Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment: A Systematic Review and Meta-analysis.

Importance: The association between statin-induced reduction in low-density lipoprotein cholesterol (LDL-C) levels and the absolute risk reduction of individual, rather than composite, outcomes, such as all-cause mortality, myocardial infarction, or stroke, is unclear. Objective: To assess the association between absolute reductions in LDL-C levels with treatment with statin therapy and all-cause mortality, myocardial infarction, and stroke to facilitate shared decision-making between clinicians and patients and inform clinical guidelines and policy. Data Sources: PubMed and Embase were searched to identify eligible trials from January 1987 to June 2021. Study Selection: Large randomized clinical trials that examined the effectiveness of statins in reducing total mortality and cardiovascular outcomes with a planned duration of 2 or more years and that reported absolute changes in LDL-C levels. Interventions were treatment with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) vs placebo or usual care. Participants were men and women older than 18 years. Data Extraction and Synthesis: Three independent reviewers extracted data and/or assessed the methodological quality and certainty of the evidence using the risk of bias 2 tool and Grading of Recommendations, Assessment, Development and Evaluation. Any differences in opinion were resolved by consensus. Meta-analyses and a meta-regression were undertaken. Main Outcomes and Measures: Primary outcome: all-cause mortality. Secondary outcomes: myocardial infarction, stroke. Findings: Twenty-one trials were included in the analysis. Meta-analyses showed reductions in the absolute risk of 0.8% (95% CI, 0.4%-1.2%) for all-cause mortality, 1.3% (95% CI, 0.9%-1.7%) for myocardial infarction, and 0.4% (95% CI, 0.2%-0.6%) for stroke in those randomized to treatment with statins, with associated relative risk reductions of 9% (95% CI, 5%-14%), 29% (95% CI, 22%-34%), and 14% (95% CI, 5%-22%) respectively. A meta-regression exploring the potential mediating association of the magnitude of statin-induced LDL-C reduction with outcomes was inconclusive. Conclusions and Relevance: The results of this meta-analysis suggest that the absolute risk reductions of treatment with statins in terms of all-cause mortality, myocardial infarction, and stroke are modest compared with the relative risk reductions, and the presence of significant heterogeneity reduces the certainty of the evidence. A conclusive association between absolute reductions in LDL-C levels and individual clinical outcomes was not established, and these findings underscore the importance of discussing absolute risk reductions when making informed clinical decisions with individual patients.

Transmission of SARS-CoV-2 by children: a rapid review, 30 December 2019 to 10 August 2020.

BackgroundThe role of children in the transmission of SARS-CoV-2 during the early pandemic was unclear.AimWe aimed to review studies on the transmission of SARS-CoV-2 by children during the early pandemic.MethodsWe searched MEDLINE, Embase, the Cochrane Library, Europe PubMed Central and the preprint servers medRxiv and bioRxiv from 30 December 2019 to 10 August 2020. We assessed the quality of included studies using a series of questions adapted from related tools. We provide a narrative synthesis of the results.ResultsWe identified 28 studies from 17 countries. Ten of 19 studies on household and close contact transmission reported low rates of child-to-adult or child-to-child transmission. Six studies investigated transmission of SARS-CoV-2 in educational settings, with three studies reporting 183 cases from 14,003 close contacts who may have contracted COVID-19 from children index cases at their schools. Three mathematical modelling studies estimated that children were less likely to infect others than adults. All studies were of low to moderate quality.ConclusionsDuring the early pandemic, it appeared that children were not substantially contributing to household transmission of SARS-CoV-2. School-based studies indicated that transmission rates in this setting were low. Large-scale studies of transmission chains using data collected from contact tracing and serological studies detecting past evidence of infection would be needed to verify our findings.

A cost-effectiveness and budget impact analysis of C-reactive protein point-of-care testing to guide antibiotic prescribing for acute respiratory tract infections in primary care settings in Ireland: a decision-analytic model.

