Biomarkers of drug-induced liver injury: progress and utility in research,medicine, and regulation

Introduction: The difficulty of understanding and diagnosing drug-induced liver injury (DILI) has led to proliferation of serum and genetic biomarkers. Many applications of these biomarkers have been proposed, including investigation of mechanisms, prediction of DILI during early trials or before initiation of therapy in patients, and diagnosis of DILI during therapy.

Areas covered: We review the definition and categories of DILI, describe recent developments in DILI biomarker development, and provide guidance for future directions in DILI biomarker research.

Expert commentary: There are major obstacles to DILI biomarker development and implementation, including the low prevalence of idiosyncratic DILI (IDILI), weak associations of IDILI with genetic variants, and lack of specificity of many biomarkers for the liver. Certain serum biomarkers, like miR-122, may have clinical utility in early-presenting patients with either intrinsic or idiosyncratic DILI in the future, while others likely will not find use. Future research should focus on implementation of biomarkers to predict later injury and outcome in early presenters with intrinsic DILI, and on development of biomarkers of adaptation and repair in the liver that can be used to determine if a liver test abnormality is likely to be clinically significant in IDILI.     

A double-blind placebo-controlled clinical investigation into pain reduction effect of placing the pain spot outside the intersection area of the two currents of interferential therapy compared to traditional method

Background: Interferential therapy (IFT) is applied to intersect in the painful area but no confirmed effect with this method. Experimentally, the highest voltage of IFT is induced outside the intersection of the two currents. Placing the painful area outside the intersection point (external application) would reveal a better effect.

Objectives: To examine the effect of external application in pain compared to traditional method.

Design: A double-blind placebo-controlled clinical investigation.

Setting: A public hospital.

Participants: 168 LBP subjects.

Interventions: Assignment: (1) external IFT, (2) placebo external IFT, (3) traditional IFT and (4) placebo traditional IFT. Groups 1 and 3 received 20 min of IFT at 100 Hz and groups 2 and 4 received sham IFT.

Main outcome measures: Before and after IFT session, pain severity (VAS), pressure threshold (PPT), pain distribution and ROM were assessed.

Results: IFT changed all outcomes similarly. VAS and ROM improved statistically, P < 0.03. A trend of better VAS reduced with active IFTs.

Conclusions: No therapeutic difference between the two methods.     

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

Objective: The individual response to targeted tyrosine kinase inhibitors (TKIs) in the treatment of metastatic renal cell cancer (mRCC) is highly variable. Outlined in this article are findings on potential biomarkers for TKI treatment outcome in mRCC and an evaluation of the status of clinical implementation.

Methods: Articles were selected by two independent reviewers using a systematic search in five medical databases on renal cell carcinoma, TKIs, and pharmacogenetics.

Results: Many researchers have focused on predictive biomarkers for treatment outcome of targeted therapies in mRCC patients. Attempts to explain differences in efficacy and toxicity of TKIs by use of genetic variants in genes related to the pharmacokinetics and pharmacodynamics of the drug have been successful.

Conclusion: Most findings on potential biomarkers have not been validated and therefore biomarker testing to guide choice of therapy and dose in mRCC is not yet feasible.     

The creation of the diagnostic accuracy quality scale (DAQS)

Background:

The utility of a dedicated clinical test is dependent on the diagnostic accuracy values and the quality of the study in which the test was examined. Scales allow a summative scoring of bias within a study. At present, there are no scales advocated to measure the bias of diagnostic accuracy studies.

Objective:

The objective of this study was to create a new diagnostic accuracy quality scale (DAQS) that provides a quantitative summary of the methodological quality of studies evaluating clinical tests and measures.

Design:

The study used a four-round Delphi survey designed to create, revise, and develop consensus for a quality scale.

Methods:

The four-round Delphi involved a work team and a respondent group of experts. An initial round among the work team created a working document, which was then modified and revised, with opportunities to create new items threaded in the second round. Rounds III and IV involved voting on the importance of each of the proposed items and consensus development from the respondent group. Consensus for the selection of an item required a 75% approval for the importance of that item.

