 95% CI: 1.19–1.47, p

Abstract Background Osteoarthritis is a common, painful and disabling long-term condition. Delivery of high-quality guideline-informed osteoarthritis care that successfully promotes and maintains supported self-management is imperative. However, osteoarthritis care remains inconsistent, including under use of core non-pharmacological approaches of education, exercise and weight loss. Community pharmacies are an accessible healthcare provider. United Kingdom government initiatives are promoting their involvement in a range of long-term conditions, including musculoskeletal conditions. It is not known what an enhanced community pharmacy role for osteoarthritis care should include, what support is needed to deliver such a role, and whether it would be feasible and acceptable to community pharmacy teams. In this (PharmOA) study, we aim to address these gaps, and co-design and test an evidence-based extended community pharmacy model of service delivery for managing osteoarthritis. Methods Informed by the Theoretical Domains Framework, Normalisation Process Theory, and the Medical Research Council (MRC) framework for developing complex interventions, we will undertake a multi-methods study involving five phases: 1. Systematic review to summarise currently available evidence on community pharmacy roles in supporting adults with osteoarthritis and other chronic (non-cancer) pain. 2. Cross-sectional surveys and one-to-one qualitative interviews with patients, healthcare professionals and pharmacy staff to explore experiences of current, and potential extended community pharmacy roles, in delivering osteoarthritis care. 3. Stakeholder co-design to: a) agree on the extended role of community pharmacies in osteoarthritis care; b) develop a model of osteoarthritis care within which the extended roles could be delivered (PharmOA model of service delivery); and c) refine existing tools to support community pharmacies to deliver extended osteoarthritis care roles (PharmOA tools). 4. Feasibility study to explore the acceptability and feasibility of the PharmOA model of service delivery and PharmOA tools to community pharmacy teams. 5. Final stakeholder workshop to: a) finalise the PharmOA model of service delivery and PharmOA tools, and b) if applicable, prioritise recommendations for its wider future implementation. Discussion This novel study paves the way to improving access to and availability of high-quality guideline-informed, consistent care for people with osteoarthritis from within community pharmacies.

Objectives To test the feasibility of a randomised controlled trial (RCT) of a novel preoperative tailored sleep intervention for patients undergoing total knee replacement.Design Feasibility two-arm two-centre RCT using 1:1 randomisation with an embedded qualitative study.Setting Two National Health Service (NHS) secondary care hospitals in England and Wales.Participants Preoperative adult patients identified from total knee replacement waiting lists with disturbed sleep, defined as a score of 0–28 on the Sleep Condition Indicator questionnaire.Intervention The REST intervention is a preoperative tailored sleep assessment and behavioural intervention package delivered by an Extended Scope Practitioner (ESP), with a follow-up phone call 4 weeks postintervention. All participants received usual care as provided by the participating NHS hospitals.Outcome measures The primary aim was to assess the feasibility of conducting a full trial. Patient-reported outcomes were assessed at baseline, 1-week presurgery, and 3 months postsurgery. Data collected to determine feasibility included the number of eligible patients, recruitment rates and intervention adherence. Qualitative work explored the acceptability of the study processes and intervention delivery through interviews with ESPs and patients.Results Screening packs were posted to 378 patients and 57 patients were randomised. Of those randomised, 20 had surgery within the study timelines. An appointment was attended by 25/28 (89%) of participants randomised to the intervention. Follow-up outcomes measures were completed by 40/57 (70%) of participants presurgery and 15/57 (26%) postsurgery. Where outcome measures were completed, data completion rates were 80% or higher for outcomes at all time points, apart from the painDETECT: 86% complete at baseline, 72% at presurgery and 67% postsurgery. Interviews indicated that most participants found the study processes and intervention acceptable.Conclusions This feasibility study has demonstrated that with some amendments to processes and design, an RCT to evaluate the clinical and cost-effectiveness of the REST intervention is feasible.Trial registration number ISRCTN14233189.

Abstract The Extremely Brilliant Source (EBS) is the experimental implementation of the novel Hybrid Multi Bend Achromat (HMBA) storage ring magnetic lattice concept, which has been realised at European Synchrotron Radiation Facility. We present its successful commissioning and first operation. We highlight the strengths of the HMBA design and compare them to the previous designs, on which most operational synchrotron X-ray sources are based. We report on the EBS storage ring’s significantly improved horizontal electron beam emittance and other key beam parameters. EBS extends the reach of synchrotron X-ray science confirming the HMBA concept for future facility upgrades and new constructions.