BACKGROUND: Approximately 60% of antibiotics issued in primary care are for acute respiratory tract infections (RTIs), which are largely self-limiting and do not require antibiotics. Point-of-care testing (POCT) devices that measure C-reactive protein (CRP)-a biomarker for infection-can be used to guide prescribing decisions. OBJECTIVE: We evaluated the cost-effectiveness and budget impact of a national CRP POCT program to guide antibiotic prescribing for acute RTIs in primary care in Ireland. METHODS: We compared CRP POCT with and without enhanced communication skills training of general practitioners against usual care. A probabilistic decision tree was used to investigate cost-effectiveness from the perspective of the healthcare system. The model considered outcomes for the Irish population over a 5-year time horizon. Inputs were synthesized from published studies. Cost-effectiveness was estimated using an incremental cost per prescription avoided. RESULTS: CRP POCT with and without communication training were more costly but more effective than usual care over 5 years. CRP POCT alone was dominated, while the combined intervention had a cost per prescription avoided of €111 (95% CI: €45-243) versus usual care. The budget impact was costly over 5 years, but potential budget savings were available depending on the implementation scenario. The findings were largely robust to sensitivity analyses. CONCLUSIONS: CRP POCT reduces antibiotic prescribing, but increases healthcare costs. The most cost-effective program of CRP POCT includes enhanced communication skills training. Further research on the impact of CRP POCT beyond 5 years is warranted, as well as the potential impact on antimicrobial resistance.

The relationship between procedural volume and patient outcomes for percutaneous coronary interventions: a systematic review and meta-analysis.

BACKGROUND: The relationship between procedural volume and outcomes for percutaneous coronary interventions (PCI) is contentious, with previous reviews suggesting an inverse volume-outcome relationship. The aim of this study was to systematically review contemporary evidence to re-examine this relationship. METHODS: A systematic review and meta-analysis was undertaken to examine the relationship between PCI procedural volume (both at hospital- and operator-levels) and outcomes in adults. The primary outcome was mortality. The secondary outcomes were complications, healthcare utilisation and process outcomes. Searches were conducted from 1 January 2008 to 28 May 2019. Certainty of the evidence was assessed using 'Grading of Recommendations, Assessment, Development and Evaluations' (GRADE). Screening, data extraction, quality appraisal and GRADE assessments were conducted independently by two reviewers. RESULTS: Of 1,154 unique records retrieved, 22 observational studies with 6,432,265 patients were included. No significant association was found between total PCI hospital volume and mortality (odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.69-1.03, I 2 = 86%). A temporal trend from significant to non-significant pooled effect estimates was observed. The pooled effect estimate for mortality was found to be significantly in favour of high-volume operators for total PCI procedures (OR: 0.77, 95% CI: 0.63-0.94, I 2 = 93%), and for high-volume hospitals for primary PCI procedures (OR: 0.77, 95% CI: 0.62-0.94, I 2 = 78%). Overall, GRADE certainty of evidence was 'very low'. There were mixed findings for secondary outcomes. CONCLUSIONS: A volume-outcome relationship may exist in certain situations, although this relationship appears to be attenuating with time, and there is 'very low' certainty of evidence. While volume might be important, it should not be the only standard used to define an acceptable PCI service and a broader evaluation of quality metrics should be considered that encompass patient experience and clinical outcomes. Systematic review registration: PROSPERO, CRD42019125288.

Immune response following infection with SARS-CoV-2 and other coronaviruses: A rapid review.

