The aetiology and burden of myeloproliferative neoplasms in the United Kingdom: the MyelOproliferative neoplasmS: an In-depth case-control (MOSAICC) study protocol.

BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that affect approximately 8 people in every 100,000 individuals in the UK. Little is known about the aetiology of MPNs, as previous studies have been hampered by small sample sizes, thus it is important to understand the cause of MPNs in a larger study to identify prevention strategies and improve treatment strategies. This study aims to determine environmental, lifestyle, genetic and medical causes of MPNs and to assess the relevance of occupational carcinogen exposures and quality of life impacts. METHODS: A UK-wide case-control study of 610 recently diagnosed MPN patients (within 24 months) receiving clinical care at 21 NHS study sites in Scotland, England, Wales and Northern Ireland and 610 non-blood relative/friend controls is underway. Data on occupational and residential history, medical and environmental factors, and quality of life are being collected from the participants via a structured interview and self-complete questionnaires. Clinical data is being provided by the clinical team. Blood, saliva and toenail samples are also being collected for genetic and elemental analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (95%CI) will be calculated using a p < 0.05 to investigate potential risk factors for the MPN clinical and genetic subtypes, and further analyses will be conducted based on the type of data and outcome of interest at a later stage. DISCUSSION: The study design is most effective for investigating the aetiology of rare diseases. The study will enable identification of potential causes of MPNs through in-depth assessment of potential risk factors with potential for longer follow-up of a number of outcomes.

The JAK2V617F mutation and the role of therapeutic agents in alleviating myeloproliferative neoplasm symptom burden.

Alleviating symptom burden in patients with myeloproliferative neoplasms (MPNs) is imperative to achieving optimal management. Research remains to elucidate the relationship between the JAK2V617F (Janus kinase 2) mutation present in many MPN patients, and the symptomatology they experience. This retrospective study analysed data collected from MPN patients included in the Myeloproliferative Neoplasms: An In-depth Case-Control (MOSAICC) pilot study. The MPN Symptom Assessment Form was administered, and median symptom scores were compared between JAK2V617F-positive and JAK2V617F-negative groups. Multivariate logistic regression analysis adjusted for confounding variables. Overall, 106 MPN patients participated: 65.1% were JAK2V617F positive, 30.2% were JAK2V617F negative and 4.7% had an unknown status. Multivariate analysis revealed a low symptom burden for early satiety (p < 0.01), dizziness (p < 0.05), cough (p < 0.05) and bone pain (p < 0.01) in those receiving venesection alone. Interferon alpha was significantly associated (p < 0.05) with severe burden for 16 of the 27 symptoms. JAK2V617F-positive females experienced a greater symptom burden than JAK2V617F-positive males. There was no discernible relationship between the JAK2V617F mutation and symptom burden in MPN patients, unlike the therapeutic agents investigated. Larger studies are required to validate these results and identify mechanisms of symptom development and control in MPN patients.

National initiative to promote public involvement in medicine safety: the use of a cross-sectional population survey to identify candidate behaviours for intervention development in Scotland.

OBJECTIVES: The aim of this study was to explore the public's current awareness of the safe use of medicines in general, and over-the-counter (OTC) analgesics (painkillers) in particular, as well as their information-seeking and advice-seeking, medicine use and disposal. SETTING: General population, Scotland. PARTICIPANTS: Adults (aged >16 years) living in Scotland. INTERVENTIONS: A cross-sectional survey was undertaken in collaboration with Ipsos MORI (a market research company). The content was informed by a multi-stakeholder prioritisation event and supplemented with information from earlier studies. RESULTS: The survey was completed in March 2020 by 1000 respondents, most of whom had used a pharmacy in the previous 12 months to obtain a medicine. Of the 1000 respondents, 39% (n=389) were 55 years and over; 52% (n=517) were women; and 58% were degree-educated.On receipt of a new prescription, up to 29.8% (95% CI 27.0% to 32.7%) of respondents proactively sought specific information or advice from the pharmacist. Few (5.2% (95% CI 4.0% to 6.8%) respondents 'always' discussed their new prescription medicine with pharmacy staff and 28.9% (95% CI 26.2% to 31.8%) reported 'never' engaging in this behaviour. Respondents aged >35 years were less likely to engage in this behaviour.Just over half (53% (95% CI 50.5% to 56.7%)) the respondents reported oral OTC analgesic use at least once in the previous month.In terms of medicine disposal, 29.3% (95% CI 26.6% to 32.2%) of respondents considered waste bin disposal to be of low or no harm. CONCLUSIONS: This study identified low levels of information-seeking and advice-seeking from pharmacy personnel especially on receipt of new prescription medicines. Potentially unsafe behaviours were identified in the use and disposal of medicines. These results will inform the development of interventions to promote advice-seeking and increase awareness regarding safe medicine use.