Objectives To develop consensus on the principles and key actions for collaborative working in practice between general practice, community pharmacy and patients and their carers.Design Three-round modified eDelphi study, starting from an established conceptual model of collaboration between general practitioners (GPs) and community pharmacists.Setting Community pharmacies and general practices in England, UK.Participants A panel of 123 experts: 43% from a community pharmacy background; 36% from a GP background; 13% patients, carers or patient representatives and 8% from academic or commissioner backgrounds. Panellist numbers reduced by approximately 30% in rounds 2 and 3.Primary and secondary outcome measures Consensus between expert panellists, defined as at least 75% agreement.Results A high level of consensus (>80%) was achieved on all components of a model of collaboration composed of Fundamental Principles of Collaboration and Key Activities for Action, supported by a series of aspirational statements and suggested practical actions. The fundamental principles and key activities are appended by contextual points. The findings indicate that collaboration in practice involves team members other than just GPs and community pharmacists and recognises that patients often want to know how each professional team is involved in their care. This study also provides insights into how collaboration between general practice and community pharmacy settings appears to have shifted during the COVID-19 pandemic, especially through opportunities for virtual collaboration and communication that can transcend the need for close geographical proximity.Conclusion A consensus-based model of collaboration between general practice teams, community pharmacy teams, and patients and their carers has been developed. It is practically focused, values the patient voice and incorporates general practice and community pharmacy team members. While developed in England, the model is likely to also have applicability to other countries with similar health systems that include general practices and community pharmacies.

Aims In UK there are around 76,000 hip fractures occur each year 10% to 15% of which are undisplaced intracapsular. There is considerable debate whether internal fixation is the most appropriate treatment for undisplaced fractures in older patients. This study describes cannulated hip screws survivorship analysis for patients aged ≥ 60 years with undisplaced intra-capsular fractures. Methods This was a retrospective cohort study of consecutive patients aged ≥ 60 years who had cannulated screws fixation for Garden I and II fractures in a teaching hospital between March 2013 and March 2016. The primary outcome was further same-side hip surgery. Descriptive statistics were used and Kaplan-Meier estimates calculated for implant survival. Results A total of 114 operations were performed on 112 patients with a mean age of 80.2 years (SD 8.9). The 30-day and one-year mortality were 1% (n = 1) and 13% (n = 15), respectively. Median follow-up was 6.6 years (interquartile range 6.0 to 7.3). Kaplan-Meier estimates showed a survivorship of 95% at one year and 90% at five years (95% confidence interval 84% to 95%) for cannulated screws. Nine patients underwent further hip surgery: four revision to total hip arthroplasty, one revision to hemiarthroplasty, three removals of screws, and one haematoma washout. Posterior tilt was assessable in 106 patients; subsequent surgery was required in two of the six patients identified with a posterior angle > 20° (p = 0.035 vs angle < 20°). Of the 100 patients with angle < 20°, five-year survivorship was 91%, with seven patients requiring further surgery. Conclusion This study of cannulated hip screw fixation for undisplaced fractures in patients aged ≥ 60 years reveals a construct survivorship without further operation of 90% at five years. Cannulated screws can be considered a safe reliable treatment option for Garden I and II fractures. Caution should be taken if posterior tilt angle on lateral view exceeds 20°, due to a higher failure rate and reoperation, and considered for similar management to Garden III and IV injuries. Cite this article: Bone Jt Open 2022;3(3):182–188.

Objectives In 2014/2015, 46% of community pharmacies were commissioned by local authorities to provide emergency hormonal contraception (EHC) free without prescription in England. Commissioning EHC services influences EHC prescribing from General Practice (GP)—greater community pharmacy provision reduces GP prescribing. This study aimed to examine predictors of GP and pharmacy EHC activity, describing them using path analysis. From this, commissioners and policy-makers may understand ways to influence this.Study design Cross-sectional study of routinely recorded data, obtained through freedom of information requests to local authorities.Setting Community pharmacies and general practices in England, UK.Participants All local authorities in England were included in the study (147 areas). The study population were all girls, adolescents and women aged 12–55. Of the 147 areas, data from 80 local authorities were obtained covering an eligible female population of 9 380 153.Primary and secondary outcome measures Correlation between community pharmacy and GP EHC activity.Results Data from 80 local authorities were analysed, representing 60% of the eligible female population in England. A significant negative correlation was found between rates of community pharmacy provision and GP prescribing (−0.458, p

