Causes of chest pain in primary care – a systematic review and meta-analysis

Aim

To investigate the frequencies of different and relevant underlying etiologies of chest pain in general practice.

Methods

We systematically searched PubMed and EMBASE. Two reviewers independently rated the eligibility of publications and assessed the risk of bias of included studies. We extracted data to calculate the relative frequencies of different underlying conditions and investigated the variation across studies using forest plots, I², tau², and prediction intervals. With respect to unexplained heterogeneity, we provided qualitative syntheses instead of pooled estimates.

Results

We identified 11 eligible studies comprising about 6500 patients. The overall risk of bias was rated as low in 6 studies comprising about 3900 patients. The relative frequencies of different conditions as the underlying etiologies of chest pain reported by these studies ranged from 24.5 to 49.8% (chest wall syndrome), 13.8 to 16.1% (cardiovascular diseases), 6.6 to 11.2% (stable coronary heart disease), 1.5 to 3.6% (acute coronary syndrome/myocardial infarction), 10.3 to 18.2% (respiratory diseases), 9.5 to 18.2% (psychogenic etiologies), 5.6 to 9.7% (gastrointestinal disorders), and 6.0 to 7.1% (esophageal disorders).

Conclusion

This information may be of practical value for general practitioners as it provides the pre-test probabilities for a range of underlying diseases and may be suitable to guide the diagnostic process.Chest pain is a common complaint in all health care settings and can be caused by a wide range of conditions – from diseases with favorable prognosis like musculoskeletal disorders to acute and potentially life-threatening conditions like coronary heart disease (1). Most patients with chest pain are initially seen by their general practitioner (GP) who faces the challenge to triage them. To fulfill this task, GPs need to know the relevant etiologies and their respective frequencies. In an intuitive process of probabilistic reasoning GPs combine the initial likelihood for a given etiology (pre-test probability) with their findings from the patient’s history and the clinical examination in order to reach a final or at least tentative diagnosis (post-test probability) (2,3).Important information is provided by studies of symptoms, which investigate patients presenting with a defined symptom in a health care setting. In particular, they (4) aim to answer three main questions: How often do patients present with the respective symptom? What are the underlying conditions and their respective frequencies? What is the prognosis of these patients? While in the medical literature there are many studies on effects of treatment, causation of disease, or on diagnostic tests, studies of symptoms are not performed as often. As the results of single studies can show large variations, it is desirable to summarize existing information in a systematic review.Therefore, we conducted a systematic review of studies investigating the symptom of chest pain in primary care. Since knowledge of relevant etiologies and their respective frequencies has the highest practical value for clinicians, we confine the current article to the reporting on this research question.     

Mercury as an environmental stimulus in the development of autoimmunity – A systematic review

Autoimmune diseases result from an interplay of genetic predisposition and factors which stimulate the onset of disease. Mercury (Hg), a well-established toxicant, is an environmental factor reported to be linked with autoimmunity. Hg exists in several chemical forms and is encountered by humans in dental amalgams, certain vaccines, occupational exposure, atmospheric pollution and seafood. Several studies have investigated the effect of the various forms of Hg, including elemental (Hg⁰), inorganic (iHg) and organic mercury (oHg) and their association with autoimmunity. In vitro studies using peripheral blood mononuclear cells (PBMC) from healthy participants have shown that methylmercury (MeHg) causes cell death at lower concentrations than iHg albeit exposure to iHg results in a more enhanced pro-inflammatory profile in comparison to MeHg. In vivo research utilising murine models susceptible to the development of metal-induced autoimmunity report that exposure to iHg results in a lupus-like syndrome, whilst mice exposed to MeHg develop autoimmunity without the formation of immune complexes. Furthermore, lower concentrations of IgE are detected in MeHg-treated animals in comparison with those treated with iHg. It appears that, oHg has a negative impact on animal models with existing autoimmunity. The research conducted on humans in this area is diverse in study design and the results are conflicting. There is currently no evidence to implicate a role for Hg⁰ exposure from dental amalgams in the development or perpetuation of autoimmune disease, apart from some suggestion of individual sensitivity. Several studies have consistently shown a positive correlation between iHg exposure and serum autoantibody concentrations in gold miners, although the clinical impact of iHg remains unknown. Furthermore, a limited number of studies have reported individuals with autoimmune disease have higher concentrations of blood Hg compared to healthy controls. In summary, it appears that iHg perpetuates markers of autoimmunity to a greater extent than oHg, albeit the impact on clinical outcomes in humans is yet to be elucidated.     