Results:

Sixteen individuals with a variety of research/professional backgrounds made up the respondent group. Modification and revision of the initial work team instrument created a scale with 21 items that reflected potential areas of methodological bias.

Limitations:

The new scale needs validation through weighted assessment. In addition, there was a large proportion of physical therapist/researchers on the work team and the respondent group.

Conclusions:

Systematic reviews allow summation of evidence for clinical tests and scales are essential to critique the quality of the articles included in the review. The DAQS may serve this role for diagnostic accuracy studies.     

Repetition of intentional drug overdose: a population-based study

Context: Intentional overdose is a leading method of self-harm and suicide, and repeat attempts strongly predict eventual death by suicide.

Objectives: To determine the risk of recurrence after a first intentional overdose. Secondary objectives included characterization of the temporal course and potential predictors of repeat overdose, a strong risk factor for death from suicide.

Methods: Design: Population-based cohort study.

Setting: Ontario, Canada, from 1 April 2002 to 31 March 2013.

Participants: All Ontario residents presenting to an emergency department after a first intentional overdose.

Main outcome measures: The incidence and timing of recurrent overdose.

Results: We followed 81,675 patients discharged from hospital after a first intentional overdose. Overall, 13,903 (17.0%) returned with a repeat overdose after a median interval of 288 (inter-quartile range: 62 to 834) days. Of these, 4493 (5.5%) had multiple repeat episodes. Factors associated with repeat self-poisoning included psychiatric care in the preceding year (adjusted hazard ratio [aHR] 1.55; 95% confidence interval [CI] 1.50 to 1.61), alcohol dependence (aHR 1.41; 95% CI 1.35 to 1.46) and documented depression (aHR 1.39; 95% CI 1.34 to 1.44). Female sex, rural residence, lower socioeconomic status, ingestion of psychoactive drugs and younger age were also weakly associated with repeat overdose.

Discussion: Hospital presentation for repetition of intentional overdose is common, with recurrent episodes often far removed from the first. While several factors predict overdose repetition, none is particularly strong.

Conclusion: Secondary prevention initiatives should be implemented for all individuals who present to the emergency department and survive intentional overdose.     

Towards diagnostic application of non-coding RNAs in neuroblastoma

Introduction: Neuroblastoma is a solid cancer of childhood, which is devastating upon recurrence. Markers for minimal residual disease and early detection of relapse are eagerly awaited to improve the outcome of affected patients. Several miRNAs have been identified as key regulators of neuroblastoma pathogenesis.

Areas covered: Here, we focus on miRNAs that have been linked to MYCN, a prominent oncogenic driver, and we review the hitherto known interactions between miRNAs and other important players in neuroblastoma.

Expert commentary: Existing diagnostic miRNA signatures remain to be established in clinical settings. Moreover, inhibition of individual oncogenic miRNAs or enhancement of tumor suppressive miRNA function could represent a new therapeutic approach in cancer treatment, including NB.     

Pain pattern classification and directional preference for patients with neck pain

Objectives:

Pain Pattern Classification (PPC) and Directional Preference (DP) have been shown to be predictive of health care outcomes and serve to guide orthopedic clinical decision making. We conducted a prospective, observational cohort study to verify the association between PPC, DP, and clinical outcomes.

Methods:

Clinical outcome measures including pain intensity and disability were completed at first examination and follow-up by 335 patients. A Pearson’s chi-squared test was used to determine differences in prevalence rates for the categorical variables, and two-sample t-tests were used to determine differences in rates for the continuous variables. A Tukey’s range test was used to determine differences in follow-up pain intensity and disability for neck pain dual-classification schemes.