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

The ageing population has resulted in an increase in multimorbidity and polypharmacy, and subsequently the complexity of optimising elderly patients’ medicines. The need for deprescribing can arise from factors such as increased susceptibility to adverse effects of medicines in older age, due to functional and cognitive changes, which increases elderly people’s risk of harm. Previous questionnaire-survey-based research suggests that patients tend not to disagree with deprescribing, but qualitative research on patients’ perspectives on deprescribing appears sparse and focused on specific conditions, circumstances (e.g., terminal illness) or medicines. Further exploration of this area is therefore important for health professionals, and greater understanding in particular is needed about elderly patients’ perspectives on the acceptability of deprescribing and how best to conduct deprescribing consultations. This study aims to explore these issues, with an approach informed by the Theoretical Framework of Acceptability (TFA). Semi-structured, audio-recorded interviews will therefore be undertaken with a purposive sample of approximately 20 hospital in-patients who are ≥65years of age, prescribed at least one regular medicine and have multimorbidities and/or frailty. Two acute Trusts were identified through existing networks where patients will be identified by the ward pharmacist and recruited to the study by the researcher. Due to the nature of the discussion and the potential vulnerable nature of participants, a distress protocol has been created to support management of any distress or fatigue that may occur. The TFA has been used so far to develop the study objectives and interview guide topics. The interview guide has been structured into five broad topics, which will cover the constructs of the TFA. Interview recordings will be transcribed verbatim and analysed using the Framework Analysis technique, informed by the TFA.

Ginger is well known for its pungent flavour and health-benefitting properties, both of which are imparted by various gingerol derivatives and other volatile constituents. Although there has been a considerable amount of research into the chemical constituents found in fresh ginger, there is little information available on the quality of Australian-grown dried ginger, particularly that intended for processing purposes. Here, we investigate differences in the chemical composition of three samples of processing-grade ginger, ranging from very poor to good quality. Gingerols and 6-shogaol were quantified using high performance liquid chromatograph (HPLC), while gas chromatography coupled with mass spectrometry (GC-MS) was used to identify and semi-quantify the volatile constituents and other gingerol derivatives. Significant differences were found between the samples in their content of gingerols and [6]-shogaol, as well as in their total phenolic content and antioxidant capacity. A total of 100 volatile compounds were identified in the dried ginger samples, including 54 terpenoid derivatives and 35 gingerol derivatives. Several compounds are reported from ginger for the first time, including limonene glycol and neryl laurate. In addition, we provide the second report of the presence of shyobunol, geranyl-p-cymene and geranyl-α-terpinene in ginger.

COVID-19 vaccines are safe and highly effective, but some individuals experience unpleasant reactions to vaccination. As the majority of adults in the United States have received a COVID-19 vaccine this year, there is an unprecedented opportunity to study the genetics of reactions to vaccination via surveys of individuals who are already part of genetic research studies. Here, we have queried 17,440 participants in the Helix DNA Discovery Project and Healthy Nevada Project about their reactions to COVID-19 vaccination. Our genome-wide association study identifies an association between severe difficulties with daily routine after vaccination and HLA-A∗03:01. This association was statistically significant only for those who received the Pfizer-BioNTech vaccine (BNT162b2; n = 3,694; p = 4.70E−11; OR = 2.07 [95% CI 1.67–2.56]), and showed a smaller effect size in those who received the Moderna vaccine (mRNA-1273; n = 3,610; p = 0.005; OR = 1.32 [95% CI 1.09–1.59]). In Pfizer-BioNTech recipients, HLA-A∗03:01 was associated with a 2-fold increase in risk of self-reported severe difficulties with daily routine following vaccination. The effect was consistent across ages, sexes, and whether the person had previously had a COVID-19 infection. The reactions experienced by HLA-A∗03:01 carriers were driven by associations with chills, fever, fatigue, and generally feeling unwell.

Population-based association analyses of rare genetic variants with complex traits are limited by the availability of data from sufficiently large cohorts. Here, Cirulli et al. report gene-based collapsing analysis of exomes from 49,960 participants of the UK Biobank and 21,866 participants of the Healthy Nevada Project over a total of 4377 traits.