Meta-analysis of factors associated with antidiabetic drug prescribing for type 2 diabetes mellitus.

BACKGROUND: There is a lack of consensus on prescribing alternatives to initial metformin therapy and intensification therapy for type 2 diabetes mellitus (T2DM) management. This review aimed to identify/quantify factors associated with prescribing of specific antidiabetic drug classes for T2DM. METHODS: Five databases (Medline/PubMed, Embase, Scopus, Web of Science) were searched using the synonyms of each concept (patients with T2DM, antidiabetic drugs and factors influencing prescribing) in both free text and Medical Subject Heading (MeSH) forms. Quantitative observational studies evaluating factors associated with antidiabetic prescribing of metformin, sulfonylurea, thiazolidinedione, Dipeptidyl-peptidase 4 inhibitors (DPP4-I), sodium glucose transporter 2 inhibitors (SGLT2-I), Glucagon-Like peptide receptor agonist (GLP1-RA) and insulin in outpatient settings and published from January 2009 to January 2021 were included. Quality assessment was performed using a Newcastle-Ottawa scale. The validation was done for 20% of identified studies. The pooled estimate was measured using a three-level random-effect meta-analysis model based on odds ratio [95% confidence interval]. Age, sex, body mass index (BMI), glycaemic control (HbA1c) and kidney-related problems were quantified. RESULTS: Of 2331 identified studies, 40 met the selection criteria. Of which, 36 and 31 studies included sex and age, respectively, while 20 studies examined baseline BMI, HbA1c and kidney-related problems. The majority of studies (77.5%, 31/40) were rated as good and despite that the overall heterogeneity for each studied factor was more than 75%, it is mostly related to within-study variance. Older age was significantly associated with higher sulfonylurea prescription (1.51 [1.29-1.76]), yet lower prescribing of metformin (0.70 [0.60-0.82]), SGLT2-I (0.57 [0.42-0.79]) and GLP1-RA (0.52 [0.40-0.69]); while higher baseline BMI showed opposite significant results (sulfonylurea: 0.76 [0.62-0.93], metformin: 1.22 [1.08-1.37], SGLT2-I: 1.88 [1.33-2.68], and GLP1-RA: 2.35 [1.54-3.59]). Both higher baseline HbA1c and having kidney-related problems were significantly associated with lower metformin prescription (0.74 [0.57-0.97], 0.39 [0.25-0.61]), but more insulin prescriptions (2.41 [1.87-3.10], 1.52 [1.10-2.10]). Also, DPP4-I prescriptions were higher for patients with kidney-related problems (1.37 [1.06-1.79]) yet lower among patients with higher HbA1c (0.82 [0.68-0.99]). Sex was significantly associated with GLP1-RA and thiazolidinedione prescribing (F:M; 1.38 [1.19-1.60] and 0.91 [0.84-0.98]). CONCLUSION: Several factors were identified as potential determinants of antidiabetic drug prescribing. The magnitude and significance of each factor differed by antidiabetic class. Patient's age and baseline BMI had the most significant association with the choice of four out of the seven studied antidiabetic drugs followed by the baseline HbA1c and kidney-related problems which had an impact on three studied antidiabetic drugs, whereas sex had the least impact on prescribing decision as it was associated with GLP1-RA and thiazolidinedione only.

Audit and feedback interventions involving pharmacists to influence prescribing behaviour in general practice: a systematic review and meta-analysis.

