Cormack in the year () stated that “Literature Review” means to systematically read, critically appraise, and then synthesize the material into a coherent, structured, and logical review of the literature. Key words: Training and Development, Evaluation and effectiveness of training, Employee’s attitude, Satisfaction of employees 1 For the past 15 years, I have played an integral part in the development of a successful new department focused on human resources. I managed the complete hiring process for new drivers, owner We would like to show you a description here but the site won’t allow blogger.com more
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Try out PMC Labs and tell us what you think. Learn More. HMG-CoA reductase inhibitors statins are a widely used class of drug, and like all medications have potential for adverse effects AEs.
Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins.
In meta-analyses of randomized controlled trials RCTsmuscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome Literature review hr shared services CYP 3A4 system.
An array of additional risk factors for statin AEs are those that amplify or reflect mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, literature review hr shared services, thyroid disease, and genetic mutations linked to mitochondrial dysfunction.
Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many non-muscle statin AEs, literature review hr shared services.
Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients.
Awareness and vigilance for Literature review hr shared services should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.
HMG-CoA reductase inhibitors statins have been the best selling prescription drug class in the US and include atorvastatin, the best-selling prescription drug in the world — indeed in history.
In literature review hr shared services, benefits have been objectively shown to exceed risks on average for both total mortality and total morbidity indexed by serious adverse eventsspecifically in clinical-trial equivalent middle-aged men who are at high cardiovascular risk. There is need for awareness of risks as well as benefits of all drugs, literature review hr shared services, particularly those that, like statins, are used on a wide scale where even uncommon effects can translate to significant public health impact.
Statins inhibit the enzyme HMG-CoA reductase, at a stage literature review hr shared services in the mevalonate pathway. This report reviews evidence related to statin induction of AEs and evidence for a dose-response relationship, and describes reported drug interactions.
Muscle AEs are emphasized as they are the best recognized AEs of statins liver AEs are perhaps second most recognizedand the AEs on which much of the information on mechanism, drug interactions, and dose-response has been obtained — information that, as we show, has relevance to other statin AEs.
We seek to place other statin AEs in the context this evidence provides, proposing that mitochondrial dysfunction may underlie additional AEs reported on statins. The best recognized and most commonly reported AEs of statins are muscle AEs, 2627 and include muscle pain, fatigue and weakness as well as rhabdomyolysis. While individual randomized controlled trials RCTs often fail to show an excess of muscle problems or symptoms, meta-analysis of randomized double-blind, placebo-controlled trials have shown increased myositis in patients receiving statins relative to placebo odds ratio [OR] literature review hr shared services. In contrast to myositis, myalgia was not increased on average based on meta-analysis of RCTs that compared statins to placebo relative risk [RR] 1.
Rather, evidence has shown that statins reduce pain and improve walking distance in many individuals for instance, but not confined to, persons with peripheral arterial disease29 an effect that may arise through improved blood flow deriving from endothelial function benefits in persons with endothelial dysfunction. In support of this view, triangulating evidence suggest that statins have a causal role in myalgia as well as muscle weakness in some people.
For instance: A double-blind, placebo-controlled, literature review hr shared services, crossover biopsy study showed partially reversible mitochondrial myopathy in persons reporting non-CK-elevating or minimally CK-elevating muscle symptoms on statins. This observation underscores a critically important point relevant to drug AEs in general, which merits emphasis and has relevance to other reported statin AEs.
A significant increase in rates of a problem on drug vs placebo in RCTs supports a causal link between that drug and that AE, in some persons. However, absence of an average significant increase in a problem, or even presence of a significant average reduction in a problem, does not preclude causal occurrence of that problem in some individuals.
In the case of statins, a potential basis for opposing effects occurring in muscle and in other organs can be identified, literature review hr shared services.
Evidence supports the proposition that antioxidant effects of statins underlie or contribute literature review hr shared services many fundamental statin benefits — including benefits to flow and oxygen delivery 46 - 48 and inflammation. RCTs are important for evaluating average effects that may have relevance to use of a drug for treatment in a group overall. However, AEs are important to an literature review hr shared services even if they do not occur on average, and non-RCT data, including case-based data, have recognized importance in AE assessments, literature review hr shared services.
Muscle effects arising on statins literature review hr shared services not uniformly resolve fully with statin discontinuation. Rhabdomyolysis is among the best-recognized and most feared complications of statins; it occurs when muscle damage is severe, leading to a marked elevation of CK e. in excess of 10 times the upper limit of normal often accompanied by evidence of renal dysfunction and occasionally renal failure and death.
However, the recognition of rhabdomyolysis as a statin complication does not rest on randomized trial data, which even on meta-analysis do not support a significant increase e. A case report has suggested that misinterpretation of evidence-based medicine from RCTs on statin rhabdomyolysis may have fatal consequences — and perhaps has had.
Rates rose to 5. Emphasizing that figures for a larger group need not apply to subgroups within that group, per year of therapy the number needed to treat, to see one case of rhabdomyolysis was 22, for statin monotherapy overall, but for older patients with diabetes mellitus treated with combined statin and fibrate, and 9. In the setting of statin rhabdomyolysis, other organs may also be severely affected. Renal failure is well recognized and is a consequence of the rhabdomyolysis, but concurrent heart, 96, pancreas, 96liver, 96-bone marrow, 96, respiratory, 9698 and CNS toxicity 96— or all of the above 96 — are also reported.
A range of sources support a dose relation for statin AEs Table II 37, -although there may exist AEs that are not dose dependent. Meta-analyses of RCTs comparing lower vs higher potency statins are of greatest relevance among the clinical trial data because these examine similar patients within the same study placed on drugs of different potencies. CK elevation OR 6. CK elevation OR 9, literature review hr shared services.
LFT transaminase elevation OR 2. Rechallenge data also support dose-related effects. This study design examines muscle symptom recurrence in persons with prior statin AEs. Patients rechallenged with same-or-higher potency statins relative to the potency of the statin on which problems originally arose usually re-experienced the problem, and did so significantly more frequently than those rechallenged with lower potency statins.
target LDL-C level. Fibrates, particularly gemfibrozil, amplify the risk of rhabdomyolysis on statins most powerfully for cerivastatin, and are present in many statin rhabdomyolysis reports, 8299,- likely due to their effect of impeding statin metabolism and perhaps their additional lipid-modifying effects. Other cholesterol-lowering drugs have also been implicated in muscle toxicity and in statin rhabdomyolysis cases, although less frequently.
Fibrates affect the metabolic pathways of statins, leading to a functionally increased dose. Indeed, a high plurality of excess rhabdomyolysis cases on cerivastatin now withdrawn occurred in combination expressly with gemfibrozil.
Drug interactions arise when drugs inhibit metabolic pathways of statins, compete for metabolism with statins, or cause similar or interacting toxicity. Additionally, apparent interactions may arise when drugs serve as markers for existing problems literature review hr shared services signal vulnerability to statin AEs. Several widely used statins — atorvastatin, simvastatin, and lovastatin and previously cerivastatin, now off the market — are metabolized by the cytochrome P CYP 3A4 pathway.
Regarding the former, increases in simvastatin concentrations may be several times greater than in atorvastatin concentrations with concurrent CYP3A4 inhibitors. Grapefruit juice and perhaps pomegranate juice inhibit CYP3A4 and have been presumptively linked to statin rhabdomyolysis. The CYP3A pathway has a prominent role in drug metabolism in liver and intestine and approximately half of prescription drugs are metabolized by CYP3A4.
This competition may increase statin concentrations and the risk of dose-related statin AEs. Individuals may differ in their response to individual statins, in terms of both efficacy and tolerability, due to pharmacogenomic differences, including those that affect statin hepatic uptake, clearance, and CYP pathways.
Fibrates have special relevance to statin AEs, and as noted above, gemfibrozil, in particular, interferes with statin metabolism an effect that was found to be singularly powerful in combination with cerivastatin Additionally, fibrates themselves may be linked to rhabdomyolysis.
In addition to dose and drug interactions, literature review hr shared services, a multitude of other factors have been associated with an increased risk of statin AEs. Reported risk factors and corresponding citations are delineated in Table IV. Most risk factors depicted can be viewed as sharing one or both of two primary mediating pathways: increased statin exposure e. dose, drug interactions, genetic variants or other factors that affect clearance or hepatic uptake or mitochondrial derangement or vulnerability with factors producing mitochondrial problems or serving as a marker for existing ones.
Reduced concentrations of coenzyme Q10 are particularly a problem in the setting of existing mitochondrial dysfunction because ample coenzyme Q10 can bypass a range of respiratory chain defects, 23 - 25 fostering adequate ATP production and improving the redox state. Additionally, toxicity of certain interacting drugs may be mediated through mitochondrial mechanisms as Table III showsand mitochondrial-relevant genetic defects have been disproportionately found in patients who experience statin myopathy reviewed belowstrongly supporting mitochondrial vulnerability.
Metabolic syndrome factors, literature review hr shared services, particularly hypertension, are linked to increased risk of statin AEs; and these factors, including obesity, hypertriglyceridemia, hyperglycemia and particularly hypertension, have been linked to mitochondrial dysfunction and mitochondrial DNA defects. While a medley of potential mechanisms may cause or contribute to statin AEs and these merit more full review in another venuemitochondrial mechanisms have been repeatedly implicated in muscle AEs.
Additionally, statins predispose to mitochondrial defects Table V, literature review hr shared services 3132,, - — in all users and, to a greater degree, in vulnerable individuals.
Dose-dependent reductions in coenzyme Q10 20 - 22 can reduce cell energy, promote oxidation,promote apoptosis, and unmask silent mitochondrial defects. Statins reduce 20 - 22 and coenzyme Q10 supplementation increases - serum coenzyme Q10 levels. The ability to demonstrate tissue changes in coenzyme Q10 with administration of either agent is more variable; however, irrespective of changes in tissue coenzyme Q10 levels, changes in tissue mitochondrial and respiratory function clearly occur improved with coenzyme Q10, impaired with statins.
Mitochondrial Adverse Effects AEs with Statins in Individuals and Families: Evidence from Case Reports a. Muscle is highly aerobically dependent and selectively vulnerable to mitochondrial pathology. The occurrence of failure of other organs in concert with rhabdomyolysis is noteworthy in this regard, and multiple organ injury or failure has been reported in the context of statin rhabdomyolysis. Cognitive problems are second only to muscle problems among patient reports of statin AEs.
For instance, mitochondrial encephalomyopathy resulting from heritable coenzyme Q10 deficiency classically produces fatigue, muscle symptoms, and cognitive problems, although the literature review hr shared services referred for analysis are often relatively severe. Table VII, literature review hr shared services, 28 31,- shows those AEs for which there is RCT support in some subject groups and provides, in some cases, additional non-RCT evidence.
Randomized trials have recognized limitations for AE detection, due in part to selection considerations. This issue is not specific to statins, but is germane to assessment of risks and benefits for all drugs, literature review hr shared services.
Statin Adverse Effects AEs Supported by Evidence from Randomized Controlled Trials RCTs a. When the average effect of drug on outcome is harmful in RCTs, then it can be concluded that adverse consequences to that outcome occur in at least some individuals. However, when average effects are not harmful, AEs to that outcome are not on that basis literature review hr shared services. Recall that randomized trials seek to determine the overall or average impact of a drug on an outcome in the selected samplein order to assess whether the drug may be used to benefit that outcome on average.
It is worth re-emphasizing that harms in an individual are important even if benefits occur on average. Case reports coupled with triangulating evidence can represent an important source of evidence regarding occurrence of specific AEs, and case reports and case series are reportedly the primary grounds upon which label changes with drugs occur. Table VIII, literature review hr shared services, 15, - characterizes reported AEs that do not have identified RCT support.
Statin Adverse Effects AEs Supported or Suggested by Case Series, Case Studies and Observational Designs ab. Effect modification literature review hr shared services leading to statins producing different effects on the same outcome in different individuals — is recognized in the context of statin and other lipid-lowering drug effects on lipids,and has previously been discussed literature review hr shared services relation to statin muscle effects benefits to walking occur in some, 29 while detriments occur in others As Table VII shows, a similar theme pervades other statin effects, literature review hr shared services, with statins reported to benefit and worsen proteinuria and to benefit and worsen arrhythmia, cardiac function, and an array of other outcomes.
We speculate that a common source of effect modification underlies many of these reported benefits and harms — with statin-induced antioxidant effects and improved flow benefiting many organs in some individuals; and statin-induced pro-oxidant effects and mitochondrial dysfunction adversely affecting a range of organs and outcomes in other individuals.
Indeed, even RCT evidence has differed for the same outcome in different subject groups, generally along the lines this proposition predicts. Observational and limited randomized trial data variably suggest partial though incomplete benefit of coenzyme Q10 supplementation to muscle symptoms; and to other AEs of statins observational data.
Tracy Figliola, Director of Global Mobility and Global HR Shared Services at Equinix
, time: 30:19School Start Times, Sleep, Behavioral, Health, and Academic Outcomes: a Review of the Literature
For the past 15 years, I have played an integral part in the development of a successful new department focused on human resources. I managed the complete hiring process for new drivers, owner We would like to show you a description here but the site won’t allow blogger.com more Nov 25, · In summary, various designs of wearable technology applications in healthcare are discussed in this literature review. Further evaluation studies for those applications are needed to confirm the benefits of wearable technologies for the future. Citation: Wu, M. & Luo, J. (Fall, ). Wearable technology applications in healthcare: A literature
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