Background: An animated, video-based, virtual patient (VP) has been developed to allow pharmacists to learn how, and practice how, to advise patients taking non-vitamin K oral anticoagulants, a group of high-risk medicines. VPs are well-established resources but have historically only been accessed within specific online teaching sessions or at university sites; this new VP represents a mobile design that can be accessed from anywhere. Objective: To investigate the usability and acceptability of the VP application with a focus on exploring perspectives on accessibility. Methods: The study used an exploratory sequential mixed method design consisting of a satisfaction survey and interviews. Survey data were analysed descriptively to assess satisfaction with the application and to identify interview discussion areas. Interview data were analysed using the Framework Approach to thematic analysis. Participants were hospital or community pharmacists, or pre-registration pharmacists. Results: A total of 94 survey responses were collected and 22 respondents went on to take part in an interview. Participants reported liking the concept and delivery of the VP, particularly the high-quality technology. They also reported finding it usable, and appeared to favour its mobility and accessibility, particularly as the VP can be used on any internet accessible device, including mobile phones, with no specific requirements. Amendments that were suggested included quickening the delivery of some animations and improving navigation within the application, possibly through a button to return to the previous step should a mistake be made. Conclusions: The mobile VP appeared to be functional and usable, with the majority of users reporting satisfaction with use across a range of devices. Users reported positively about the VP's remote access, but navigation around the application requires development.

Objectives A collaborative service initiative involving community pharmacists and a specialist mental health pharmacist was developed to provide pharmacist reviews for care home residents with intellectual disabilities (IDs). This study aimed to characterise the medicines and lifestyle risk outcomes of the service and determine how these align with national priority issues in ID.Design Descriptive statistical analysis of routinely collected service delivery data.Setting Residential care homes in the Wirral, England for people with ID.Participants 160 residents.Interventions Pharmacist review of residents’ medicines and lifestyle risk factors between November 2019 and May 2020.Primary and secondary outcome measures Numbers of medicines prescribed, the nature of pharmacists’ interventions/recommendations and general practitioner (GP)/psychiatrist acceptance.Results The 160 residents were prescribed 1207 medicines, 74% were prescribed ≥5 medicines and 507 interventions/recommendations were made, averaging 3.3 per resident. The highest proportion (30.4%) were lifestyle risk related, while changing and stopping medicines accounted for 17.9% and 12.8%, respectively. Of the recommendations discussed with GPs/psychiatrists, 86% were accepted. Medicines with anticholinergic properties were prescribed for 115 (72%) residents, of whom 43 (37%) had a high anticholinergic burden score. Pharmacists recommended anticholinergic discontinuation or dose reduction for 28 (24%) residents. The pharmacists made interventions/recommendations about constipation management for 10% of residents and about respiratory medicines for 17 (81%) of the 21 residents with respiratory diagnoses.Conclusions The findings indicate considerable polypharmacy among the residents and a high level of pharmacists’ interventions/recommendations about medicines and lifestyle risk, most of which were accepted by GPs/psychiatrists. This included anticholinergic burden reduction and improving respiratory disease and constipation management, which are national priority issues. Wider adoption of collaborative pharmacist review models could have similar benefits for residential populations with ID and potentially reduce pressure on other health services.

Abstract Background Community pharmacy Common Ailments Services can ease the considerable workload pressures on primary and secondary care services. However, evidence is needed to determine whether there are benefits of extending such services beyond their typically limited scope. This study therefore aimed to evaluate a new community pharmacy model of a service for patients with ear, nose and throat (ENT) and eye conditions who would otherwise have had to seek primary care appointments or emergency care. Methods People with specified ENT or eye conditions registered with General Practitioners in Staffordshire or Shropshire who presented at participating community pharmacies were offered a consultation with a pharmacist trained to provide the service. The service included provision of relevant self-care advice and, where clinically appropriate, supply of non-prescription medicines or specified prescription-only medicines (POMs), including antibiotics, under Patient Group Directions. Patients received a follow up telephone call from the pharmacist five days later. Data were collected on the characteristics of patients accessing the service, the proportion of those who were treated by the pharmacist without subsequently seeing another health professional about the same condition, and patient reported satisfaction from a questionnaire survey. Results A total of 408 patients accessed the service, of whom 61% received a POM, 15% received advice and medicine supplied under the common ailments service, 9% received advice and purchased a medicine, 10% received advice only and 5% were referred onwards. Sore throat accounted for 45% of diagnoses where a POM was supplied, 32% were diagnosed with acute otitis media and 15% were diagnosed with acute bacterial conjunctivitis. The number of patients successfully followed up was 309 (76%), of whom 264 (85%) had not seen another health professional for the same symptoms, whilst 45 (15%) had seen another health professional, usually their GP. The questionnaire was completed by 259 patients (response rate 63%) of whom 96% reported being very satisfied or satisfied with the service. Conclusions The study demonstrates that pharmacists can effectively diagnose and treat these conditions, with a high degree of patient satisfaction. Wider adoption of such service models could substantially benefit primary care and emergency care services.