Results:

The prevalence of DP was 82.4%. The prevalence of CEN, Non-CEN, and Non-Classifiable (NC) was 15.2%, 42.1%, and 25.1%, respectively. The prevalence of DP was lowest for patients with sub-acute symptoms and who were <45 years old. Patients classified as DP CEN had, on average 2.62 NDI units less than patients classified as Non-DP. Patients classified as DP CEN had, on average, 0.90 pain intensity units less than patients classified as Non-DP at follow-up. Patients who demonstrated DP CEN did not have clinically significant lower pain intensity or disability at follow-up than patients who demonstrated Non-DP.

Discussion:

The results of this investigation need to be interpreted with caution with respect to the study design and it’s subsequent strengths and limitations.

Level of Evidence:

1b.     

The effect on the patient flow in a local health care after implementing reverse triage in a primary care emergency department: a longitudinal follow-up study

Objective: Reverse triage means that patients who are not considered to be in need of medical services are not placed on the doctor’s list in an emergency department (ED) but are sent, after face-to-face evaluation by a triage nurse, to a more appropriate health care unit. It is not known how an abrupt application of such reverse triage in a combined primary care ED alters the demand for doctors’ services in collaborative parts of the health care system.

Design: An observational study.

Setting: Register-based retrospective quasi-experimental longitudinal follow-up study based on a before–after setting in a Finnish city.

Subjects: Patients who consulted different doctors in a local health care unit.

Main outcome measures: Numbers of monthly visits to different doctor groups in public and private primary care, and numbers of monthly referrals to secondary care ED from different sources of primary care were recorded before and after abrupt implementation of the reverse triage.

Results: The beginning of reverse triage decreased the number of patient visits to a primary ED doctor without increasing mortality. Simultaneously, there was an increase in doctor visits in the adjacent secondary care ED and local private sector. The number of patients who came to secondary care ED without a referral or with a referral from the private sector increased.

Conclusions: The data suggested that the reverse triage causes redistribution of the use of doctors’ services rather than a true decrease in the use of these services.     

Quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections in general practice: a RAND Appropriateness Method

Objective: To develop quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections, tailored to the Danish general practice setting.

Design: A RAND/UCLA Appropriateness Method was used.

Setting: General practice.

Subjects: A panel of nine experts, mainly general practitioners, was asked to rate the relevance of 64 quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections based on guidelines. Subsequently, a face-to-face meeting was held to resolve misinterpretations and to achieve consensus.

Main outcome measures: The experts were asked to rate the indicators on a nine-point Likert scale. Consensus of appropriateness for a quality indicator was reached if the overall panel median rating was 7–9 with agreement.

Results: A total of 50 of the 64 proposed quality indicators attained consensus. Consensus was achieved for 12 indicators focusing on the diagnostic process and 19 indicators focusing on the decision about antibiotic treatment and choice of antibiotics, respectively.

Conclusion: These newly developed quality indicators may be used to strengthen Danish general practitioners’ focus on their management of patients with acute respiratory tract infections and to identify where there is a need for future quality improvements.     

Patient trajectories in a Norwegian unit of municipal emergency beds

Objective: The Coordination reform was implemented in Norway from 2012, aiming at seamless patient trajectories. All municipalities are required to establish emergency care beds (MEBs) to avoid unnecessary hospital admissions. We aimed to examine occupancy rate, patient characteristics, diagnoses and discharge level of municipal care in a small MEB unit.

Design: Cross-sectional, observational study.

Setting: A two-bed emergency care unit.

Subjects: All patients admitted to the unit during one year.

Main outcome measures: Patients’ age and gender, comorbidity, main diagnoses and municipal care level on admission and discharge, diagnostic and therapeutic initiatives, occupancy rate.

Results: Sixty admissions were registered, with total bed occupancy 194 days, and an occupancy rate of 0.27. The patients (median age 83 years, 57% women) had mostly infections, musculoskeletal symptoms or undefined conditions. Some 48% of the stays exceeded three days and 43% of the patients were subsequently transferred to nursing homes or hospitals.

Conclusion: Occupancy rate was low. Patient selection was not according to national standards, and stays were longer. Many patients were transferred to nursing homes, indicating that the unit was an intermediate pathway or a short cut to institutional care. It is unclear whether the unit avoided hospital admissions.     