In this review, we systematically searched and summarized the evidence on the immune response and reinfection rate following SARS-CoV-2 infection. We also retrieved studies on SARS-CoV and MERS-CoV to assess the long-term duration of antibody responses. A protocol based on Cochrane rapid review methodology was adhered to and databases were searched from 1/1/2000 until 26/5/2020. Of 4744 citations retrieved, 102 studies met our inclusion criteria. Seventy-four studies were retrieved on SARS-CoV-2. While the rate and timing of IgM and IgG seroconversion were inconsistent across studies, most seroconverted for IgG within 2 weeks and 100% (N = 62) within 4 weeks. IgG was still detected at the end of follow-up (49-65 days) in all patients (N = 24). Neutralizing antibodies were detected in 92%-100% of patients (up to 53 days). It is not clear if reinfection with SARS-CoV-2 is possible, with studies more suggestive of intermittent detection of residual RNA. Twenty-five studies were retrieved on SARS-CoV. In general, SARS-CoV-specific IgG was maintained for 1-2 years post-infection and declined thereafter, although one study detected IgG up to 12 years post-infection. Neutralizing antibodies were detected up to 17 years in another study. Three studies on MERS-CoV reported that IgG may be detected up to 2 years. In conclusion, limited early data suggest that most patients seroconvert for SARS-CoV-2-specific IgG within 2 weeks. While the long-term duration of antibody responses is unknown, evidence from SARS-CoV studies suggest SARS-CoV-specific IgG is sustained for 1-2 years and declines thereafter.

Alternative clinical specimens for the detection of SARS-CoV-2: A rapid review.

The collection of nasopharyngeal swabs to test for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an invasive technique with implications for patients and clinicians. Alternative clinical specimens from the upper respiratory tract may offer benefits in terms of collection, comfort and infection risk. The objective of this review was to synthesise the evidence for detection of SARS-CoV-2 ribonucleic acid (RNA) using reverse transcription polymerase chain reaction (RT-PCR) tested saliva or nasal specimens compared with RT-PCR tested nasopharyngeal specimens. Searches were conducted in PubMed, Embase, Europe PMC and NHS evidence from December 2019 to 20 July 2020. Eighteen studies were identified; 12 for saliva, four for nasal and two included both specimen types. For saliva-based studies, the proportion of saliva samples testing positive relative to all positive samples in each study ranged from 82.9% to 100%; detection in nasopharyngeal specimens ranged from 76.7% to 100%; positive agreement between specimens for overall detection ranged from 65.4% to 100%. For nasal-based studies, the proportion of nasal swabs testing positive relative to all positive samples in each study ranged from 81.9% to 100%; detection in nasopharyngeal specimens ranged from 70% to 100%; positive agreement between specimens for overall detection ranged from 62.3% to 100%. The results indicate an inconsistency in the detection of SARS-CoV-2 RNA in the specimen types included, often with neither the index nor the reference of interest detecting all known cases. Depending on the test environment, these clinical specimens may offer a viable alternative to standard. However, at present the evidence is limited, of variable quality, and relatively inconsistent.

SARS-CoV-2 detection, viral load and infectivity over the course of an infection.

OBJECTIVES: To summarise the evidence on the detection pattern and viral load of SARS-CoV-2 over the course of an infection (including any asymptomatic or pre-symptomatic phase), and the duration of infectivity. METHODS: A systematic literature search was undertaken in PubMed, Europe PubMed Central and EMBASE from 30 December 2019 to 12 May 2020. RESULTS: We identified 113 studies conducted in 17 countries. The evidence from upper respiratory tract samples suggests that the viral load of SARS-CoV-2 peaks around symptom onset or a few days thereafter, and becomes undetectable about two weeks after symptom onset; however, viral loads from sputum samples may be higher, peak later and persist for longer. There is evidence of prolonged virus detection in stool samples, with unclear clinical significance. No study was found that definitively measured the duration of infectivity; however, patients may not be infectious for the entire duration of virus detection, as the presence of viral ribonucleic acid may not represent transmissible live virus. CONCLUSION: There is a relatively consistent trajectory of SARS-CoV-2 viral load over the course of COVID-19 from respiratory tract samples, however the duration of infectivity remains uncertain.

Quantifying patient preferences for symptomatic breast clinic referral: a decision analysis study.