Epidemiological and genetic studies on COVID-19 are currently hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict COVID-19 cases using cross-sectional self-reported disease-related symptoms. Here, we demonstrate that this COVID-19 prediction model has reasonable and consistent performance across multiple independent cohorts and that our attempt to improve upon this model did not result in improved predictions. Using the existing COVID-19 prediction model, we then conducted a GWAS on the predicted phenotype using a total of 1,865 predicted cases and 29,174 controls. While we did not find any common, large-effect variants that reached genome-wide significance, we do observe suggestive genetic associations at two SNPs (rs11844522, p = 1.9x10-7; rs5798227, p = 2.2x10-7). Explorative analyses furthermore suggest that genetic variants associated with other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. This study represents a first effort that uses a symptom-based predicted phenotype as a proxy for COVID-19 in our pursuit of understanding the genetic susceptibility of the disease. We conclude that the inclusion of symptom-based predicted cases could be a useful strategy in a scenario of limited testing, either during the current COVID-19 pandemic or any future viral outbreak.

Virtual patients are an active learning pedagogical tool which simulate clinical scenarios in a three-dimensional environment. Their use in pharmacy education is under-researched in comparison to other healthcare professions. In the United Kingdom, pre-registration training refers to a year of workplace based training which pharmacy graduates must complete prior to professional registration as pharmacists. This study aimed to evaluate pre-registration pharmacists' perceptions on the integration, usefulness and enjoyment of completing virtual patient simulations or non-interactive case studies as part of their training. Pre-registration trainees completed three virtual patient simulations or three non-interactive case studies on the topics of: emergency hormonal contraception, renal function and childhood illnesses. Telephone interviews were conducted with twenty pre-registration pharmacists, exploring their perspectives on the use of the virtual patient or non-interactive case studies. Data was analysed using the five-stage framework approach. Four main themes emerged from the data: case study design; usefulness of the case studies as a training tool; support in pre-registration training; utility of the learning tools. Trainees also identified technical issues they had experienced while completing the virtual patient simulations, specifically with keyword recognition. Pre-registration trainees who used the virtual patients provided comments relating to the novelty, realism and enjoyment in completing them. Trainees in both groups reported developing knowledge and skills from completing the case studies; those who used the virtual patient commented on the development of communication skills and an increase in confidence for practice and those who used the non-interactive cases focused on knowledge acquisition and numeracy. Participants were enthusiastic about virtual patients as a novel training tool which provided an opportunity for learners to practice realistic scenarios in a safe environment. Virtual patients offer the potential to 'bridge the gap' in pharmacist pre-registration sector-related training variation, promote learning through reflection on doing and increase overall preparedness for practice.

Ginger is best known for its aromatic odour, spicy flavour and health-benefiting properties. Its flavour is derived primarily from two compound classes (gingerols and shogaols), with the overall quality of the product depending on the interaction between these compounds. Consequently, a robust method for determining the ratio of these compounds would be beneficial for quality control purposes. This study investigated the feasibility of using hyperspectral imaging to rapidly determine the ratio of 6-gingerol to 6-shogoal in dried ginger powder. Furthermore, the performance of several pre-processing methods and two multivariate models was explored. The best-performing models used partial least squares regression (PSLR) and least absolute shrinkage and selection operator (LASSO), using multiplicative scatter correction (MSC) and second derivative Savitzky–Golay (2D-SG) pre-processing. Using the full range of wavelengths (~400–1000 nm), the performance was similar for PLSR (R2 ≥ 0.73, RMSE ≤ 0.29, and RPD ≥ 1.92) and LASSO models (R2 ≥ 0.73, RMSE ≤ 0.29, and RPD ≥ 1.94). These results suggest that hyperspectral imaging combined with chemometric modelling may potentially be used as a rapid, non-destructive method for the prediction of gingerol-to-shogaol ratios in powdered ginger samples.

