-
The Cochrane Database of Systematic... Jun 2018Fluphenazine is one of the first drugs to be classed as an 'antipsychotic' and has been widely available for five decades. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Fluphenazine is one of the first drugs to be classed as an 'antipsychotic' and has been widely available for five decades.
OBJECTIVES
To compare the effects of oral fluphenazine with placebo for the treatment of schizophrenia. To evaluate any available economic studies and value outcome data.
SEARCH METHODS
We searched the Cochrane Schizophrenia Group's Trials Register (23 July 2013, 23 December 2014, 9 November 2016 and 28 December 2017 ) which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There is no language, date, document type, or publication status limitations for inclusion of records in the register.
SELECTION CRITERIA
We sought all randomised controlled trials comparing oral fluphenazine with placebo relevant to people with schizophrenia. Primary outcomes of interest were global state and adverse effects.
DATA COLLECTION AND ANALYSIS
For the effects of interventions, a review team inspected citations and abstracts independently, ordered papers and re-inspected and quality assessed trials. We extracted data independently. Dichotomous data were analysed using fixed-effect risk ratio (RR) and the 95% confidence interval (CI). Continuous data were excluded if more than 50% of people were lost to follow-up, but, where possible, mean differences (MD) were calculated. Economic studies were searched and reliably selected by an economic review team to provide an economic summary of available data. Where no relevant economic studies were eligible for inclusion, the economic review team valued the already-included effectiveness outcome data to provide a rudimentary economic summary.
MAIN RESULTS
From over 1200 electronic records of 415 studies identified by our initial search and this updated search, we excluded 48 potentially relevant studies and included seven trials published between 1964 and 1999 that randomised 439 (mostly adult participants). No new included trials were identified for this review update. Compared with placebo, global state outcomes of 'not improved or worsened' were not significantly different in the medium term in one small study (n = 50, 1 RCT, RR 1.12 CI 0.79 to 1.58, very low quality of evidence). The risk of relapse in the long term was greater in two small studies in people receiving placebo (n = 86, 2 RCTs, RR 0.39 CI 0.05 to 3.31, very low quality of evidence), however with high degree of heterogeneity in the results. Only one person allocated fluphenazine was reported in the same small study to have died on long-term follow-up (n = 50, 1 RCT, RR 2.38 CI 0.10 to 55.72, low quality of evidence). Short-term extrapyramidal adverse effects were significantly more frequent with fluphenazine compared to placebo in two other studies for the outcomes of akathisia (n = 227, 2 RCTs, RR 3.43 CI 1.23 to 9.56, moderate quality of evidence) and rigidity (n = 227, 2 RCTs, RR 3.54 CI 1.76 to 7.14, moderate quality of evidence). For economic outcomes, we valued outcomes for relapse and presented them in additional tables.
AUTHORS' CONCLUSIONS
The findings in this review confirm much that clinicians and recipients of care already know, but they provide quantification to support clinical impression. Fluphenazine's global position as an effective treatment for psychoses is not threatened by the outcome of this review. However, fluphenazine is an imperfect treatment and if accessible, other inexpensive drugs less associated with adverse effects may be an equally effective choice for people with schizophrenia.
Topics: Administration, Oral; Akathisia, Drug-Induced; Antipsychotic Agents; Fluphenazine; Humans; Placebos; Randomized Controlled Trials as Topic; Recurrence; Schizophrenia
PubMed: 29893410
DOI: 10.1002/14651858.CD006352.pub3 -
International Archives of Occupational... Jan 2023Human health risk assessments of glyphosate have focused on animal toxicology data for determining neurotoxic potential. Human epidemiological studies have not yet been... (Review)
Review
PURPOSE
Human health risk assessments of glyphosate have focused on animal toxicology data for determining neurotoxic potential. Human epidemiological studies have not yet been systematically reviewed for glyphosate neurotoxicity hazard identification. The objective of this systematic literature review was to summarize the available epidemiology of glyphosate exposure and neurological outcomes in humans.