OBJECTIVES: Decision analysis study that incorporates patient preferences and probability estimates to investigate the impact of women's preferences for referral or an alternative strategy of watchful waiting if faced with symptoms that could be due to breast cancer. SETTING: Community-based study. PARTICIPANTS: Asymptomatic women aged 30-60 years. INTERVENTIONS: Participants were presented with 11 health scenarios that represent the possible consequences of symptomatic breast problems. Participants were asked the risk of death that they were willing to take in order to avoid the health scenario using the standard gamble utility method. This process was repeated for all 11 health scenarios. Formal decision analysis for the preferred individual decision was then estimated for each participant. PRIMARY OUTCOME MEASURE: The preferred diagnostic strategy was either watchful waiting or referral to a breast clinic. Sensitivity analysis was used to examine how each varied according to changes in the probabilities of the health scenarios. RESULTS: A total of 35 participants completed the interviews, with a median age 41 years (IQR 35-47 years). The majority of the study sample was employed (n=32, 91.4%), with a third-level (university) education (n=32, 91.4%) and with knowledge of someone with breast cancer (n=30, 85.7%). When individual preferences were accounted for, 25 (71.4%) patients preferred watchful waiting to referral for triple assessment as their preferred initial diagnostic strategy. Sensitivity analysis shows that referral for triple assessment becomes the dominant strategy at the upper probability estimate (18%) of breast cancer in the community. CONCLUSIONS: Watchful waiting is an acceptable strategy for most women who present to their general practitioner (GP) with breast symptoms. These findings suggest that current referral guidelines should take more explicit account of women's preferences in relation to their GPs initial management strategy.

Health and use of health services of people who are homeless and at risk of homelessness who receive free primary health care in Dublin.

BACKGROUND: Homeless populations experience poorer physical and mental health, and more barriers to accessing adequate healthcare. This study investigates the health of this population, following the provision of a free to access primary care service for homeless people in Dublin (Safetynet). The health of this group will be compared to previous studies on homelessness conducted in Dublin prior to the establishment of this service (in 1997 and 2005). METHODS: Participants were recruited through Safetynet clinics. A 133-item questionnaire was administered to determine participants' physical and mental well-being, use of health services and healthcare needs. Prescription data was extracted from participants' electronic health records. RESULTS: A total of 105 participants were recruited. The majority were < 45 years of age (69%), male (75%), single (52%), Irish (74%) and had children (52%). Multimorbidity was common; with 5.3 ± 2.7 (mean ± SD) physical conditions reported per person. A large proportion of participants had at some point received a formal diagnosis of a mental health condition (70%; 73/105), including depression (50%; 52/105), addiction disorder (39%), anxiety (36%; 38/105), schizophrenia (13%; 14/105) and bipolar disorder (6%; 6/105). With regards to illicit drug use, 60% (63/105) of participants reported ever using drugs, while 33% (35/105) reported being active drug users. Based on AUDIT C criteria, 53% had an alcohol problem. Compared to previous studies, participants reported more positive ratings of health (70% vs. 57% in 1997 and 46% in 2005). The proportion of participants on one or more prescription medication was higher than in previous studies (81% vs. 32% in 1997 and 49% in 2005) and there was a decrease in attendance at outpatients departments (17% vs. 27% in 2005) and a trend towards a decrease in attendance at Accident and Emergency departments (A & E) (29% vs. 37% in 2005). CONCLUSIONS: This vulnerable population has many physical and mental health problems. Use of drugs, alcohol and smoking is common. Following the establishment of Safetynet, self-reported health was rated more positively, there was also a decrease in the use of A & E and outpatient services and an increase in prescription medicines.

Prevalence of prescribing in pregnancy using the Irish primary care research network: a pilot study.

