ABSTRACT
The convergence of an interdisciplinary team of neurocritical care specialists to organize the Curing Coma Campaign is the first effort of its kind to coordinate national and international research efforts aimed at a deeper understanding of disorders of consciousness (DoC). This process of understanding includes translational research from bench to bedside, descriptions of systems of care delivery, diagnosis, treatment, rehabilitation, and ethical frameworks. The description and measurement of varying confounding factors related to hospital care was thought to be critical in furthering meaningful research in patients with DoC. Interdisciplinary hospital care is inherently varied across geographical areas as well as community and academic medical centers. Access to monitoring technologies, specialist consultation (medical, nursing, pharmacy, respiratory, and rehabilitation), staffing resources, specialty intensive and acute care units, specialty medications and specific surgical, diagnostic and interventional procedures, and imaging is variable, and the impact on patient outcome in terms of DoC is largely unknown. The heterogeneity of causes in DoC is the source of some expected variability in care and treatment of patients, which necessitated the development of a common nomenclature and set of data elements for meaningful measurement across studies. Guideline adherence in hemorrhagic stroke and severe traumatic brain injury may also be variable due to moderate or low levels of evidence for many recommendations. This article outlines the process of the development of common data elements for hospital course, confounders, and medications to streamline definitions and variables to collect for clinical studies of DoC.
Subject(s)
Brain Injuries, Traumatic , Common Data Elements , Humans , Consciousness Disorders/diagnosis , Consciousness Disorders/therapy , Consciousness Disorders/etiology , Brain Injuries, Traumatic/complications , HospitalsABSTRACT
BACKGROUND: White matter hyperintensities (WMHs) on MRI are associated with cognitive dysfunction, particularly slow processing speed and executive dysfunction. However, it is not clear whether WMHs burden affects isolated executive function independent of aging when WMHs are assessed separately in periventricular hyperintensity (PVH) and deep and subcortical white matter hyperintensity (DSWMH). PURPOSE: To assess the relationship between the degree of WMHs and the performance on the Trail Making Test (TMT), which can evaluate isolated ability of set-shifting and working memory. METHODS: 74 participants who visited our memory clinic and underwent the TMT subtests (TMT-A and TMT-B) and the Mini-Mental State Examination (MMSE). All subjects performed the TMT within the time limits and their MMSE scores were 24 or higher, and they were diagnosed as having normal cognition or mild cognitive impairment. The extent of PVH and DSWMH was graded from 0 to 3 using the Fazekas scale. We obtained testing time to complete the TMT-A and TMT-B, and calculated TMT-B minus TMT-A. We performed correlation analyses between the degree of WMHs and the time measures of the TMT subtests with adjustment of age. RESULTS: Average scores of the MMSE were not different among the groups either by PVH grade or by DSWMH grade. In contrast, average time required for the TMT-A, TMT-B, and TMT-B minus TMT-A increased along with exacerbation of PVH and DSWMH grade. After the adjustment of age we found significant association between only DSWMH grade and the time difference of TMT-B minus TMT-A. CONCLUSIONS: Exacerbation of PVH and DSWMH differentially affected isolated executive functions assessed by the TMT subtests independent of age and general cognitive function.
Subject(s)
Executive Function , White Matter , Humans , Trail Making Test , White Matter/diagnostic imaging , Cognition , Memory, Short-TermABSTRACT
BACKGROUND: The understanding of fatal familial insomnia (FFI), a rare neurodegenerative autosomal dominant prion disease, has improved in recent years as more cases were reported. This work aimed to propose new diagnostic criteria for FFI with optimal sensitivity, specificity, and likelihood ratio. METHODS: An international group of experts was established and 128 genetically confirmed FFI cases and 281 non-FFI prion disease controls are enrolled in the validation process. The new criteria were proposed based on the following steps with two-round expert consultation: (1) Validation of the 2018 FFI criteria. (2) Diagnostic item selection according to statistical analysis and expert consensus. (3) Validation of the new criteria. RESULTS: The 2018 criteria for possible FFI had a sensitivity of 90.6%, a specificity of 83.3%, with a positive likelihood ratio (PLR) of 5.43, and a negative likelihood ratio (NLR) of 0.11; and the probable FFI criteria had a sensitivity of 83.6%, specificity of 92.9%, with a PLR of 11.77, and a NLR of 0.18. The new criteria included more specific and/or common clinical features, two exclusion items, and summarized a precise and flexible diagnostic hierarchy. The new criteria for possible FFI had therefore reached a better sensitivity and specificity (92.2% and 96.1%, respectively), a PLR of 23.64 and a NLR of 0.08, whereas the probable FFI criteria showed a sensitivity of 90.6%, a specificity of 98.2%, with a PLR of 50.33 and a NLR of 0.095. CONCLUSIONS: We propose new clinical diagnostic criteria for FFI, for a better refining of the clinical hallmarks of the disease that ultimately would help an early recognition of FFI and a better differentiation from other prion diseases.
Subject(s)
Insomnia, Fatal Familial , Prion Diseases , Humans , Insomnia, Fatal Familial/diagnosis , Insomnia, Fatal Familial/genetics , Prion Diseases/diagnosis , Sensitivity and SpecificityABSTRACT
BACKGROUND: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. SUMMARY: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.
Subject(s)
Angiotensin Receptor Antagonists/pharmacology , COVID-19/complications , Heparin, Low-Molecular-Weight/pharmacology , SARS-CoV-2/pathogenicity , Stroke/etiology , COVID-19/virology , Humans , Spike Glycoprotein, Coronavirus/metabolism , Stroke/diagnosisABSTRACT
The global pandemic due to the Coronavirus Disease 2019 (COVID-19) has placed tremendous strain on healthcare services. This review provides guidance to neurologists on the appropriate management of neurological and neurocritical conditions and diseases during the COVID-19 pandemic in the emergency room and the intensive care unit. The guidance is based on official recommendations and manuals that were urgently produced by the international and domestic societies with the contributions of an expert panel including this author.
Subject(s)
Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , COVID-19 , Emergency Service, Hospital , Humans , Intensive Care Units , SARS-CoV-2ABSTRACT
Nonconvulsive status epilepticus (NCSE) has rapidly expanded from classical features such as staring, repetitive blinking, chewing, swallowing, and automatism to include coma, prolonged apnea, cardiac arrest, dementia, and higher brain dysfunction, which were demonstrated mainly after the 2000s by us and other groups. This review details novel clinical features of NCSE as a manifestation of epilepsy, but one that is underdiagnosed, with the best available evidence. Also, we describe the new concept of epilepsy-related organ dysfunction (Epi-ROD) and a novel electrode and headset which enables prompt electroencephalography.
ABSTRACT
Mainly after 2000, we have reported novel manifestations of nonconvulsive status epilepticus (NCSE), such as reversible protracted coma, posthyperventilation apnea, and higher brain dysfunctions, including Klüver-Bucy syndrome. In this review, we discuss the progress in clinical practice and research of NCSE with best available evidence, especially the spectrum of electroencephalographic abnormalities in NCSE, clinical manifestations of malignant NCSE, relationship between sudden unexpected death in epilepsy (SUDEP) and NCSE, and a strategy for real-time neuromonitoring. In addition, we propose some new concepts, NCSE, such as the antiepileptic drug-responsive neurological deficit (ADND), critical NCSE, fosphenytoin challenge test, epilepsy-related organ dysfunction (Epi-ROD), and a Neurocritical Score (Integrated Scale) for the comprehensive and serial evaluation of neurocritical conditions. We emphasize the need for the neuromonitoring of NCSE of broader neurological and neurocritical manifestations not only in the intensive care unit but also in the emergency room, outpatient clinic, inpatient ward, and social settings.
Subject(s)
Status Epilepticus , Anticonvulsants/therapeutic use , Death, Sudden , Humans , Patient Care Team , Practice Guidelines as Topic , Status Epilepticus/complications , Status Epilepticus/drug therapyABSTRACT
The clinical spectrum of nonconvulsive status epilepticus (NCSE) is rapidly expanding from classical manifestations, such as staring, repetitive blinking, chewing, swallowing, and automatism to novel manifestations, such as acute and protracted coma, apnea, cognitive impairment, higher brain dysfunction, and cardiac arrest. It is only in the last decade that these novel NCSE manifestations have been revealed, which is certainly reflective of modern advances in critical care neurology, such as the introduction and spread of continuous electroencephalography (cEEG) monitoring. Although NCSE is a relatively frequent, treatable condition but with a high mortality rate, physicians are still unfamiliar with its clinical manifestations, thus leading to underdiagnosis. In this review, the clinical manifestations, epidemiology, diagnosis, and management of NCSE are critically described using the best available evidence and perspectives, including my hypothesis on epileptic organ dysfunction; in particular, the possible causal relationship between NCSE and cardiac arrhythmia, such as atrial fibrillation is also discussed.
Subject(s)
Status Epilepticus/diagnosis , Status Epilepticus/physiopathology , Animals , Cognition Disorders/complications , Cognition Disorders/physiopathology , Critical Care , Electroencephalography/methods , Humans , Monitoring, Physiologic/methods , Status Epilepticus/classification , Status Epilepticus/therapyABSTRACT
BACKGROUND: Different aspects of acute stroke management and strategies for stroke prevention derive from two viewpoints: specific traditional and historical backgrounds and evidence-based medicine from modern randomized controlled trials (RCTs), meta-analysis and authorized clinical practice guidelines (GLs). Regarding stroke, GLs have been published by national and international organizations in different languages, most frequently in English. Cerebrovascular Diseases published the European GLs for the management of ischemic stroke and transient ischemic attacks in 2003, with an update in 2008. At about the same time (in 2004), the first Japanese GLs for the management of stroke appeared in Japanese. The first English version of the updated Japanese GLs was published only in 2011 and included differently approved drugs and drug dosages as compared with other American or European countries. METHODS: Since 2011, the authors have met repeatedly and have compared the latest versions of published European and Japanese GLs for ischemic and hemorrhagic strokes. Many aspects have only been addressed in one but left out in the other GLs, which consequently founded the basis for the comparison. Classification of evidence levels and recommendation grades defined by the individual committees differed between both original GLs. RESULTS: Aspects of major importance were surprisingly similar and hence did not need extensive interpretation. Other aspects of ischemic stroke management differed significantly, e.g. the dosage of recombinant tissue plasminogen activator approved in Japan is lower (0.6 mg/kg) than in Europe (0.9 mg/kg), which derived from different practices in cardiovascular treatment prior to the design of acute ischemic stroke RCTs. Furthermore, comedication with neuroprotective agents (edaravone), intravenous anticoagulants (argatroban) or antiplatelet agents within 1-2 days after stroke onset is recommended in Japan but not in Europe. For cardioembolic stroke prevention, a major difference consists in a higher international normalized ratio target (2.0-3.0) in younger subjects versus in those >70 years (1.6-2.6), without age restrictions in Europe. CONCLUSION: This brief survey - when compared with the lengthy original recommendations - provides a stimulating basis for an extended interest among Japanese and European stroke clinicians to learn from their individual experiences and to strengthen efforts for joint cooperation in treating and preventing stroke all around the globe.
Subject(s)
Brain Ischemia/therapy , Practice Guidelines as Topic , Anticoagulants/administration & dosage , Anticoagulants/therapeutic use , Brain Edema/etiology , Brain Edema/prevention & control , Brain Ischemia/complications , Brain Ischemia/diagnosis , Brain Ischemia/drug therapy , Brain Ischemia/prevention & control , Brain Ischemia/surgery , Decompressive Craniectomy , Disease Management , Europe , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/therapeutic use , Hemodilution , Hospital Units/standards , Humans , Hypertension/complications , Hypertension/drug therapy , Japan , Neuroimaging/standards , Neuroprotective Agents/therapeutic use , Patient Transfer/standards , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/therapeutic use , Referral and Consultation/standards , Risk Factors , Secondary Prevention/standards , Thromboembolism/prevention & control , Thrombolytic Therapy/standardsABSTRACT
BACKGROUND: Different aspects of acute stroke management and strategies for stroke prevention derive from two viewpoints: specific traditional and historical backgrounds and evidence-based medicine from modern randomized controlled trials (RCTs), meta-analysis and authorized clinical practice guidelines (GLs). Regarding intracerebral hemorrhage (ICH), Cerebrovascular Diseases published the 2006 European stroke initiative recommendations for the management of ICH. In 2009, the revised Japanese GLs for the management of stroke, including that of ICH, appeared in Japanese. Whereas GLs for the prevention and treatment of ischemic stroke were presented in detail, recommendations with regard to ICH are relatively rare both in Japan and Europe. METHODS: Since 2011, the authors have met repeatedly and have compared the latest versions of published European and Japanese GLs for ischemic and hemorrhagic strokes. Many aspects have only been addressed in one but left out in the other GLs, which consequently founded the basis for the comparison. Classification of evidence levels and recommendation grades defined by the individual committees differed between both original GLs. RESULTS: Aspects of major importance were similar and hence did not need extensive interpretation, mostly due to a lack of evidence from appropriate RCTs worldwide. The target level to which systolic blood pressure should be lowered is quite high; <170 mm Hg for patients with known hypertension in Europe and <180 mm Hg in Japan. The results of ongoing clinical trials are awaited for the optimal target level and optimal medications. Concerning ICH associated with oral anticoagulant therapy, both guidelines give similar recommendations, namely that anticoagulation should be discontinued and the international normalized ratio of prothrombin time should be normalized with prothrombin complex concentrate or fresh-frozen plasma and additional vitamin K. Patients with ICH were treated surgically, often based on individual decisions - more frequently in Japan, depending on the association with hypertension. Patients with large or intraventricular bleedings were only treated if a life-saving performance was considered, irrespective of the neurological outcome. Infra- and supratentorial differences were similarly addressed in both GLs. CONCLUSION: This brief survey - when compared with the lengthy original recommendations - provides a stimulating basis for an extended interest among Japanese and European stroke clinicians to learn from their individual experiences and to strengthen efforts for joint cooperation in treating and preventing stroke all around the globe.
Subject(s)
Cerebral Hemorrhage/therapy , Practice Guidelines as Topic , Airway Management , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Brain Edema/etiology , Brain Edema/therapy , Cerebral Hemorrhage/complications , Cerebral Hemorrhage/diagnosis , Cerebral Hemorrhage/drug therapy , Cerebral Hemorrhage/prevention & control , Cerebral Hemorrhage/surgery , Clinical Trials as Topic , Contraindications , Disease Management , Europe , Hemostatic Techniques , Hemostatics/administration & dosage , Hemostatics/therapeutic use , Humans , Hypertension/complications , Hypertension/drug therapy , Intracranial Hypertension/etiology , Intracranial Hypertension/therapy , Japan , Primary Prevention/standards , Risk Factors , Secondary Prevention/standards , Seizures/drug therapy , Seizures/etiology , Thromboembolism/prevention & controlSubject(s)
Aortic Dissection/surgery , Aortic Dissection/therapy , Moyamoya Disease/surgery , Practice Guidelines as Topic/standards , Aortic Dissection/physiopathology , Cerebral Amyloid Angiopathy/physiopathology , Cerebral Amyloid Angiopathy/therapy , Dementia, Vascular/physiopathology , Dementia, Vascular/therapy , Humans , Intracranial Embolism/physiopathology , Intracranial Embolism/therapy , Intracranial Thrombosis/physiopathology , Intracranial Thrombosis/therapy , Moyamoya Disease/physiopathologySubject(s)
Cognition Disorders/rehabilitation , Movement Disorders/rehabilitation , Practice Guidelines as Topic/standards , Speech Disorders/rehabilitation , Stroke Rehabilitation , Urinary Bladder, Neurogenic/rehabilitation , Cognition Disorders/etiology , Cognition Disorders/physiopathology , Humans , Movement Disorders/etiology , Movement Disorders/physiopathology , Speech Disorders/etiology , Speech Disorders/physiopathology , Stroke/complications , Stroke/physiopathology , Urinary Bladder, Neurogenic/etiology , Urinary Bladder, Neurogenic/physiopathologySubject(s)
Neurosurgical Procedures/standards , Practice Guidelines as Topic/standards , Subarachnoid Hemorrhage/therapy , Vascular Surgical Procedures/standards , Cerebral Arteries/pathology , Cerebral Arteries/physiopathology , Cerebral Arteries/surgery , Evidence-Based Medicine/methods , Evidence-Based Medicine/standards , Humans , Neurosurgical Procedures/methods , Perioperative Care/methods , Perioperative Care/standards , Subarachnoid Hemorrhage/physiopathology , Vascular Surgical Procedures/methodsSubject(s)
Asymptomatic Diseases/therapy , Carotid Artery Diseases/diagnosis , Cerebral Hemorrhage/diagnosis , Practice Guidelines as Topic/standards , Brain Infarction/diagnosis , Brain Infarction/physiopathology , Brain Infarction/therapy , Carotid Artery Diseases/etiology , Carotid Artery Diseases/physiopathology , Cerebral Hemorrhage/physiopathology , Cerebral Hemorrhage/therapy , Humans , Intracranial Aneurysm/diagnosis , Intracranial Aneurysm/etiology , Intracranial Aneurysm/physiopathologySubject(s)
Cerebral Infarction/therapy , Ischemic Attack, Transient/therapy , Practice Guidelines as Topic/standards , Anticoagulants/therapeutic use , Cerebral Infarction/complications , Cerebral Infarction/physiopathology , Fibrinolytic Agents/therapeutic use , Humans , Hypothermia, Induced/standards , Ischemic Attack, Transient/complications , Ischemic Attack, Transient/physiopathology , Neuroprotective Agents/therapeutic use , Platelet Aggregation Inhibitors/therapeutic useSubject(s)
Stroke/therapy , Brain Edema/etiology , Brain Edema/physiopathology , Brain Edema/therapy , Humans , Hypertension/etiology , Hypertension/physiopathology , Hypertension/therapy , Japan/epidemiology , Practice Guidelines as Topic/standards , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/therapy , Risk Reduction Behavior , Stroke/complications , Stroke/epidemiology , Stroke/prevention & controlSubject(s)
Hypertension/complications , Hypertension/physiopathology , Intracranial Hemorrhage, Hypertensive/physiopathology , Intracranial Hemorrhage, Hypertensive/therapy , Practice Guidelines as Topic/standards , Brain Edema/physiopathology , Brain Edema/prevention & control , Brain Edema/therapy , Gastrointestinal Diseases/physiopathology , Gastrointestinal Diseases/prevention & control , Gastrointestinal Diseases/therapy , Hemostatic Techniques/standards , Humans , Hypertension/drug therapy , Seizures/physiopathology , Seizures/prevention & control , Seizures/therapyABSTRACT
BACKGROUND AND PURPOSE: Many guidelines for management of stroke have been published throughout the world, but no postpublication external review of any set of stroke guidelines by users, using standard checklists, has been reported. The purpose of this article is to present the results of an external review of the Japanese Guidelines for the Management of Stroke 2004, conducted several months postpublication. METHODS: Forty-one evaluators, who had not been involved in developing the guidelines, were selected from representative stroke centers and institutions in Japan. They consisted of 30 physicians including 22 stroke specialists, and 11 nurse practitioners. Three standard checklists, ie, Appraisal of Guidelines for Research and Evaluation (AGREE) instrument, checklist by Shaneyfelt et al, and the Conference on Guideline Standardization (COGS) checklist, were used. RESULTS: Confidence ratios according to the AGREE checklist were 75%, 77%, and 86% for stroke specialists, physicians other than stroke specialists, and nurse practitioners, respectively. The average scores were 2.98, 3.13, and 3.29, [corrected] respectively. The confidence ratios according to the checklist by Shaneyfelt et al were 72%, 73% and 86% respectively, and those for the COGS checklist were 66%, 74%, and 91%, respectively. CONCLUSIONS: Although it is impossible to compare our results with those for other stroke guidelines, because none of them has been externally reviewed by users postpublication, our results seem better than those for published guidelines for treatment of other diseases in Japan. These results should be helpful in the process of updating stroke guidelines in Japan and elsewhere.
Subject(s)
Evidence-Based Medicine/standards , Guideline Adherence/standards , Practice Guidelines as Topic/standards , Stroke/therapy , Humans , Japan , Neurology/standardsSubject(s)
Cerebral Hemorrhage/complications , Cerebral Hemorrhage/ethnology , Sex Characteristics , Venous Thrombosis/ethnology , Venous Thrombosis/epidemiology , Acute Disease , Female , Humans , Intermittent Pneumatic Compression Devices , Japan/epidemiology , Male , Risk Factors , Venous Thrombosis/therapyABSTRACT
The T allele of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been shown to be a risk factor for stroke. Previous meta-analyses have shown that the individuals with the TT genotype have 1.26-1.37 times the risk for stroke as compared to those with the CC genotype. We performed a meta-analysis of all 5 Japanese studies that investigated the relationship between the MTHFR 677T allele and stroke. The risk of stroke was found to increase in a dose-dependent manner (OR for CT genotype: 1.35, 95% CI; 1.07-1.31, OR for TT genotype: 2.05, 95%CI; 1.51-2.78). This estimate was almost twice as high as those reported from Europe, suggesting that Japanese individuals may be more susceptible to stroke related to the MTHFR 677T allele, although this may be due to publication biases. Two studies have reported that the MTHFR 677T allele is a risk factor for leukoaraiosis, and many studies have investigated whether the MTHFR 677T allele is a risk factor for dementia, especially Alzheimer's disease. We performed a systematic review of all the 21 published articles on the relationship between the MTHFR 677T allele and dementia. Of the 21 studies, 4 used multivariate analysis. Of the remaining 17 studies, which used univariate analysis, only 4 employed matched controls. The reported adjusted OR for Alzheimer's disease was 1.54 or 1.73 for the TT genotype vs the CC genotype and 0.96 or 1.31 per T allele. None of these results are statistically significant. Although the combined unadjusted ORs for Alzheimer's disease and vascular dementia were 1.18 (95%CI; 0.94-1.49) and 1.33 (95%CI; 0.66-2.68) respectively, these estimates were undermined by the heterogeneity and the possible persence of potential confounding variables.