METHODS
As of December 2021, 25 eligible epidemiological studies of glyphosate exposure and neurological endpoints were identified and assessed for five quality dimensions using guidance from the U.S. Environmental Protection Agency. Studies that assessed personal use of glyphosate were prioritized, whereas those assessing indirect exposure (other than personal use) were rated as low quality, since biomonitoring data indicate that indirect metrics of glyphosate exposure almost always equate to non-detectable glyphosate doses.
RESULTS
Overall, the scientific evidence on glyphosate and neurotoxicity in humans is sparse and methodologically limited, based on nine included epidemiological studies of neurodegenerative outcomes (two high quality), five studies of neurobehavioral outcomes (two high quality), six studies of neurodevelopmental outcomes (none high quality), and five studies of other and mixed neurological outcomes (one high quality). The five high-quality studies showed no association between glyphosate use and risk of depression, Parkinson disease, or peripheral nerve conduction velocity. Results were mixed among the eight moderate-quality studies, which did not demonstrate consistent associations with any neurological endpoints or categories. Low-quality studies were considered uninformative about possible neurotoxic effects due primarily to questionable assessments of indirect exposure.
CONCLUSIONS
No association has been demonstrated between glyphosate and any neurological outcomes in humans. To move the state of science forward, epidemiological studies should focus on scenarios involving direct and frequent use of glyphosate while collecting information on validated health outcomes, concomitant agricultural exposures, and relevant personal characteristics.
Topics: Animals; Humans; Environmental Exposure; Herbicides; Glycine; Risk Assessment; Neurotoxicity Syndromes; Glyphosate
PubMed: 35604441
DOI: 10.1007/s00420-022-01878-0 -
Pharmacogenomics Apr 2023To analyze roles of single nucleotide variants (SNVs) on weight loss with US FDA-approved medications. We searched the literature up until November 2022. Preferred... (Meta-Analysis)
Meta-Analysis Review
To analyze roles of single nucleotide variants (SNVs) on weight loss with US FDA-approved medications. We searched the literature up until November 2022. Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were followed. 14 studies were included in qualitative analysis and seven in meta-analysis. SNVs in , , , , , , and were evaluated relative to weight loss with glucagon-like peptide-1 agonists (13 studies) or naltrexone-bupropion (one study). gene (rs1049353), gene (rs6923761, rs10305420), gene (rs7903146) were associated with weight loss in at least one study involving glucagon-like peptide-1 agonist(s). The meta-analysis did not identify any consistent effect of SNVs. Pharmacogenetic interactions for exenatide, liraglutide, naltrexone-bupropion and weight loss were identified, but the directionality was inconsistent.
Topics: Adult; Humans; Hypoglycemic Agents; Pharmacogenetics; Naltrexone; Bupropion; Peptides; Venoms; Glucagon-Like Peptide 1; Weight Loss; Glucagon-Like Peptide-1 Receptor; Diabetes Mellitus, Type 2; Protein Serine-Threonine Kinases
PubMed: 36999540
DOI: 10.2217/pgs-2022-0192 -
Indian Journal of Pharmacology 2019Suicide is a public health problem, and the number of paraphenylenediamine (PPD)-containing hair dye poisoning with suicidal intentions is increasing in developing... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Suicide is a public health problem, and the number of paraphenylenediamine (PPD)-containing hair dye poisoning with suicidal intentions is increasing in developing countries. In order to better understand this situation, we aimed to conduct a systematic review and meta-analysis to estimate the prevalence and complications associated with hair dye poisoning in developing countries.
METHODS
We conducted a systematic review of epidemiological studies using MeSh terms and text keywords to identify studies from the inception to March 2016 about hair dye poisoning with suicidal intentions in developing countries. A meta-analysis was used to calculate the pooled prevalence proportion of hair dye poisoning and its major complications. Data extraction, data analysis, and risk of bias assessment were performed.