The risk of systemic lupus erythematosus associated with Epstein–Barr virus infection: a systematic review and meta-analysis

Previous systematic reviews have found a higher sero-prevalence of EBV antibodies in SLE patients compared with controls. Because many studies have been published, there is a need to apply more precise systematic review methods. We examined the association between EBV and SLE patients by conducting a systematic review and meta-analysis of case–control studies that examined the prevalence of EBV antibodies and the DNA-positive rate. We searched the MEDLINE and EMBASE databases from 1966 to 2018 with no language restrictions. The Mantel–Haenszel odds ratios (OR) for EBV antibody sero-positivity were calculated, and meta-analyses were conducted. Quality assessment was performed using a modified version of the Newcastle–Ottawa scale, and 33 studies were included. Most studies found a higher sero-prevalence of VCA IgG and EA IgG in SLE patients compared with controls. Meta-analysis demonstrated a significantly higher OR for sero-positivity to VCA IgG and EA IgG for SLE cases (2.06 [95% confidence interval (CI) 1.30–3.26, p = 0.002] and 7.70, [95% CI 4.64–12.76, p < 0.001], respectively). The overall OR for the DNA-positive rate for SLE patients compared with controls was 3.86 (95% CI 1.52–9.83, p = 0.005). Other antibodies, i.e., VCA IgA/IgM, EBNA IgA, and EA IgA/IgM, also demonstrated a significant difference between SLE patients and controls. These findings support previous systematic reviews; however, publication bias cannot be excluded. The methodological conduct of studies could be improved, particularly when selecting controls and analyses of laboratory conduct.

     

Pancreatitis and cholecystitis in primary acute symptomatic Epstein-Barr virus infection – Systematic review of the literature

Acute pancreatitis and acalculous cholecystitis have been occasionally reported in primary acute symptomatic Epstein-Barr virus infection. We completed a review of the literature and retained 48 scientific reports published between 1966 and 2016 for the final analysis. Acute pancreatitis was recognized in 14 and acalculous cholecystitis in 37 patients with primary acute symptomatic Epstein-Barr virus infection. In all patients, the features of acute pancreatitis or acalculous cholecystitis concurrently developed with those of primary acute symptomatic Epstein-Barr virus infection. Acute pancreatitis and acalculous cholecystitis resolved following a hospital stay of 25 days or less. Acalculous cholecystitis was associated with Gilbert-Meulengracht syndrome in two cases. In conclusion, this thorough analysis indicates that acute pancreatitis and acalculous cholecystitis are unusual but plausible complications of primary acute symptomatic Epstein-Barr virus infection. Pancreatitis and cholecystitis deserve consideration in cases with severe abdominal pain. These complications are usually rather mild and resolve spontaneously without sequelae.     

Acute cellular rejection in intra-abdominal solid organ allografts – immunology under the light microscope

Solid organ transplant of kidney, liver, pancreas, and small intestine is commonly performed as a cure for several chronic and occasionally acute causes of end-stage organ failure. Immune-mediated rejection on the one hand and immune compromise on the other are the two extremes of the problems patients and their physicians have to balance to create an optimum environment for both the grafts and the host. In achieving this balance the pathologist is often called upon to provide valuable information from allograft biopsies. While these organs have different structure, varying susceptibilities, and diverse clinical contexts that could influence graft well-being, they share the same basic immunologic mechanisms leading to rejection or complications of immunosuppression such as infections and post-transplant lymphoproliferative diseases. This review describes the underlying immunological mechanisms common to these organs, as well as describes specific and basic aspects of allograft injury that a pathologist, especially one who is only occasionally called upon to serve this function, should be aware of, with emphasis on acute cellular rejection.     