BACKGROUND: To establish the prevalence and patterns of prescribing to pregnant women in an Irish primary care setting. METHODS: We reviewed electronic healthcare records routinely collected in primary care, of pregnant women attending nine Dublin-based General Practices affiliated to the Irish Primary Care Research Network (IPCRN) for antenatal care between January 2007 and October 2013 (n = 2,361 pregnancies). RESULTS: Excluding folic acid, 46.8% (n = 1,104) of pregnant women were prescribed at least one medication. Amoxicillin (11.1%, n = 263) and co-amoxiclav (8.0%, n = 190) were the most commonly prescribed medication followed by topical clotrimazole (4.9%, n = 117), salbutamol inhalers (4.1%, n = 96) and paracetamol (4.0%, n = 95). General Medical Services (GMS) patients were more likely to receive a prescription than private patients (OR 2.81; 95%CI (2.28, 3.47)). We applied the US FDA pregnancy-risk categories as a proxy measure of prescribing appropriateness, with FDA Category D and X medications considered inappropriate. FDA Category D drugs were prescribed in 5.9% (n = 140) of pregnancies. FDA Category X drugs were prescribed in 4.9% (n = 116) of pregnancies but after exclusion of oral contraceptives, progestogens, infertility treatments Category X medications were prescribed in 0.6% (n = 13) of pregnancies. After the initial antenatal consultation the prescribing prevalence of FDA Category D medications reduced to 4.7% (n = 110) and Category X to 3.1% (n = 72). CONCLUSIONS: The overall prevalence of prescribing to pregnant women in our cohort is low compared to studies internationally, however similar levels of prescribing for FDA Category D and X were found. Following the initial antenatal consultation levels of prescribing of the FDA Category D and X medications reduced, however there is potential to further reduce their use in early pregnancy. The IPCRN database has provided valuable information on the current practice of antenatal prescribing within this pilot group of practices however it is limited by the absence of morbidity and pregnancy outcome data.

Developing an international register of clinical prediction rules for use in primary care: a descriptive analysis.

PURPOSE: We describe the methodology used to create a register of clinical prediction rules relevant to primary care. We also summarize the rules included in the register according to various characteristics. METHODS: To identify relevant articles, we searched the MEDLINE database (PubMed) for the years 1980 to 2009 and supplemented the results with searches of secondary sources (books on clinical prediction rules) and personal resources (eg, experts in the field). The rules described in relevant articles were classified according to their clinical domain, the stage of development, and the clinical setting in which they were studied. RESULTS: Our search identified clinical prediction rules reported between 1965 and 2009. The largest share of rules (37.2%) were retrieved from PubMed. The number of published rules increased substantially over the study decades. We included 745 articles in the register; many contained more than 1 clinical prediction rule study (eg, both a derivation study and a validation study), resulting in 989 individual studies. In all, 434 unique rules had gone through derivation; however, only 54.8% had been validated and merely 2.8% had undergone analysis of their impact on either the process or outcome of clinical care. The rules most commonly pertained to cardiovascular disease, respiratory, and musculoskeletal conditions. They had most often been studied in the primary care or emergency department settings. CONCLUSIONS: Many clinical prediction rules have been derived, but only about half have been validated and few have been assessed for clinical impact. This lack of thorough evaluation for many rules makes it difficult to retrieve and identify those that are ready for use at the point of patient care. We plan to develop an international web-based register of clinical prediction rules and computer-based clinical decision support systems.

The Alvarado score for predicting acute appendicitis: a systematic review.

BACKGROUND: The Alvarado score can be used to stratify patients with symptoms of suspected appendicitis; the validity of the score in certain patient groups and at different cut points is still unclear. The aim of this study was to assess the discrimination (diagnostic accuracy) and calibration performance of the Alvarado score. METHODS: A systematic search of validation studies in Medline, Embase, DARE and The Cochrane library was performed up to April 2011. We assessed the diagnostic accuracy of the score at the two cut-off points: score of 5 (1 to 4 vs. 5 to 10) and score of 7 (1 to 6 vs. 7 to 10). Calibration was analysed across low (1 to 4), intermediate (5 to 6) and high (7 to 10) risk strata. The analysis focused on three sub-groups: men, women and children. RESULTS: Forty-two studies were included in the review. In terms of diagnostic accuracy, the cut-point of 5 was good at 'ruling out' admission for appendicitis (sensitivity 99% overall, 96% men, 99% woman, 99% children). At the cut-point of 7, recommended for 'ruling in' appendicitis and progression to surgery, the score performed poorly in each subgroup (specificity overall 81%, men 57%, woman 73%, children 76%). The Alvarado score is well calibrated in men across all risk strata (low RR 1.06, 95% CI 0.87 to 1.28; intermediate 1.09, 0.86 to 1.37 and high 1.02, 0.97 to 1.08). The score over-predicts the probability of appendicitis in children in the intermediate and high risk groups and in women across all risk strata. CONCLUSIONS: The Alvarado score is a useful diagnostic 'rule out' score at a cut point of 5 for all patient groups. The score is well calibrated in men, inconsistent in children and over-predicts the probability of appendicitis in women across all strata of risk.

Predicting streptococcal pharyngitis in adults in primary care: a systematic review of the diagnostic accuracy of symptoms and signs and validation of the Centor score.

BACKGROUND: Stratifying patients with a sore throat into the probability of having an underlying bacterial or viral cause may be helpful in targeting antibiotic treatment. We sought to assess the diagnostic accuracy of signs and symptoms and validate a clinical prediction rule (CPR), the Centor score, for predicting group A ß-haemolytic streptococcal (GABHS) pharyngitis in adults (> 14 years of age) presenting with sore throat symptoms. METHODS: A systematic literature search was performed up to July 2010. Studies that assessed the diagnostic accuracy of signs and symptoms and/or validated the Centor score were included. For the analysis of the diagnostic accuracy of signs and symptoms and the Centor score, studies were combined using a bivariate random effects model, while for the calibration analysis of the Centor score, a random effects model was used. RESULTS: A total of 21 studies incorporating 4,839 patients were included in the meta-analysis on diagnostic accuracy of signs and symptoms. The results were heterogeneous and suggest that individual signs and symptoms generate only small shifts in post-test probability (range positive likelihood ratio (+LR) 1.45-2.33, -LR 0.54-0.72). As a decision rule for considering antibiotic prescribing (score ≥ 3), the Centor score has reasonable specificity (0.82, 95% CI 0.72 to 0.88) and a post-test probability of 12% to 40% based on a prior prevalence of 5% to 20%. Pooled calibration shows no significant difference between the numbers of patients predicted and observed to have GABHS pharyngitis across strata of Centor score (0-1 risk ratio (RR) 0.72, 95% CI 0.49 to 1.06; 2-3 RR 0.93, 95% CI 0.73 to 1.17; 4 RR 1.14, 95% CI 0.95 to 1.37). CONCLUSIONS: Individual signs and symptoms are not powerful enough to discriminate GABHS pharyngitis from other types of sore throat. The Centor score is a well calibrated CPR for estimating the probability of GABHS pharyngitis. The Centor score can enhance appropriate prescribing of antibiotics, but should be used with caution in low prevalence settings of GABHS pharyngitis such as primary care.

Optimized retrieval of primary care clinical prediction rules from MEDLINE to establish a Web-based register.

OBJECTIVES: Identifying clinical prediction rules (CPRs) for primary care from electronic databases is difficult. This study aims to identify a search filter to optimize retrieval of these to establish a register of CPRs for the Cochrane Primary Health Care field. STUDY DESIGN AND SETTING: Thirty primary care journals were manually searched for CPRs. This was compared with electronic search filters using alternative methodologies: (1) textword searching; (2) proximity searching; (3) inclusion terms using specific phrases and truncation; (4) exclusion terms; and (5) combinations of methodologies. RESULTS: We manually searched 6,344 articles, revealing 41 CPRs. Across the 45 search filters, sensitivities ranged from 12% to 98%, whereas specificities ranged from 43% to 100%. There was generally a trade-off between the sensitivity and specificity of each filter (i.e., the number of CPRs and total number of articles retrieved). Combining textword searching with the inclusion terms (using specific phrases) resulted in the highest sensitivity (98%) but lower specificity (59%) than other methods. The associated precision (2%) and accuracy (60%) were also low. CONCLUSION: The novel use of combining textword searching with inclusion terms was considered the most appropriate for updating a register of primary care CPRs where sensitivity has to be optimized.

Validity of British Thoracic Society guidance (the CRB-65 rule) for predicting the severity of pneumonia in general practice: systematic review and meta-analysis.

BACKGROUND: The CRB-65 score is a clinical prediction rule that grades the severity of community-acquired pneumonia in terms of 30-day mortality. AIM: The study sought to validate CRB-65 and assess its clinical value in community and hospital settings. DESIGN OF STUDY: Systematic review and meta-analysis of validation studies of CRB-65. METHOD: Medline (1966 to June 2009), Embase (1988 to November 2008), British Nursing Index (BNI) and PsychINFO were searched, using a diagnostic accuracy search filter combined with subject-specific terms. The derived (index) rule was used as a predictive model and applied to all validation studies. Comparison was made between the observed and predicted number of deaths stratified by risk group (low, intermediate, and high) and setting of care (community or hospital). Pooled results are presented as risk ratios (RRs) in terms of over-prediction (RR>1) or under-prediction (RR<1) of 30-day mortality. RESULTS: Fourteen validation studies totalling 397 875 patients are included. CRB-65 performs well in hospitalised patients, particularly in those classified as intermediate (RR 0.91, 95% confidence interval [CI] = 0.71 to 1.17) or high risk (RR 1.01, 95% CI = 0.87 to 1.16). In community settings, CRB-65 over-predicts the probability of 30-day mortality across all strata of predicted risk, low (RR 9.41, 95% CI = 1.75 to 50.66), intermediate (RR 4.84, 95% CI = 2.61 to 8.69), and high (RR 1.58, 95% CI = 0.59 to 4.19). CONCLUSION: CRB-65 performs well in stratifying severity of pneumonia and resultant 30-day mortality in hospital settings. In community settings, CRB-65 appears to over-predict the probability of 30-day mortality across all strata of predicted risk. Caution is needed when applying CRB-65 to patients in general practice.

A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency.

Polymorphisms in folate-related genes have emerged as important risk factors in a range of diseases including neural tube defects (NTDs), cancer, and coronary artery disease (CAD). Having previously identified a polymorphism within the cytoplasmic folate enzyme, MTHFD1, as a maternal risk factor for NTDs, we considered the more recently identified mitochondrial paralogue, MTHFD1L, as a candidate gene for NTD association. We identified a common deletion/insertion polymorphism, rs3832406, c.781-6823ATT(7-9), which influences splicing efficiency and is strongly associated with NTD risk. Three alleles of rs3832406 were detected in the Irish population with varying numbers of ATT repeats: Allele 1 consists of ATT(7), whereas Alleles 2 and 3 consist of ATT(8) and ATT(9), respectively. Allele 2 of this triallelic polymorphism showed a decreased case risk as demonstrated by case-control logistic regression (P=0.002) and by transmission disequilibrium test (TDT) (P=0.001), whereas Allele 1 showed an increased case risk. Allele 3 showed no influence on NTD risk and represents the lowest frequency allele (0.15). Additional single nucleotide polymorphism (SNP) genotyping in the same genomic region provides additional supportive evidence of an association. We demonstrate that two of the three alleles of rs3832406 are functionally different and influence the splicing efficiency of the alternate MTHFD1L mRNA transcripts.

Comparison of self-reported health & healthcare utilisation between asylum seekers and refugees: an observational study.

BACKGROUND: Adult refugees and asylum seekers living in Western countries experience a high prevalence of mental health problems, especially post traumatic stress disorder (PTSD), depression and anxiety. This study compares and contrasts the prevalence of health problems, and potential risk factors as well as the utilisation of health services by asylum seekers and refugees in the Irish context. METHODS: Cross sectional study using validated self reported health status questionnaires of adult asylum seekers (n = 60) and refugees (n = 28) from 30 countries, living in Ireland. Outcome measures included: general health status (SF-36), presence of PTSD symptoms and anxiety/depression symptoms. Data on chronic conditions and pre or post migration stressors are also reported. The two groups are compared for utilisation of the health care system and the use of over the counter medications. RESULTS: Asylum seekers were significantly more likely than refugees to report symptoms of PTSD (OR 6.3, 95% CI: 2.2-17.9) and depression/anxiety (OR 5.8, 95% CI: 2.2-15.4), while no significant difference was found in self-reported general health. When adjusted by multivariable regression, the presence of more than one chronic disease (OR 4.0, 95%CI: 1.3-12.7; OR 3.4, 95% CI: 1.2-10.1), high levels of pre migration stressors (OR 3.6, 95% CI: 1.1-11.9; OR 3.3, 95% CI: 1.0-10.4) or post migration stressors (OR 17.3, 95% CI: 4.9-60.8; OR 3.9, 95% CI: 1.2-12.3) were independent predictors of self reported PTSD or depression/anxiety symptoms respectively, however, residence status was no longer significantly associated with PTSD or depression/anxiety. Residence status may act as a marker for other explanatory variables; our results show it has a strong relationship with post migration stressors (chi2 = 19.74, df = 1, P < 0.001).In terms of health care utilisation, asylum seekers use GP services more often than refugees, while no significant difference was found between these groups for use of dentists, medication, hospitalisation or mental health services. CONCLUSION: Asylum seekers have a higher level of self reported PTSD and depression/anxiety symptoms compared to refugees. However, residence status appears to act as a marker for post migration stressors. Compared to refugees, asylum seekers utilise GP services more often, but not mental health services.

Polymorphism in the human DJ-1 gene is not associated with sporadic dementia with Lewy bodies or Parkinson's disease.

Genetic analysis of early onset Parkinson's disease (PD) has indicated that the mutation DJ-1 gene is one cause of autosomal recessive PD. Its role in the development of late onset PD and other Lewy body associated disorders such as dementia with Lewy bodies (DLB) is however unknown. We have therefore determined the influence of a common polymorphism in the DJ-1 gene that shows strong linkage disequilibrium with other DJ-1 polymorphisms, in late onset PD and DLB. No alteration in the frequency of the intron 1 deletion allele was seen in PD or DLB, nor were DJ-1 genotypes altered by disease. Stratification of the cases according to the apolipoprotein E epsilon4 allele additionally failed to show any significant association. The DJ-1 gene does not appear to be a significant risk factor for late onset Lewy body disease in this population.

Regulation of attention and response to therapy in dementia by butyrylcholinesterase.

OBJECTIVES: To determine the response of patients with different butyrylcholinesterase genotypes to therapy, and the influence of butyrylcholinesterase on cognition. Acetylcholine plays a key role in attention and memory and reduced cortical acetylcholine is associated with the severity of dementia. Inhibitors of the enzyme acetylcholinesterase are an effective dementia treatment, though the role of the related enzyme butyrylcholinesterase is less well understood. METHODS: We examined the response of a cohort of dementia patients enrolled in a trial of a cholinesterase inhibitor who had been genotyped at the butyrylcholinesterase locus. Additionally a prospectively assessed cohort of dementia patients was genotyped and rate of cognitive decline examined, along with baseline cognitive performance in a group of elderly non-demented individuals. We identified that the presence of reduced-activity butyrylcholinesterase variants correlates with preserved attentional performance and reduced rate of cognitive decline. During cholinesterase inhibitor therapy, patients with normal butyrylcholinesterase show improved attention, though patients carrying reduced-activity enzyme do not, possibly due to being at ceiling performance. Butyrylcholinesterase did not however affect attentional performance in non-demented individuals with mild cognitive impairment. CONCLUSIONS: These findings indicate that the butyrylcholinesterase enzyme is a major regulator of attention especially in cholinergic deficiency states through its ability to hydrolyse acetylcholine. Pharmacologic manipulation of this enzyme may be a viable strategy in dementia treatment and, with butyrylcholinesterase genotyping, may provide pharmacogenomic treatment of dementia.