Abstract Background Approximately 20% of patients experience chronic pain after total knee replacement. There is little evidence for effective interventions for the management of this pain, and current healthcare provision is patchy and inconsistent. Given the complexity of this condition, multimodal and individualised interventions matched to pain characteristics are needed. We have undertaken a comprehensive programme of work to develop a care pathway for patients with chronic pain after total knee replacement. This protocol describes the design of a randomised controlled trial to evaluate the clinical- and cost-effectiveness of a complex intervention care pathway compared with usual care. Methods This is a pragmatic two-armed, open, multi-centred randomised controlled trial conducted within secondary care in the UK. Patients will be screened at 2 months after total knee replacement and 381 patients with chronic pain at 3 months postoperatively will be recruited. Recruitment processes will be optimised through qualitative research during a 6-month internal pilot phase. Patients are randomised using a 2:1 intervention:control allocation ratio. All participants receive usual care as provided by their hospital. The intervention comprises an assessment clinic appointment at 3 months postoperatively with an Extended Scope Practitioner and up to six telephone follow-up calls over 12 months. In the assessment clinic, a standardised protocol is followed to identify potential underlying causes for the chronic pain and enable appropriate onward referrals to existing services for targeted and individualised treatment. Outcomes are assessed by questionnaires at 6 and 12 months after randomisation. The co-primary outcomes are pain severity and pain interference assessed using the Brief Pain Inventory at 12 months after randomisation. Secondary outcomes relate to resource use, function, neuropathic pain, mental well-being, use of pain medications, satisfaction with pain relief, pain frequency, capability, health-related quality of life and bodily pain. After trial completion, up to 30 patients in the intervention group will be interviewed about their experiences of the care pathway. Discussion If shown to be clinically and cost-effective, this care pathway intervention could improve the management of chronic pain after total knee replacement. Trial registration ISRCTN registry (ISRCTN92545361), prospectively registered on 30 August 2016.

Significant magnetic cross talks were observed between neighboring magnets on the Extremely Brilliant Source (EBS) low emittance storage ring. The main sources for these cross talks are the short longitudinal distances between magnets, which reach 47 mm in some cases. It affects mainly the dipole bending angles and the quadrupole gradients. A 1% bending angle correction was applied to the (permanent) bending magnets before their installation in the storage ring to compensate for the cross talks, while gradient errors as high as 1.8% were observed on quadrupoles. Intensive 3D magnetic simulations gave the longitudinal distribution of the cross talk errors for various magnet pairs and current settings. The error distribution depends on the magnet pairs: cross talks may create errors at magnet edges or all along the magnets, with same or opposite polarity. The simulations were validated by magnetic measurements, the discrepancies between measured and simulated values being in the 10^{-4} range with respect to the nominal gradients. Cross talk induced gradient errors were added to all quadrupoles and neighboring magnets in the lattice model. Even if it complicated the commissioning, the cross talks have no impact on the final performances of the lattice as the design machine parameters were reached for the most part.

BackgroundThe Healthy Living Pharmacy (HLP) project, launched in England, UK in 2009 was a novel approach of introducing public health services within community pharmacy to tackle local health inequalities. A national roll-out followed a reported successful pilot; subsequent local evaluations ensued.ObjectivesTo summarise reported outcomes and investigate contextual factors that indicate the presence, absence and maturity of implementation determinants, thus offering useful lessons to stakeholders in implementing future initiatives to achieve successful outcomes.MethodsA systematic review was conducted to identify all publications reporting on the HLP project. All HLP articles and conference abstracts were considered for inclusion and were assessed for methodological quality. The Consolidated Framework for Implementation Research (CFIR) was utilised to identify potential implementation determinants reported. Each article was then analysed to identify reported economic, humanistic or clinical outcomes.ResultsThe review included six peer-reviewed journal articles and 12 conference abstracts. Joanna Briggs Institute Qualitative Assessment and Review Instrument indicated deficiencies in methodological quality. Through adoption of the CFIR framework, the implementation determinants relevant to the implementation of HLP into community pharmacy were identified. A resonating issue emerged in that the absence of adopting an evidence-based implementation process limited the ability to capture meaningful outcome data. This resulted in a lack of evidence to support sustainability and the failure to address many of the well cited barriers, e.g. lack of awareness amongst patients, public and other healthcare professionals, and weak support for future investment in resource for training and dissemination.ConclusionsHealthcare systems are increasingly called on to adopt evidence-based interventions that improve quality, control costs, and maximize value, thus offering opportunity to accelerate the implementation of clinical pharmacy services and programs aimed at improving patient care. Interventions, such as the HLP project require focused efforts on implementation and evaluation of those implementation efforts to produce effective and lasting changes in complex health care systems.