Pain perception in Parkinson’s disease: A systematic review and meta-analysis of experimental studies

While hyperalgesia (increased pain sensitivity) has been suggested to contribute to the increased prevalence of clinical pain in Parkinson’s disease (PD), experimental research is equivocal and mechanisms are poorly understood. We conducted a meta-analysis of studies comparing PD patients to healthy controls (HCs) in their response to experimental pain stimuli. Articles were acquired through systematic searches of major databases from inception until 10/2016. Twenty-six studies met inclusion criteria, comprising 1292 participants (PD = 739, HCs = 553). Random effects meta-analysis of standardized mean differences (SMD) revealed lower pain threshold (indicating hyperalgesia) in PD patients during unmedicated OFF states (SMD = 0.51) which was attenuated during dopamine-medicated ON states (SMD = 0.23), but unaffected by age, PD duration or PD severity. Analysis of 6 studies employing suprathreshold stimulation paradigms indicated greater pain in PD patients, just failing to reach significance (SMD = 0.30, p = 0.06). These findings (a) support the existence of hyperalgesia in PD, which could contribute to the onset/intensity of clinical pain, and (b) implicate dopamine deficiency as a potential underlying mechanism, which may present opportunities for the development of novel analgesic strategies.     

Prospective biomarkers of Alzheimer’s disease: A systematic review and meta-analysis

ObjectiveAlzheimer’s disease (AD) involves a series of pathological changes and some biomarkers were reported to assist in monitoring and predicting disease progression before the emergence of clinical symptoms. We aimed to identify prospective biomarkers and quantify their effect on AD progression.MethodsPubMed, EMBASE and Web of Science databases were searched for prospective cohort studies published up to October 2021. Eligible studies were included, and the available data were extracted. Meta-analyses were conducted based on random-effect models. Relative risk (RR) with 95% confidence interval (CI) was adopted as the final effect size.ResultsTotally 48,769 articles were identified, of which 84 studies with 20 prospective biomarkers were included in meta-analyses. In the present study, 15 biomarkers were associated with AD progression, comprising CSF Aβ42 (RR=2.49, 95%CI=1.68–3.69), t-tau (RR=1.88, 95%CI=1.49–2.37), p-tau (RR=1.74, 95%CI=1.37–2.21), tau/Aβ42 ratio (RR=5.11, 95%CI=2.01–13.00); peripheral blood Aβ42/Aβ40 (RR=1.26, 95%CI=1.05–1.51), t-tau (RR=1.33, 95%CI=1.08–1.64), NFL (RR=1.75, 95%CI=1.07–2.87); whole, left and right hippocampal volume (HV) (whole: RR=1.65, 95%CI=1.39–1.95; left: RR=2.60, 95%CI=1.02–6.64; right: RR=1.43, 95%CI=1.23–1.66), entorhinal cortex (EC) volume (RR=1.69, 95%CI=1.24–2.30), medial temporal lobe atrophy (MTA) (RR=1.52, 95%CI=1.33–1.74), 18 F-FDG PET (RR=2.24, 95%CI=1.29–3.89), 11 C-labeled Pittsburgh Compound B PET (11 C-PIB PET) (RR=3.91, 95%CI=1.06–14.41); APOE ε4 (RR=2.16, 1.83–2.55). A total of 70 articles were included in the qualitative review, in which 61 biomarkers were additionally associated with AD progression.ConclusionCSF Aβ42, t-tau, p-tau, tau/Aβ42; peripheral blood t-tau, Aβ42/Aβ40, NFL; whole, left and right HV, EC volume, MTA, 18 F-FDG PET, 11 C-PIB PET; APOE ε4 may be promising prospective biomarkers for AD progression.     

Cryptococcus and cryptococcosis in Iran during 1969–2019: A systematic review and meta-analysis

ObjectiveLimited data are available on the epidemiology and etiology of cryptococcal infections in the Middle East. We aimed to conduct the systematic review and meta-analysis to summarize the epidemiological data on prevalence of Cryptococcus species complexes in trees and their surroundings, bird guano and secretions, animals, and highlight the reported episodes of cryptococcosis in Iran.Materials and methodsTwelve databases, including PubMed, Science Direct, Scopus, Proquest, Google Scholar, Embase, and the ISI Web of Science, as well as the national databases, from January 1969 to October 2019 were searched. Furthermore, gray literature (e.g., thesis, congress abstracts) was evaluated using Iran Doc and www.thesis.research.ac.ir. Search process was accomplished on English or Persian language articles using the following keywords: “Cryptococcus”, “Cryptococcosis”, “invasive fungal infection”, “Humans”, “Birds”, “Pigeon”, “Animals”, “Tree”, “Eucalyptus”, and “Iran”, both alone and in combination.ResultsOverall 36 studies were eligible regarding Cryptococcus and cryptococcosis in Iran. The total prevalence rates of Cryptococcus species in the tree was 4.7% (95% CI: 2.3–7.8), and in bird guano was 20.4% (95% CI: 10.7–32.2). Cryptococcosis in animal, and human were 1.7% (95% CI: 0.01–5.1), and 2.8% (95% CI: 0.7v6.1), respectively. The highest prevalence of Cryptococcus in the trees (14.6%), and bird guano (89.4%) in Khorasan, animals (8.9%) in Chaharmahal and Bakhtiari, and human (4.4%) in Mazandaran provinces were reported.ConclusionsGiven the significant risk of Cryptococcus species for susceptible humans, mainly HIV-infected patients, it seems quite necessary to adopt concrete preventive strategies to pinpoint the environmental habitats of this yeast.     

Development of the concept of patient-centredness – A systematic review

ObjectivePatient-centredness is often linked to high-quality patient care, but the concept is not well-defined. This study aims to provide an overview of how patient-centredness has been defined in the literature since Mead and Bower’s review in 2000, and to provide an updated definition of the concept.Method & designWe performed a systematic literature search in PubMed to identify original articles with a sufficient definition of patient-centredness. We analysed extracted data defining patient-centredness.ResultsEighty articles were included. The dimensions “biopsychosocial”, “patient-as-person”, “sharing power and responsibility” and “therapeutic alliance” corresponded to four of five dimensions described by Mead and Bower. “Coordinated care” was a new dimension.ConclusionThe identified dimensions are encompassed by three elements: the patient, the doctor-patient relationship and the framework of care i.e. the health care system. The additional focus on coordinated care could reflect increasing complexity of the health care system.Practice implicationsNarrowing down the understanding of patient-centredness to these three focus areas, viz. 1) understanding of the patients’ experience of the illness in their life situation, 2) the professional’s relationship with the patient, and 3) coordination of care in the system, could make the operationalisation and implementation of a patient-centred approach more manageable.     

Beta-adrenergic drugs and risk of Parkinson’s disease: A systematic review and meta-analysis

BackgroundParkinson’s Disease (PD) is a neurodegenerative disorder manifested by rest tremor, rigidity, bradykinesia, and postural instability. Recent pharmaco-epidemiological studies evaluating beta-adrenergic drug use and risk of PD have reported conflicting findings.ObjectivesThis systematic review and meta-analyses evaluate the association between beta-adrenergic (agonists and antagonists) drugs’ use and PD.MethodsAn electronic literature search of eight databases was performed from inception to July 2021 to identify pharmaco-epidemiological studies (case-control and cohort) reporting the risk of PD in beta-adrenergic users compared to non-users. We used the generic inverse variance method and RevMan (5.3.5) to estimate pooled adjusted risk ratios (aRRs) of PD using a random-effects model.ResultsOf 3168 records, 15 studies (10 case-control; five cohort) with 6508,877 participants, including 87,011 PD cases, were included. In the pooled analysis (n = 10) including any beta-antagonist users, compared with non-users, the aRR for PD was 1.19 (CI: 1.05,1.35); for any beta-agonist users (n = 8) aRR for PD was 0.87 (CI: 0.78,0.97). Propranolol users had a significantly increased risk of PD (aRR:1.91; CI:1.20,3.06), whereas salbutamol use was associated with reduced risk of PD (aRR:0.95; CI:0.92,0.99). Significant heterogeneity (I² >87%) was observed, but the majority (n = 13) of the studies were of high quality, based on the JBI tool.ConclusionsBeta-antagonist use was associated with a modestly increased risk of PD, whereas beta-agonist use was associated with a modest decreased risk of PD. Future epidemiological studies should address the issues of protopathic bias and indirect association using appropriate epidemiological methods.     

Computerized cognitive training in Parkinson’s disease: A systematic review and meta-analysis

Cognitive impairment is a central non-motor symptom of Parkinson’s disease (PD), and there are no established treatments. Computerized cognitive training (CCT) is a safe and efficacious strategy but its efficacy in PD is unclear. We aimed to investigate the efficacy of CCT on cognitive, psychosocial and daily function, and assess potential effect moderators in people with PD without dementia. Randomized controlled trials of CCT were included in multivariate meta-analyses and meta-regressions. Seventeen studies (16 trials) encompassing 679 participants were included. The pooled effect of CCT relative to control was small and statistically significant for overall cognitive function (g=0.16; 95% CI 0.02–0.29). There was robust evidence for benefit on clinical measures of global cognition across 10 trials (g=0.33; 95% CI 0.19–0.48), especially in PD with mild cognitive impairment (PD-MCI), as well as on individual cognitive domains. Greater CCT dose and PD-MCI population were associated with larger effect sizes, but no statistically significant differences were found between subgroups. There was no significant difference in the efficacy of home-based compared to supervised training. Our findings suggest that CCT is associated with cognitive benefits in PD, including when delivered remotely. Larger, well-powered trials are warranted to examine what specific CCT regimens are most likely to promote cognitive and everyday functioning in the long-term.     

Are worksite interventions effective in increasing physical activity? A systematic review and meta-analysis

Abstract

Worksite interventions have the potential to reach a broad and captive audience and overcome one of the most widely cited barriers to increasing physical activity (PA), namely, a lack of time. A systematic review and random effects, meta-analysis assessed the effectiveness of worksite interventions to enhance PA. Thirty-seven intervention evaluations reporting 55 unique interventions met our inclusion criteria. Results indicate that, overall, worksite interventions have small, positive effects on PA and this effect is smaller when fitness, as opposed to self-report, outcome measures are reported (ds = 0.15 versus 0.23). Worksite interventions targeting PA specifically as opposed to general lifestyle change were found to be more effective whether evaluated in terms of increased fitness (0.29 versus 0.08) or increased self-reported PA (0.27 versus 0.14). Those promoting walking as opposed to other forms of PA were also more effective (0.54 versus 0.16). Interventions providing individually tailored information or instructions were not found to be more effective, but there was evidence that specific goal setting and goal review techniques may enhance fitness gains.     

Exercise interventions in Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials

AimsTo assess the potential multi-domain benefits of exercise interventions on patients with Alzheimer’s disease (AD), as well as to determine the specific effects of different exercise modalities (aerobic, strength, or combined training).MethodsA systematic search was conducted in PubMed and Web of Science until March 2021 for randomized controlled trials assessing the effect of exercise interventions (compared with no exercise) on patients with AD. Outcomes included cognitive function (mini-mental state examination [MMSE] test), physical function (e.g., 6-minute walking test [6MWT]), functional independence (Barthel index), and neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]). A random-effects meta-analysis was conducted.Results28 studies (total n = 1337 participants, average age 79–90 years) were included in the systematic review, of which 21 could be meta-analyzed. Although considerable heterogeneity was found, exercise interventions induced several significant benefits, including in Barthel index (n = 147 patients, mean difference [MD]=8.36 points, 95% confidence interval [CI]=0.63–16.09), 6MWT (n = 369, MD=84 m, 95% CI=44–133)), and NPI (n = 263, MD=−4.4 points, 95% CI=−8.42 to −0.38). Benefits were also found in the MMSE test, albeit significance was only reached for aerobic exercise (n = 187, MD=2.31 points, 95% CI 0.45–4.27).ConclusionsExercise interventions appear to exert multi-domain benefits in patients with AD.     

Is living alone a risk factor of frailty? A systematic review and meta-analysis

ObjectivesTo examine the association of living alone with frailty in cross-sectional and longitudinal studies by a systematic review and meta-analysis.DesignSystematic review and meta-analysis.Setting and participantsCommunity-dwelling older adults with a mean age of >60 years.MethodsA systematic search of the literature was conducted according to the PRISMA guidelines. We searched PubMed in February 2019 without language restriction for cohort studies that examined the associations between living alone and frailty. The reference lists of the relevant articles and the included articles were reviewed for additional studies. We calculated pooled odds ratios (OR) of the presence and incidence of frailty for living alone from cross-sectional and longitudinal studies.ResultsAmong the 203 studies identified, data of 44 cross-sectional studies (46 cohorts) and 6 longitudinal studies were included in this review. The meta-analysis showed that older adults living alone were more likely to be frail than those who were not (46 cohorts: pooled OR = 1.28, 95 % confidence interval (CI) = 1.13–1.45, p < 0.001). Gender-stratified analysis showed that only men living alone were at an increased risk of being frail (20 cohorts: pooled OR = 1.71, 95 %CI = 1.49–1.96), while women were not (22 cohorts: pooled OR = 1.00, 95 %CI = 0.83–1.20). No significant association was observed in a meta-analysis of longitudinal studies (6 cohorts: pooled OR = 0.88, 95 %CI = 0.76–1.03).Conclusions/ImplicationsThe present systematic review and meta-analysis showed a significant cross-sectional association between living alone and frailty, especially in men. However, living alone did not predict incident frailty. More studies controlling for important confounders, such as social networks, are needed to further enhance our understanding of how living alone is associated with frailty among older adults.     

Cortisol hypersecretion and the risk of Alzheimer’s disease: A systematic review and meta-analysis

BackgroundMorning cortisol levels have been reported to be elevated among patients with Alzheimer’s disease (AD); yet no meta-analysis has been conducted to confirm the existence and magnitude of this association. It also remains unclear whether hypercortisolism is a risk factor for AD.MethodsPubMed, EMBASE, and PsycINFO were systematically searched for eligible studies. Cross-sectional data were pooled using random-effects meta-analyses; the differences in morning cortisol levels between patients and cognitively normal controls were quantified. Longitudinal studies were qualitatively synthesised due to methodological heterogeneity.Results17,245 participants from 57 cross-sectional studies and 19 prospective cohort studies were included. Compared with cognitively normal controls, AD patients had moderately increased morning cortisol in blood (g = 0.422, P < 0.001; I² = 48.5 %), saliva (g = 0.540, P < 0.001; I² = 13.6 %), and cerebrospinal fluids (g = 0.565, P = 0.003; I² = 75.3 %). A moderate elevation of morning cortisol was also detected in cerebrospinal fluids from patients with mild cognitive impairment (MCI) versus controls (g = 0.309, P = 0.001; I² = 0.0 %). Cohort studies suggested that higher morning cortisol may accelerate cognitive decline in MCI or mild AD patients, but the results in cognitively healthy adults were inconsistent.ConclusionsMorning cortisol was confirmed to be moderately elevated in AD patients and may have diagnostic and prognostic values for AD.     

Cell adhesion molecules in endometrial cancer – A systematic review

Adhesive molecules are responsible for the cell-cell interaction and the surrounding intercellular environment creating normal tissue architecture. The role of adhesion proteins in cancer refers to angiogenesis, loss of tissue continuity, and deprivation of intercellular contact with the extracellular matrix, promoting the spread of cancer through the formation of metastases. The integrity of the epithelium is disturbed – with disturbances in the whole mechanism of cell connections, thanks to which cancer cells infiltrate surrounding tissues, and move to lymphatic and blood vessels. Adhesive molecules are divided into five main families: cadherin, catenins, integrins, the immunoglobulin superfamily and non-classical adhesion molecules. In the present review we describe the role of all five families of adhesive molecules in endometrial cancer.