INTRODUCTION: Pharmacists, as experts in medicines, are increasingly employed in general practices and undertake a range of responsibilities. Audit and feedback (A&F) interventions are effective in achieving behaviour change, including prescribing. The extent of pharmacist involvement in A&F interventions to influence prescribing is unknown. This review aimed to assess the effectiveness of A&F interventions involving pharmacists on prescribing in general practice compared with no A&F/usual care and to describe features of A&F interventions and pharmacist characteristics. METHODS: Electronic databases (MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, (Social) Science Citation Indexes, ISI Web of Science) were searched (2012, 2019, 2020). Cochrane systematic review methods were applied to trial identification, selection, and risk of bias. Results were summarized descriptively and heterogeneity was assessed. A random-effects meta-analysis was conducted where studies were sufficiently homogenous in design and outcome. RESULTS: Eleven cluster-randomized studies from 9 countries were included. Risk of bias across most domains was low. Interventions focussed on older patients, specific clinical area(s), or specific medications. Meta-analysis of 6 studies showed improved prescribing outcomes (pooled risk ratio: 0.78, 95% confidence interval: 0.64-0.94). Interventions including both verbal and written feedback or computerized decision support for prescribers were more effective. Pharmacists who received study-specific training, provided ongoing support to prescribers or reviewed prescribing for individual patients, contributed to more effective interventions. CONCLUSIONS: A&F interventions involving pharmacists can lead to small improvements in evidence-based prescribing in general practice settings. Future implementation of A&F within general practice should compare different ways of involving pharmacists to determine how to optimize effectiveness.PRISMA-compliant abstract included in Supplementary Material 1.

Use of sedative-hypnotic medications and risk of dementia: A systematic review and meta-analysis.

AIMS: Growing evidence suggests an association between the use of sedative-hypnotic medications and risk of dementia. The aim of this study is to examine this association using a meta-analysis approach. METHODS: MEDLINE (PubMed) and Scopus were systematically searched for studies published in English only. The quality of studies was evaluated using the Newcastle-Ottawa scale, and an overall odds ratio was pooled using a random-effects model. RESULTS: A total of 35 articles were included in the analysis. Pooled odds ratios (ORs) for dementia from all records were (OR; 1.33, 95% CI 1.19-1.49) for benzodiazepine (BZD) combined use (Subgroup-1), (OR: 1.46, 95% CI 1.23-1.73) for short-acting BZD use (Subgroup-2), (OR: 1.72, 95% CI 1.48-1.99) for long-acting BZD use (Subgroup-3), (OR: 1.13, 95% CI 0.97-1.32) for BZDs without specification of duration of action (Subgroup-4), (OR: 1.64, 95% CI 1.13-2.38) for the combined BZDs and Z-drugs, (OR: 1.43, 95% CI 1.17-1.74) for Z-drugs only, (OR: 1.14, 95% CI 0.88-1.46) for antidepressant use, (OR: 0.97, 95% CI 0.68-1.39) for antipsychotic use and (OR: 0.98, 95% CI 0.85-1.13) for anticonvulsant use. When sensitivity analysis was performed, association between overall use of BZDs and short-acting BZDs with the increased risk of dementia disappeared after exclusion of studies that were not adjusted for age covariate (OR: 1.2, 95% CI 1.0-1.44) and (OR: 1.22, 95% CI 0.75-2.01), respectively. Adjustment for protopathic bias by introduction of a lag period showed no evidence of increased risk of dementia with the use of BZDs (Subgroup-1) (OR: 1.14, 95% CI 0.82-1.58), Z-drugs (OR: 1.29, 95% CI 0.78-2.13), and combined BZDs and Z-drugs (OR: 1.51, 95% CI 0.91-2.53). Combined use of BZDs and Z-drugs showed more positive association when only studies of non-user design were analysed (OR: 2.75, 95% CI 2.23-3.39). CONCLUSIONS: All the investigated sedative-hypnotics showed no association with increased risk of dementia except for BZDs. However, the observed association with BZDs did not persist after exclusion of studies with potential reverse causation and confounding by indication. Therefore, this association needs to be assessed carefully in future research.

Validity of Pneumonia Severity Assessment Scores in Africa and South Asia: A Systematic Review and Meta-Analysis.