[This corrects the article DOI: 10.1371/journal.pone.0213607.].

The rum industry is currently worth USD 16 billion, with production concentrated in tropical countries of the Caribbean and Asia-Pacific regions. The primary feedstock for rum production is sugar cane molasses, a by-product of sugar refineries. The main variables known to affect rum quality include the composition of the molasses, the length of fermentation, and the type of barrels and length of time used for aging the rum. The goal of this review is to provide an overview of the impact of these variables on rum quality, and to highlight current challenges and opportunities in the production of rum from molasses. In order to achieve this, we review the relevant contemporary scientific literature on these topics. The major contemporary challenges in the rum production industry include minimising the effects of variability in feedstock quality, ensuring the fermentation process runs to completion, preventing microbial contamination, and the selection and maintenance of yeast strains providing optimum ethanol production. Stringent quality management practices are required to ensure consistency in the quality and organoleptic properties of the rum from batch to batch. Further research is required to fully understand the influences of many of these variables on the final quality of the rum produced.

Tailed phages are the most abundant and diverse group of viruses on the planet. Yet, the smallest tailed phages display relatively complex capsids and large genomes compared to other viruses. The lack of tailed phages forming the common icosahedral capsid architectures T = 1 and T = 3 is puzzling. Here, we extracted geometrical features from high-resolution tailed phage capsid reconstructions and built a statistical model based on physical principles to predict the capsid diameter and genome length of the missing small-tailed phage capsids. We applied the model to 3348 isolated tailed phage genomes and 1496 gut metagenome-assembled tailed phage genomes. Four isolated tailed phages were predicted to form T = 3 icosahedral capsids, and twenty-one metagenome-assembled tailed phages were predicted to form T < 3 capsids. The smallest capsid predicted was a T = 4/3 ≈ 1.33 architecture. No tailed phages were predicted to form the smallest icosahedral architecture, T = 1. We discuss the feasibility of the missing T = 1 tailed phage capsids and the implications of isolating and characterizing small-tailed phages for viral evolution and phage therapy.

Virtual patients are an active learning pedagogical tool that simulate clinical scenarios. There is an established disparity in pre-registration examination pass rates depending on whether individuals complete their training in a community or hospital pharmacy. This study aimed to evaluate virtual patient (VP) and non-interactive (NI) case studies, concerning knowledge, skill and confidence development of pre-registration pharmacist trainees. A quasi-experimental evaluation was conducted. Pre-registration pharmacists completed three VP or NI case studies. Each case study was associated with a pre-and post-knowledge quiz. Pre-registration trainees were invited to complete a questionnaire consisting of Likert ranking statements and open-ended questions on the case study features, usability and individual development. Both learning tools significantly improved trainees’ knowledge on the topic areas (except for the NI group in case study 3). Although no significant differences in knowledge improvement were identified between the learning tools, trainees who used the VP reported the development of a wider knowledge base and skill set, an increase in confidence for practice and an opportunity to apply their learning. The sector in which pre-registration pharmacists were completing their training (community or hospital) had a significant impact on knowledge improvement in the three case studies. Future research evaluating VPs with pre-registration and qualified pharmacists should be conducted to explore their benefits and establish their effectiveness as learning tools.

Here, we describe the structure of three actinobacteriophage capsids that infect Mycobacterium smegmatis. The capsid structures were resolved to approximately six angstroms, which allowed confirmation that each bacteriophage uses the HK97-fold to form their capsid. One bacteriophage, Rosebush, may have a novel variation of the HK97-fold. Four novel accessory proteins that form the capsid head along with the major capsid protein were identified. Two of the accessory proteins were minor capsid proteins and showed some homology, based on bioinformatic analysis, to the TW1 bacteriophage. The remaining two accessory proteins are decoration proteins that are located on the outside of the capsid and do not resemble any previously described bacteriophage decoration protein. SDS-PAGE and mass spectrometry was used to identify the accessory proteins and bioinformatic analysis of the accessory proteins suggest they are used in many actinobacteriophage capsids.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (