The Potentiality of Natural Products and Herbal Medicine as Novel Medications for Parkinson's Disease: A Promising Therapeutic Approach.

As the global population ages, the prevalence of Parkinson's disease (PD) is steadily on the rise. PD demonstrates chronic and progressive characteristics, and many cases can transition into dementia. This increases societal and economic burdens, emphasizing the need to find effective treatments. Among the widely recognized causes of PD is the abnormal accumulation of proteins, and autophagy dysfunction accelerates this accumulation. The resultant Lewy bodies are also commonly found in Alzheimer's disease patients, suggesting an increased potential for the onset of dementia. Additionally, the production of free radicals due to mitochondrial dysfunction contributes to neuronal damage and degeneration. The activation of astrocytes and the M1 phenotype of microglia promote damage to dopamine neurons. The drugs currently used for PD only delay the clinical progression and exacerbation of the disease without targeting its root cause, and come with various side effects. Thus, there is a demand for treatments with fewer side effects, with much potential offered by natural products. In this study, we reviewed a total of 14 articles related to herbal medicines and natural products and investigated their relevance to possible PD treatment. The results showed that the reviewed herbal medicines and natural products are effective against lysosomal disorder, mitochondrial dysfunction, and inflammation, key mechanisms underlying PD. Therefore, natural products and herbal medicines can reduce neurotoxicity and might improve both motor and non-motor symptoms associated with PD. Furthermore, these products, with their multi-target effects, enhance bioavailability, inhibit antibiotic resistance, and might additionally eliminate side effects, making them good alternative therapies for PD treatment.

Gossypetin Prevents the Progression of Nonalcoholic Steatohepatitis by Regulating Oxidative Stress and AMP-Activated Protein Kinase.

Nonalcoholic steatohepatitis (NASH) is a severe liver metabolic disorder, however, there are still no effective and safe drugs for its treatment. Previous clinical trials used various therapeutic approaches to target individual pathologic mechanisms, but these approaches were unsuccessful because of the complex pathologic causes of NASH. Combinatory therapy in which two or more drugs are administered simultaneously to patients with NASH, however, carries the risk of side effects associated with each individual drug. To solve this problem, we identified gossypetin as an effective dual-targeting agent that activates AMP-activated protein kinase (AMPK) and decreases oxidative stress. Administration of gossypetin decreased hepatic steatosis, lobular inflammation and liver fibrosis in the liver tissue of mice with choline-deficient high-fat diet and methionine-choline deficient diet (MCD) diet-induced NASH. Gossypetin functioned directly as an antioxidant agent, decreasing hydrogen peroxide and palmitate-induced oxidative stress in the AML12 cells and liver tissue of MCD diet-fed mice without regulating the antioxidant response factors. In addition, gossypetin acted as a novel AMPK activator by binding to the allosteric drug and metabolite site, which stabilizes the activated structure of AMPK. Our findings demonstrate that gossypetin has the potential to serve as a novel therapeutic agent for nonalcoholic fatty liver disease /NASH. SIGNIFICANCE STATEMENT: This study demonstrates that gossypetin has preventive effect to progression of nonalcoholic steatohepatitis (NASH) as a novel AMP-activated protein kinase (AMPK) activator and antioxidants. Our findings indicate that simultaneous activation of AMPK and oxidative stress using gossypetin has the potential to serve as a novel therapeutic approach for nonalcoholic fatty liver disease /NASH patients.

Health-related quality of life of children born very preterm: a multinational European cohort study.

PURPOSE: This study aims to (1) describe the health-related quality of life (HRQoL) outcomes experienced by children born very preterm (28-31 weeks' gestation) and extremely preterm (< 28 weeks' gestation) at five years of age and (2) explore the mediation effects of bronchopulmonary dysplasia (BPD) and severe non-respiratory neonatal morbidity on those outcomes. METHODS: This investigation was based on data for 3687 children born at < 32 weeks' gestation that contributed to the EPICE and SHIPS studies conducted in 19 regions across 11 European countries. Descriptive statistics and multi-level ordinary linear squares (OLS) regression were used to explore the association between perinatal and sociodemographic characteristics and PedsQL™ GCS scores. A mediation analysis that applied generalised structural equation modelling explored the association between potential mediators and PedsQL™ GCS scores. RESULTS: The multi-level OLS regression (fully adjusted model) revealed that birth at < 26 weeks' gestation, BPD status and experience of severe non-respiratory morbidity were associated with mean decrements in the total PedsQL™ GCS score of 0.35, 3.71 and 5.87, respectively. The mediation analysis revealed that the indirect effects of BPD and severe non-respiratory morbidity on the total PedsQL™ GCS score translated into decrements of 1.73 and 17.56, respectively, at < 26 weeks' gestation; 0.99 and 10.95, respectively, at 26-27 weeks' gestation; and 0.34 and 4.80, respectively, at 28-29 weeks' gestation (referent: birth at 30-31 weeks' gestation). CONCLUSION: The findings suggest that HRQoL is particularly impaired by extremely preterm birth and the concomitant complications of preterm birth such as BPD and severe non-respiratory morbidity.