BACKGROUND: Although community-acquired pneumonia (CAP) severity assessment scores are widely used, their validity in low- and middle-income countries (LMICs) is not well defined. We aimed to investigate the validity and performance of the existing scores among adults in LMICs (Africa and South Asia). METHODS: Medline, Embase, Cochrane Central Register of Controlled Trials, Scopus and Web of Science were searched to 21 May 2020. Studies evaluating a pneumonia severity score/tool among adults in these countries were included. A bivariate random-effects meta-analysis was performed to examine the scores' performance in predicting mortality. RESULTS: Of 9900 records, 11 studies were eligible, covering 12 tools. Only CURB-65 (Confusion, Urea, Respiratory Rate, Blood Pressure, Age ≥ 65 years) and CRB-65 (Confusion, Respiratory Rate, Blood Pressure, Age ≥ 65 years) were included in the meta-analysis. Both scores were effective in predicting mortality risk. Performance characteristics (with 95% Confidence Interval (CI)) at high (CURB-65 ≥ 3, CRB-65 ≥ 3) and intermediate-risk (CURB-65 ≥ 2, CRB-65 ≥ 1) cut-offs were as follows: pooled sensitivity, for CURB-65, 0.70 (95% CI = 0.25-0.94) and 0.96 (95% CI = 0.49-1.00), and for CRB-65, 0.09 (95% CI = 0.01-0.48) and 0.93 (95% CI = 0.50-0.99); pooled specificity, for CURB-65, 0.90 (95% CI = 0.73-0.96) and 0.64 (95% CI = 0.45-0.79), and for CRB-65, 0.99 (95% CI = 0.95-1.00) and 0.43 (95% CI = 0.24-0.64). CONCLUSIONS: CURB-65 and CRB-65 appear to be valid for predicting mortality in LMICs. CRB-65 may be employed where urea levels are unavailable. There is a lack of robust evidence regarding other scores, including the Pneumonia Severity Index (PSI).

Sepsis scoring systems and use of the Sepsis six care bundle in maternity hospitals.

BACKGROUND: This study aimed to assess the predictive power of three different Sepsis Scoring Systems (SSSs), namely maternity Systematic Inflammatory Response Syndrome (mSIRS), quick Sepsis-related Organ Failure Assessment (qSOFA) and Modified Early Warning System (MEWS) in identifying sepsis by comparing them with positive culture. This study also sought to evaluate compliance with using the Sepsis Six Care Bundle (SSCB) operated in an individual health board. METHODS: A retrospective cohort study was conducted in 3 maternity hospitals of a single Scottish health board that admitted 2690 pregnancies in a 12 weeks period in 2016. Data for study was obtained from medical notes, handheld and electronic health records for women who were prescribed antibiotics with a confirmed or suspected diagnosis of sepsis. Data on clinical parameters was used to classify women according to mSIRS, qSOFA and MEWS as having sepsis or not and this was compared to results of positive culture to obtain sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under Receiver Operating Characteristic curve (AUROC) along with their 95% confidence intervals. Data was also obtained on SSCB compliance. RESULTS: A total of 89 women were diagnosed with sepsis, of which 14 had missing data, leaving 75 for final analysis. Sensitivity, specificity, PPV, NPV and AUROC of mSIRS and MEWS were almost similar with AUROC of both being around 50%. Only 33 (37.1%) had identifiable sepsis six sticker displayed on medical notes and only 2 (2.2%) had all elements of SSCB delivered within the recommended one-hour post-diagnosis period. Blood culture and full blood count with other lab tests had been performed for most women (97%) followed by intravenous antibiotics and fluids (93.9%). CONCLUSIONS: mSIRS and MEWS were quite similar in detecting sepsis when compared to positive culture, with their ability to detect sepsis being close to chance. This underlines the need for creating a valid SSS with high sensitivity and specificity for clinical use in obstetric settings. Clinical use of SSCB was limited despite it being a health board policy, although there is considerable possibility of improvement following detailed audits and removal of barriers for implementing SSCB.

An Observational Cohort Study Evaluating Antimicrobial Use in Peripartum Sepsis: A Tendency towards Overdiagnosis?

(1) Background: Sepsis is the leading cause of maternal death in 11-15% of women worldwide. This emphasises the importance of administrating timely and appropriate antibiotic therapy to women with sepsis. We aimed to evaluate the appropriateness of antimicrobial prescribing in women diagnosed with peripartum sepsis. (2) Method: A prospective observational cohort study in a single Scottish health region with 12,233 annual live births. Data were collected on women diagnosed with sepsis in the peripartum period using physical and electronic medical records, drug Kardex® (medication administration) and ward handover records. (3) Results: A sepsis diagnosis was concluded in 89 of the 2690 pregnancy cases reviewed, with a median hospital stay of four days. Good overall adherence to the local guidelines for the empiric antimicrobial treatment of sepsis was observed. Group B Streptococcus was associated with 20.8% of maternal sepsis cases, whilst in 60% of clinical specimens tested no causative pathogen was isolated. (4) Conclusion: The lack of specific and sensitive clinical markers for sepsis, coupled with their inconsistent clinical application to inform diagnosis, hindered effective antimicrobial stewardship. This was further exacerbated by the lack of positive culture isolates from clinical specimens, which meant that patients were often continued on broader-spectrum empiric treatment.

A Qualitative Study Investigating the Barriers to the Implementation of the 'Sepsis Six Care Bundle' in Maternity Wards.

Background: In 2014, the Sepsis Six Care Bundle (SSCB) was introduced into a Scottish health region to improve patient outcomes. Poor compliance was demonstrated with the SSCB across different specialities. This study explored determinants of non-compliance with the SSCB in maternity wards. Methods: In-depth interviews were conducted with midwives in a single Scottish health region. Convenience sampling was used to recruit interviewees. The interviews were digitally recorded, transcribed verbatim, entered into NVivo software, and analysed using thematic analysis. Results: Thirteen face-to-face interviews were completed and lasted an average of 33 min. Three main barriers were identified to SSCB implementation; the difficulty of diagnosing sepsis, the suitability of the SSCB in a maternity setting as part of the pre-conditions phase, and the lack of staff training as part of the pre-implementation phase. Conclusion: The findings emphasize the importance of adapting improvement initiatives with sufficient preparation of staff in the rationale use to the context of care bundles.

A systematic review and meta-analysis of the use of renin-angiotensin system drugs and COVID-19 clinical outcomes: What is the evidence so far?

Conflicting evidence exists about the effect of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) on COVID-19 clinical outcomes. We aimed to provide a comprehensive/updated evaluation of the effect of ACEIs/ARBs on COVID-19-related clinical outcomes, including exploration of interclass differences between ACEIs and ARBs, using a systematic review/meta-analysis approach conducted in Medline (OVID), Embase, Scopus, Cochrane library, and medRxiv from inception to 22 May 2020. English studies that evaluated the effect of ACEIs/ARBs among patients with COVID-19 were included. Studies' quality was appraised using the Newcastle-Ottawa Scale. Data were analyzed using the random-effects modeling stratified by exposure (ACEIs/ARBs, ACEIs, and ARBs). Heterogeneiity was assessed using I2 statistic. Several subgroup analyses were conducted to explore the impact of potential confounders. Overall, 27 studies were eligible. The pooled analyses showed nonsignificant associations between ACEIs/ARBs and death (OR:0.97, 95%CI:0.75,1.27), ICU admission (OR:1.09;95%CI:0.65,1.81), death/ICU admission (OR:0.67; 95%CI:0.52,0.86), risk of COVID-19 infection (OR:1.01; 95%CI:0.93,1.10), severe infection (OR:0.78; 95%CI:0.53,1.15), and hospitalization (OR:1.15; 95%CI:0.81,1.65). However, the subgroup analyses indicated significant association between ACEIs/ARBs and hospitalization among USA studies (OR:1.59; 95%CI:1.03,2.44), peer-reviewed (OR:1.93, 95%CI:1.38,2.71), good quality and studies which reported adjusted measure of effect (OR:1.30, 95%CI:1.10,1.50). Significant differences were found between ACEIs and ARBs with the latter being significantly associated with lower risk of acquiring COVID-19 infection (OR:0.24; 95%CI: 0.17,0.34). In conclusion, high-quality evidence exists for the effect of ACEIs/ARBs on some COVID-19 clinical outcomes. For the first time, we provided evidence, albeit of low quality, on interclass differences between ACEIs and ARBs for some of the reported clinical outcomes.