RESULTS
Thirty-two studies were included in the systematic review and 29 of these studies containing 5,559 subjects covering six countries were included in the meta-analysis. The pooled prevalence proportion of hair dye poisoning with suicidal intentions was 93.5% (95% confidence interval [CI] = 91.6-95.4) with a mortality rate of 14.5% (95% CI = 11.1-17.9). Of these, 73.8% were female, and 26.2% were male (sex ratio: 2.7:1). The occurrence of angioneurotic edema in hair poisoning patients was 67.1% (95% CI = 56.6-77.6), and tracheostomy intervention was considered in 47.9% (95% CI = 22.7-73.2) patients with respiratory distress. Acute renal failure was noticed in 54.7% (95% CI = 34.5-74.9) of the pooled samples and mortality rates were 14.5% (95% CI = 11.1-17.9). The pooled rate of the population studied from Asia and Africa showed 94.6% (95% CI = 92.5-96.7) and 82.9% (95% CI = 70.6-95.3), respectively, ingested hair dye with suicidal intentions. Further, studies carried out in Africa showed slightly higher mortality of 15.1% (95% CI = 6.56-23.7) than the Asians 14.3% (95% CI = 10.5-18.1).
CONCLUSION
This meta-analysis provided clear evidence of the prevalence of hair dye poisoning among individuals with suicidal intentions and had given robust evidence for policy making to curtail emerging PPD-containing hair dye poisoning in developing countries.
Topics: Developing Countries; Female; Hair Dyes; Humans; Male; Phenylenediamines; Prevalence; Suicide, Attempted
PubMed: 31831919
DOI: 10.4103/ijp.IJP_246_17 -
The Cochrane Database of Systematic... Apr 2017Schizophrenia is a chronic, disabling and severe mental disorder, characterised by disturbance in perception, thought, language, affect and motor behaviour.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Schizophrenia is a chronic, disabling and severe mental disorder, characterised by disturbance in perception, thought, language, affect and motor behaviour. Chlorpromazine and clotiapine are among antipsychotic drugs used for the treatment of people with schizophrenia.
OBJECTIVES
To determine the clinical effects, safety and cost-effectiveness of chlorpromazine compared with clotiapine for adults with schizophrenia.
SEARCH METHODS
We searched Cochrane Schizophrenia's Trials Register (last update search 16/01/2016), which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO and clinical trials registries. There are no language, date, document type, or publication status limitations for inclusion of records in the Register.
SELECTION CRITERIA
All randomised clinical trials focusing on chlorpromazine versus clotiapine for schizophrenia. We included trials meeting our selection criteria and reporting useable data.
DATA COLLECTION AND ANALYSIS
We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random-effects model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE.
MAIN RESULTS
We have included four studies, published between 1974 and 2003, randomising 276 people with schizophrenia to receive either chlorpromazine or clotiapine. The studies were poor at concealing allocation of treatment and blinding of outcome assessment. Our main outcomes of interest were clinically important change in global and mental state, specific change in negative symptoms, incidence of movement disorder (dyskinesia), leaving the study early for any reason, and costs. All reported data were short-term (under six months' follow-up).The trials did not report data for the important outcomes of clinically important change in global or mental state, or cost of care. Improvement in mental state was reported using the Positive and Negative Syndrome Scale (PANSS). When chlorpromazine was compared with clotiapine the average improvement scores for mental state using the PANSS total was higher in the clotiapine group (1 RCT, N = 31, MD 11.50 95% CI 9.42 to 13.58, very low-quality evidence). The average change scores on the PANSS negative sub-scale were similar between treatment groups (1 RCT, N = 21, MD -0.97 95% CI -2.76 to 0.82, very low-quality evidence). There was no clear difference in incidence of dyskinesia (1 RCT, N = 68, RR 3.00 95% CI 0.13 to 71.15, very low-quality evidence). Similar numbers of participants left the study early from each treatment group (3 RCTs, N = 158, RR 0.68 95% CI 0.24 to 1.88, very low-quality evidence).
AUTHORS' CONCLUSIONS
Clinically important changes in global and mental state were not reported. Only one trial reported the average change in overall mental state; results favour clotiapine but these limited data are very difficult to trust due to methodological limitations of the study. The comparative effectiveness of chlorpromazine compared to clotiapine on change in global state remains unanswered. Results in this review suggest chlorpromazine and clotiapine cause similar adverse effects, although again, the quality of evidence for this is poor, making firm conclusions difficult.
Topics: Antipsychotic Agents; Chlorpromazine; Dibenzothiazepines; Dyskinesia, Drug-Induced; Humans; Intention to Treat Analysis; Patient Dropouts; Randomized Controlled Trials as Topic; Risk; Schizophrenia
PubMed: 28387925
DOI: 10.1002/14651858.CD011810.pub2 -
The Cochrane Database of Systematic... Jan 2018Tardive dyskinesia (TD) is a disfiguring movement disorder, often of the orofacial region, frequently caused by using antipsychotic drugs. A wide range of strategies... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tardive dyskinesia (TD) is a disfiguring movement disorder, often of the orofacial region, frequently caused by using antipsychotic drugs. A wide range of strategies have been used to help manage TD, and for those who are unable to have their antipsychotic medication stopped or substantially changed, the benzodiazepine group of drugs have been suggested as a useful adjunctive treatment. However, benzodiazepines are very addictive.
OBJECTIVES
To determine the effects of benzodiazepines for antipsychotic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder, or other chronic mental illnesses.
SEARCH METHODS
On 17 July 2015 and 26 April 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers), inspected references of all identified studies for further trials and contacted authors of each included trial for additional information.
SELECTION CRITERIA
We included all randomised controlled trials (RCTs) focusing on people with schizophrenia (or other chronic mental illnesses) and antipsychotic-induced TD that compared benzodiazepines with placebo, no intervention, or any other intervention for the treatment of TD.
DATA COLLECTION AND ANALYSIS
We independently extracted data from the included studies and ensured that they were reliably selected, and quality assessed. For homogenous dichotomous data, we calculated random effects, risk ratio (RR), and 95% confidence intervals (CI). We synthesised continuous data from valid scales using mean differences (MD). For continuous outcomes, we preferred endpoint data to change data. We assumed that people who left early had no improvement.
MAIN RESULTS
The review now includes four trials (total 75 people, one additional trial since 2006, 21 people) randomising inpatients and outpatients in China and the USA. Risk of bias was mostly unclear as reporting was poor. We are uncertain about all the effects as all evidence was graded at very low quality. We found no significant difference between benzodiazepines and placebo for the outcome of 'no clinically important improvement in TD' (2 RCTs, 32 people, RR 1.12, 95% CI 0.60 to 2.09, very low quality evidence). Significantly fewer participants allocated to clonazepam compared with phenobarbital (as active placebo) experienced no clinically important improvement (RR 0.44, 95% CI 0.20 to 0.96, 1 RCT, 21 people, very low quality evidence). For the outcome 'deterioration of TD symptoms,' we found no clear difference between benzodiazepines and placebo (2 RCTs, 30 people, RR 1.48, 95% CI 0.22 to 9.82, very low quality evidence). All 10 participants allocated to benzodiazepines experienced any adverse event compared with 7/11 allocated to phenobarbital (RR 1.53, 95% CI 0.97 to 2.41, 1 RCT, 21 people, very low quality evidence). There was no clear difference in the incidence of participants leaving the study early for benzodiazepines compared with placebo (3 RCTs, 56 people, RR 2.73, 95% CI 0.15 to 48.04, very low quality evidence) or compared with phenobarbital (as active placebo) (no events, 1 RCT, 21 people, very low quality evidence). No trials reported on social confidence, social inclusion, social networks, or personalised quality of life, which are outcomes designated important by patients. No trials comparing benzodiazepines with placebo or treatment as usual reported on adverse effects.
AUTHORS' CONCLUSIONS
There is only evidence of very low quality from a few small and poorly reported trials on the effect of benzodiazepines as an adjunctive treatment for antipsychotic-induced TD. These inconclusive results mean routine clinical use is not indicated and these treatments remain experimental. New and better trials are indicated in this under-researched area; however, as benzodiazepines are addictive, we feel that other techniques or medications should be adequately evaluated before benzodiazepines are chosen.
Topics: Anti-Anxiety Agents; Antipsychotic Agents; Benzodiazepines; Clonazepam; Dyskinesia, Drug-Induced; GABA Modulators; Humans; Phenobarbital; Randomized Controlled Trials as Topic
PubMed: 29352477
DOI: 10.1002/14651858.CD000205.pub3 -
Medicine Jul 2017The Acute Physiology and Chronic Health Evaluation II (APACHE II) score is used to determine disease severity and predict outcomes in critically ill patients. However,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The Acute Physiology and Chronic Health Evaluation II (APACHE II) score is used to determine disease severity and predict outcomes in critically ill patients. However, the prognostic significance of APACHE after acute paraquat (PQ) poisoning remains unclear. The meta-analysis was aimed to study the value of APACHE II in predicting mortality in PQ-exposed Chinese and Korean patients.
METHODS
Databases that included PubMed, Embase, Cochrane Library, and the Chinese National Knowledge Infrastructure were searched through August 2016. Studies using APACHE II to predict mortality in PQ-poisoned patients were selected. The odds ratio and weighted mean difference (WMD) were used to pool binary and continuous data. Additionally, we aggregated sensitivity, specificity, and other measures of accuracy. Statistical analyses were made using the Stata V.13.0 software.
RESULTS
This study included 29 studies, and 25 studies evaluated APACHE II scores on admission. Pooled data showed that survivors had significantly lower total scores than nonsurvivors (WMD = -7.29, and I = 98.2%, both P <.05). The pooled sensitivity of an APACHE II score ≥5 for predicting mortality was 75% and the pooled specificity was 86%. The positive likelihood ratio (PLR) was 5.3 and the negative likelihood ratio (NLR) was 0.29. The pooled sensitivity of an APACHE II score ≥10 for predicting mortality was 88% and the pooled specificity was 84%. The pooled PLR and NLR was 5.5 and 0.15, respectively.
CONCLUSION
This study showed PQ-poisoned nonsurvivors had significantly higher APACHE II score than did survivors. APACHE II scores satisfactorily predicted mortality.
Topics: APACHE; China; Herbicides; Humans; Mortality; Paraquat; Prognosis; Republic of Korea
PubMed: 28746171
DOI: 10.1097/MD.0000000000006838 -
Clinical Toxicology (Philadelphia, Pa.) Apr 2014Diisocyanates have been associated with respiratory and dermal sensitization. Limited number of case reports, and a few case studies, media, and other references suggest... (Review)
Review
CONTEXT
Diisocyanates have been associated with respiratory and dermal sensitization. Limited number of case reports, and a few case studies, media, and other references suggest potential neurotoxic effects from exposures to toluene diisocyanate (TDI), 1,6 hexamethylene diisocyanate (HDI), and methylene diisocyanate (MDI). However, a systematic review of the literature evaluating the causal association on humans does not exist to support this alleged association.
OBJECTIVE
To perform systematic review examining the body of epidemiologic evidence and provide assessment of causal association based on principles of the Sir Austin Bradford Hill criteria or considerations for causal analysis.
METHODS
A comprehensive search of public databases for published abstracts, case reports, cross-sectional surveys, and cohort studies using key search terms was conducted. Additional searches included regulatory reviews, EU IUCLID and EU Risk Assessment databases, and unpublished reports in the International Isocyanate Institute database. An expert panel consisting of physicians, toxicologists, and an epidemiologist critically reviewed accepted papers, providing examination of epidemiologic evidence of each report. Finally, the Hill criteria for causation were applied to the summative analysis of identified reports to estimate probability of causal association.
RESULTS
Twelve papers reporting exposed populations with a variety of neurological symptoms or findings suitable for analysis were identified, including eleven case or case series reports, and one cross-sectional study. Three papers reported on the same population. Each of the papers was limited by paucity of diisocyanate exposure estimates, the presence of confounding exposures to known or suspected neurotoxicants, a lack of objective biological measures of exposure or neurotoxic effects, and lack of relative strength of association measures. Additionally, reported health symptoms and syndromes lacked consistency or specificity. No plausible mechanism of toxicity was found. Application of a predictive mathematical model for determining probability of causal association for neurotoxicity was calculated to be 21%.
CONCLUSION
There is insufficient evidence for a causal association of neurotoxic effects and diisocyanate exposure based on lack of evidence in all categories of the Hill criteria for causality except for temporal association of reported symptoms and alleged exposure. Future reports should attempt to address more rigorous exposure assessment and control for confounding exposures.
Topics: Animals; Causality; Central Nervous System Agents; Ecotoxicology; Environmental Exposure; Environmental Pollutants; Evidence-Based Practice; Guidelines as Topic; Humans; Isocyanates; Neurotoxicity Syndromes; Occupational Exposure; Peripheral Nervous System Agents; Toluene 2,4-Diisocyanate
PubMed: 24645904
DOI: 10.3109/15563650.2014.898769 -
Scientific Reports Mar 2022We aimed to assess the evidence regarding the usefulness of brain imaging as a diagnostic tool for delayed neurological sequelae (DNS) in patients with acute carbon... (Meta-Analysis)
Meta-Analysis
We aimed to assess the evidence regarding the usefulness of brain imaging as a diagnostic tool for delayed neurological sequelae (DNS) in patients with acute carbon monoxide poisoning (COP). Observational studies that included adult patients with COP and DNS were retrieved from Embase, MEDLINE, and Cochrane Library databases in December 2020 and pooled using a random-effects model. Seventeen studies were systematically reviewed. Eight and seven studies on magnetic resonance imaging (MRI) and computed tomography (CT), respectively, underwent meta-analysis. The pooled sensitivity and specificity of MRI for diagnosis of DNS were 70.9% (95% confidence interval [CI] 64.8-76.3%, I = 0%) and 84.2% (95% CI 80.1-87.6%, I = 63%), respectively. The pooled sensitivity and specificity of CT were 72.9% (95% CI 62.5-81.3%, I = 8%) and 78.2% (95% CI 74.4-87.1%, I = 91%), respectively. The areas under the curve for MRI and CT were 0.81 (standard error, 0.08; Q* = 0.74) and 0.80 (standard error, 0.05, Q* = 0.74), respectively. The results indicate that detecting abnormal brain lesions using MRI or CT may assist in diagnosing DNS in acute COP patients.
Topics: Adult; Brain; Carbon Monoxide Poisoning; Disease Progression; Humans; Magnetic Resonance Imaging; Nervous System Diseases; Neuroimaging
PubMed: 35241701
DOI: 10.1038/s41598-022-07191-7 -
Journal of the Peripheral Nervous... Sep 2023Several widely used medications, with a relevant efficacy profile, are toxic to the peripheral nervous system and an even larger number of agents are suspected to be... (Review)
Review
BACKGROUND AND AIMS
Several widely used medications, with a relevant efficacy profile, are toxic to the peripheral nervous system and an even larger number of agents are suspected to be neurotoxic. There are concerns about the use of these drugs in patients with Charcot-Marie-Tooth disease (CMT), a hereditary motor and sensory neuropathy. This review provides evidence-based updated recommendations on this clinically relevant topic.
METHODS
A systematic review of the available studies/reports written in English was performed from July to September 2022 including in the search string all reported putative neurotoxic drugs.
RESULTS
The results of our systematic review provide evidence-based support for the statement that use of vincristine, and possibly paclitaxel, can occasionally induce an atypical, and more severe, course of drug-related peripheral neurotoxicity in CMT patients. It is therefore reasonable to recommend caution in the use of these compounds in CMT patients. However, no convincing evidence for a similar recommendation could be found for all other drugs.
INTERPRETATION
It is important that patients with CMT are not denied effective treatments that may prolong life expectancy for cancer or improve their health status if affected by non-oncological diseases. Accurate monitoring of peripheral nerve function in CMT patients treated with any neurotoxic agent remains mandatory to detect the earliest signs of neuropathy worsening and atypical clinical courses. Neurologists monitoring CMT patients as part of their normal care package or for natural history studies should keep detailed records of exposures to neurotoxic medications and support reporting of accelerated neuropathy progression if observed.
Topics: Humans; Charcot-Marie-Tooth Disease; Hereditary Sensory and Motor Neuropathy; Neoplasms; Neurotoxicity Syndromes
PubMed: 37249082
DOI: 10.1111/jns.12566