The Design, Fabrication, and Evaluation of a Phase-Resolved Partial Discharge Sensor Embedded in a MV-Class Bushing.

This paper proposes a novel phase-resolved partial discharge (PRPD) sensor embedded in a MV-class bushing for high-accuracy insulation analysis. The design, fabrication, and evaluation of a PRPD sensor embedded in a MV-class bushing aimed to achieve the detection of partial discharge (PD) pulses that are phase-synchronized with the applied primary HV signal. A prototype PRPD sensor was composed of a flexible printed circuit board (PCB) with dual-sensing electrodes, utilizing a capacitive voltage divider (CVD) for voltage measurement, the D-dot principle for PD detection, and a signal transducer with passive elements. A PD simulator was prepared to emulate typical PD defects, i.e., a metal protrusion. The voltage measurement precision of the prototype PRPD sensor was satisfied with the accuracy class of 0.2 specified in IEC 61869-11, as the maximum corrected voltage error ratios and corrected phase errors in 80%, 100%, and 120% of the rated voltage (13.2 kilovolts (kV)) were less than 0.2% and 10 min, respectively. In addition, the prototype PRPD sensor had good linearity and high sensitivity for PD detection compared with a conventional electrical detection method. According to performance evaluation tests, the prototype PRPD sensor embedded in the MV-class bushing can measure PRPD patterns phase-synchronized with the primary voltage without any additional synchronization equipment or system. Therefore, the prototype PRPD sensor holds potential as a substitute for conventional commercial PD sensors. Consequently, this advancement could lead to the enhancement of power system monitoring and maintenance, contributing to the digitalization and minimization of power apparatus.

Natural Products as the Potential to Improve Alzheimer's and Parkinson's Disease.

Alzheimer's disease and Parkinson's disease are the two most common neurodegenerative diseases in the world, and their incidence rates are increasing as our society ages. This creates a significant social and economic burden. Although the exact cause and treatment methods for these diseases are not yet known, research suggests that Alzheimer's disease is caused by amyloid precursor protein, while α-synuclein acts as a causative agent in Parkinson's disease. The accumulation of abnormal proteins such as these can lead to symptoms such as loss of protein homeostasis, mitochondrial dysfunction, and neuroinflammation, which ultimately result in the death of nerve cells and the progression of neurodegenerative diseases. The medications currently available for these diseases only delay their progression and have many adverse effects, which has led to increased interest in developing natural products with fewer adverse effects. In this study, we selected specific keywords and thesis content to investigate natural products that are effective in treating Alzheimer's and Parkinson's diseases. We reviewed 16 papers on natural products and found that they showed promising mechanisms of action such as antioxidant, anti-inflammatory, and mitochondrial function improvement. Other natural products with similar properties could also be considered potential treatments for neurodegenerative diseases, and they can be consumed as part of a healthy diet rather than as medicine.

High Healthcare Use at Age 5 Years in a European Cohort of Children Born Very Preterm.

OBJECTIVES: To describe parent-reported healthcare service use at age 5 years in children born very preterm and investigate whether perinatal and social factors and the use of very preterm follow-up services are associated with high service use. STUDY DESIGN: We used data from an area-based cohort of births at <32 weeks of gestation from 11 European countries, collected from birth records and parental questionnaires at 5 years of age. Using the published literature, we defined high use of outpatient/inpatient care (≥4 sick visits to general practitioners, pediatricians, or nurses, ≥3 emergency room visits, or ≥1 overnight hospitalization) and specialist care (≥2 different specialists or ≥3 visits). We also categorized countries as having either a high or a low rate of children using very preterm follow-up services at age 5 years. RESULTS: Overall, 43% of children had high outpatient/inpatient care use and 48% had high specialist care use during the previous year. Perinatal factors were associated with high outpatient/inpatient and specialist care use, with a more significant association with specialist services. Associations with intermediate parental educational level and unemployment were stronger for outpatient/inpatient services. Living in a country with higher rates of very preterm follow-up service use was associated with lower use of outpatient/inpatient services. CONCLUSIONS: Children born very preterm had high healthcare service use at age 5 years, with different patterns for outpatient/inpatient and specialist care by perinatal and social factors. Longer follow-up of children born very preterm may improve care coordination and help avoid undesirable health service use.

hnRNP K supports the maintenance of RORγ circadian rhythm through ERK signaling.