Biological markers of prognosis,response to therapy and outcome in ovarian carcinoma

Introduction: Ovarian cancer (OvCa) is among the most common types of cancer and is the leading cause of death from gynecological malignancies in western countries. Cancer biomarkers have a potential for improving the management of OvCa patients at every point from screening and detection, diagnosis, prognosis, follow up, response to therapy and outcome.

Areas covered: The literature search has indicated a number of candidate biomarkers have recently emerged that could facilitate the molecular definition of OvCa, providing information about prognosis and predicting response to therapy. These potentially promising biomarkers include immune cells and their products, tumor-derived exosomes, nucleic acids and epigenetic biomarkers.

Expert commentary: Although most of the biomarkers available today require prospective validation, the development of noninvasive liquid biopsy-based monitoring promises to improve their utility for evaluations of prognosis, response to therapy and outcome in OvCa.     

Using biomarkers to guide heart failure management

Introduction: Biomarkers have revolutionized the diagnosis of heart failure (HF), but it remains unclear how to use biomarkers to guide management of HF.

Areas covered: An exhaustive literature search on using biomarkers to guide HF management was performed. HF guidelines were carefully scrutinized for references pertaining to this topic, and Medline was employed to identify further references. This review focused on natriuretic peptides, troponin, and ST2 as biomarkers used to guide HF management. Most trials have examined secondary prevention of chronic HF patients, and data on primary prevention of HF and therapy of acute HF are emerging.

Expert commentary: While the current data on using biomarkers to guide HF management remain mixed, more research is necessary to better understand how to utilize biomarkers to improve HF management.     

Drug-related problems and changes in drug utilization after medication reviews in nursing homes in Oslo,Norway

Objective: We describe the drug-related problems (DRPs) identified during medication reviews (MRs) and the changes in drug utilization after MRs at nursing homes in Oslo, Norway. We explored predictors for the observed changes.

Design: Observational before-after study.

Setting: Forty-one nursing homes.

Intervention: MRs performed by multidisciplinary teams during November 2011 to February 2014.

Subjects: In all, 2465 long-term care patients.

Main outcome measures: DRPs identified by explicit criteria (STOPP/START and NORGEP) and drug–drug interaction database; interventions to resolve DRPs; drug use changes after MR.

Results: A total of 6158 DRPs were identified, an average of 2.6 DRPs/patient, 2.0 for regular and 0.6 for pro re nata (prn) drugs. Of these patients, 17.3% had no DRPs. The remaining 82.7% of the patients had on average 3.0 DRPs/patient. Use of unnecessary drugs (43.5%), excess dosing (12.5%) and lack of monitoring of the drug use (11%) were the most frequent DRPs. Opioids and psychotropic drugs were involved in 34.4% of all DRPs. The mean number of drugs decreased after the MR from 6.8 to 6.3 for regular drugs and from 3.0 to 2.6 for prn drugs. Patients with DRPs experienced a decrease of 1.1 drugs after MR (0.5 for regular and 0.6 for prn drugs). The reduction was most pronounced for the regular use of antipsychotics, antidepressants, hypnotics/sedatives, diuretics, antithrombotic agents, antacid drugs; and for prn use of anxiolytics, opioids, hypnotics/sedatives, metoclopramide and NSAIDs.

Conclusion: The medication review resulted in less drug use, especially opioids and psychotropic drugs.     

Pharmacokinetic and pharmacodynamic changes in older adults and implications for palliative care

Background: As the population of older adults continues to increase, there will be an increase in the number of older patients requiring pain and symptom management in the setting of advanced, serious illness.

Objectives: To review age-related changes in pharmacokinetics and pharmacodynamics, and to put these changes in the context of providing palliative care to geriatric patients.

Method: Review of literature relevant to age-related changes in physiology, pharmacokinetics, and pharmacodynamics; and the practice of palliative care for geriatric patients.

Results: Multiple age related changes occur which affect the choice and dosing of medications, including those used for pain and symptom management.

Conclusion: The safe and effective management of symptoms in advanced illness for older adults depends on having a clear understanding of physical and metabolic changes and their impact of selection of drug therapy.     

Factors associated with self-rated health in primary care

Background: Self-rated health (SRH) measures one’s current general health and is a widely used health indicator. Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships are suspected to influence SRH, but studies in primary health care settings are sparse.

Objective: To examine the associations between patients’ self-rated health and their sleep problems, somatic health complaints, and unmet needs in interpersonal relationships.

Design: We collected data via questionnaires for this cross-sectional study from general practice.

Setting: Primary health care in Norway.

Subjects: 1302 consecutive patients participated.

Main outcome measures: The questionnaire included a single question about SRH, the Bergen Insomnia Scale (BIS), five questions on somatic health complaints, and three questions from the Basic Psychological Needs Scale (BPNS) pertaining to the relationships domain. We analyzed our data using ordinal logistic regression models.

Results: Our response rate was 74%. The prevalence of fair/poor SRH was 26%, with no gender differences. We revealed a significant association between increasing age and reduced SRH. The study showed that sleep problems and somatic health complaints were strongly associated with SRH, and unmet needs in relationships were also significantly and independently associated with reduced SRH in a full model analysis.

Conclusion: Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships were all associated with reduced SRH. These factors are all modifiable and could be managed both within and outside a primary care setting in order to improve SRH.

• Key Points

• There was a high prevalence of reduced SRH in clinical general practice

• Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships were all associated with reduced SRH

• These predictors are all modifiable with a potential to improve SRH

     

Updates and current challenges in microRNA research for personalized medicine in ovarian cancer

Introduction: Ovarian cancer (OC) is the second most common and the most lethal of the gynecological malignancies. Currently, there exists no effective screening tool for OC. MicroRNAs (miRNAs) are endogenous 18–23 nucleotide non-coding RNAs that refine gene expression. MiRNAs have been found to be aberrantly expressed in OC tumor tissue as well as detectable in biological fluids such as the blood, urine, and ascites and have been proposed as biomarkers and therapeutic targets for OC.

Areas covered: This review summarizes the current knowledge regarding the application of miRNAs as diagnostic, prognostic, and predictive biomarkers in OC. It describes the various tissues allowing for the analysis of miRNAs such as tumor tissue, blood, ascites and urine. It also highlights the potential of miRNAs as a therapy in other cancers and how these therapies may be applied to ovarian cancer.

Expert opinion: The study of miRNAs is an innovative and promising field for the diagnosis and treatment of ovarian cancer. Methodological issues surrounding their detection and application therapeutically remain, such as the study of various OC histotypes within the same cohort, the choice of ‘normal tissue’ for comparison and the difficulties surrounding the choice of a normalization miRNA.     

Does an in-house internist at a GP practice result in reduced referrals to hospital-based specialist care?

Objective: Consistent evidence on the effects of specialist services in the primary care setting is lacking. Therefore, this study evaluated the effects of an in-house internist at a GP practice on the number of referrals to specialist care in the hospital setting. Additionally, the involved GPs and internist were asked to share their experiences with the intervention.

Design: A retrospective interrupted times series study.

Setting: Two multidisciplinary general practitioner (GP) practices.

Intervention: An internist provided in-house patient consultations in two GP practices and participated in the multidisciplinary meetings.

Subjects: The referral data extracted from the electronic medical record system of the GP practices, including all referral letters from the GPs to specialist care in the hospital setting.

Main outcome measures: The number of referrals to internal medicine in the hospital setting. This study used an autoregressive integrated moving average model to estimate the effect of the intervention taking account of a time trend and autocorrelation among the observations, comparing the pre-intervention period with the intervention period.

Results: It was found that the referrals to internal medicine did not statistically significant decrease during the intervention period.

Conclusions: This small explorative study did not find any clues to support that an in-house internist at a primary care setting results in a decrease of referrals to internal medicine in the hospital setting.

• Key Points

• An in-house internist at a primary care setting did not result in a significant decrease of referrals to specialist care in the hospital setting.

• The GPs and internist experience a learning-effect, i.e. an increase of knowledge about internal medicine issues.

     

A systematic review to determine the optimal type and dosage of land-based exercises for treating knee osteoarthritis

Background: Exercise has been acknowledged as an effective non-pharmacological intervention for osteoarthritis. Consensus regarding the type of exercise i.e., aerobic or resistance, weight bearing or non-weight bearing, and dosage i.e., frequency, loading, duration, or intensity, is yet to be reached.

Objective: The purpose of this review was to address two questions: (1) is there a difference in clinical outcomes between different exercise programmes; and (2) what is the optimal dosage of exercises for people with knee osteoarthritis.

Methods: A systematic review was conducted. A study of published (AMED, CINAHL, MEDLINE, EMBASE, PubMed, and the Cochrane Library) and unpublished literature (WHO International Clinical Trials Registry Platform, current controlled trials and the United States National Institute of Health Trials Registry, and Open Grey) was undertaken in January 2013. Studies assessing the clinical outcomes of different types and dosages of exercise for people with osteoarthritis of the knee were included. Methodological quality was assessed using the critical appraisal skills programme (CASP) randomized controlled trial (RCT) appraisal tool.

Results: Ten studies assessing 958 knees from 916 participants were included. Exercise significantly improved pain and function for people with knee osteoarthritis. There was no significant difference in outcomes for different types of exercise i.e., aerobic versus resistance, weight bearing versus non-weight bearing. There was no significant difference in respect to the intensity of exercise i.e., high- versus lower-intensity resistance or aerobic exercises. The quality of the literature was moderate to high.

Conclusions: While exercise appears to improve symptoms and optimize function for people with knee osteoarthritis, the optimal form and dosage of exercise remains unknown.

Funding: None.

PROSPERO Registration Number: CRD42012002811.     

Learning to navigate the healthcare system in a new country: a qualitative study

Objective: Learning to navigate a healthcare system in a new country is a barrier to health care. Understanding more about the specific navigation challenges immigrants experience may be the first step towards improving health information and thus access to care. This study considers the challenges that Thai and Filipino immigrant women encounter when learning to navigate the Norwegian primary healthcare system and the strategies they use.

Design: A qualitative interview study using thematic analysis.

Setting: Norway.

Participants: Fifteen Thai and 15 Filipino immigrant women over the age of 18 who had been living in Norway at least one year.

Results: The women took time to understand the role of the general practitioner and some were unaware of their right to an interpreter during consultations. In addition to reliance on family members and friends in their social networks, voluntary and cultural organisations provided valuable tips and advice on how to navigate the Norwegian health system. While some women actively engaged in learning more about the system, they noted a lack of information available in multiple languages.

Conclusions: Informal sources play an important role in learning about the health care system. Formal information should be available in different languages in order to better empower immigrant women.     

Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series

Background: Cannabinoid hyperemesis syndrome (CHS) is characterized by symptoms of cyclic abdominal pain, nausea, and vomiting in the setting of prolonged cannabis use. The transient receptor potential vanilloid 1 (TRPV1) receptor may be involved in this syndrome. Topical capsaicin is a proposed treatment for CHS; it binds TRPV1 with high specificity, impairing substance P signaling in the area postrema and nucleus tractus solitarius via overstimulation of TRPV1. This may explain its apparent antiemetic effect in this syndrome.

Purpose: We describe a series of thirteen cases of suspected cannabis hyperemesis syndrome treated with capsaicin in the emergency departments of two academic medical centers.

Methods: A query of the electronic health record at both centers identified thirteen patients with documented daily cannabis use and symptoms consistent with CHS who were administered topical capsaicin cream for symptom management.

Results: All 13 patients experienced symptom relief after administration of capsaicin cream.

Conclusion: Topical capsaicin was associated with improvement in symptoms of CHS after other treatments failed.