Retinoic acid-related orphan receptor γ (RORγ) maintains the circadian rhythms of its downstream genes. However, the mechanism behind the transcriptional activation of RORγ itself remains unclear. Here, we demonstrate that transcription of RORγ is activated by heterogeneous nuclear ribonucleoprotein K (hnRNP K) via the poly(C) motif within its proximal promoter. Interestingly, we confirmed the binding of endogenous hnRNP K within RORγ1 and RORγ2 promoter along with the recruitment of RNA polymerase 2 through chromatin immunoprecipitation (ChIP). Furthermore, an assay for transposase accessible chromatin (ATAC)-qPCR showed that hnRNP K induced higher chromatin accessibility within the RORγ1 and RORγ2 promoter. Then we found that the knockdown of hnRNP K lowers RORγ mRNA oscillation amplitude in both RORγ and RORγ-dependent metabolic genes. Moreover, we demonstrated that time-dependent extracellular signal-regulated kinase (ERK) activation controls mRNA oscillation of RORγ and RORγ-dependent metabolic genes through hnRNP K. Taken together, our results provide new insight into the regulation of RORγ by hnRNP K as a transcriptional activator, along with its physiological significance in metabolism.

Economic costs at age five associated with very preterm birth: multinational European cohort study.

BACKGROUND: This study aims to estimate the economic costs of care provided to children born very preterm and extremely preterm across 11 European countries, and to understand what perinatal and socioeconomic factors contribute to higher costs. METHODS: Generalised linear modelling was used to explore the association between perinatal and sociodemographic characteristics and total economic costs (€, 2016 prices) during the fifth year of life. RESULTS: Lower gestational age was associated with increased mean societal costs of €2755 (p < 0.001), €752 (p < 0.01) and €657 (p < 0.01) for children born at < 26, 26-27 and 28-29 weeks, respectively, in comparison to the reference group born at 30-31 weeks. A sensitivity analyses that excluded variables (BPD, any neonatal morbidity and presence of congenital anomaly) plausibly lying on the causal pathway between gestational age at birth and economic outcomes elevated incremental societal costs by €1482, €763 and €144 at < 26, 26-27 and 28-29 weeks, respectively, in comparison to the baseline model. CONCLUSION: This study provides new evidence about the main cost drivers associated with preterm birth in European countries. Evidence identified by this study can act as inputs within cost-effectiveness models for preventive or treatment interventions for preterm birth. IMPACT: What is the key message of your article? This study provides new evidence about the magnitude and drivers of economic costs associated with preterm birth in European countries. What does it add to the existing literature? Lower gestational age is associated with increased mean societal costs during mid-childhood with indirect costs representing a key driver of increased costs. What is the impact? For policy makers, this study adds to sparse evidence about the main cost drivers associated with preterm birth in European countries beyond the first 2 years of life.

Upf1 regulates neurite outgrowth and branching by transcriptional and post-transcriptional modulation of Arc.

A large number of neuronal proteins must show correct spatiotemporal localization in order to carry out their critical functions. The mRNA transcript for the somatodendritic protein activity-regulated cytoskeleton-associated protein (Arc; also known as Arg3.1) contains two conserved introns in the 3' untranslated region (UTR), and was proposed to be a natural target for nonsense-mediated mRNA decay (NMD). However, a well-known NMD component Upf1 has differential roles in transcriptional and translational regulation of Arc gene expression. Specifically, Upf1 suppresses Arc transcription by enhancing destabilization of mRNAs encoding various transcription factors, including Mef2a. Upf1 also binds to the Arc 3'UTR, resulting in suppression of translation. Surprisingly, the Arc transcript escapes from Upf1-mediated NMD by binding to Ago2 (also known as miRISC), which blocks NMD and further suppresses Arc mRNA translation. Upf1 knockdown triggered sustained Arc expression, which contributes to Cofilin (also known as Cfl1) hyperphosphorylation and abnormal neuronal outgrowth and branching. Collectively, these data reveal that multiple levels of Upf1-mediated inhibition of Arc gene expression may allow neurons to more effectively respond to changes in neuronal activity.

Isoprocurcumenol Supports Keratinocyte Growth and Survival through Epidermal Growth Factor Receptor Activation.

Although proliferation of keratinocytes, a major type of skin cells, is a key factor in maintaining the function of skin, their ability to proliferate tends to diminish with age. To solve such a problem, researchers in medical and skin cosmetic fields have tried to utilize epidermal growth factor (EGF), but achieved limited success. Therefore, a small natural compound that can mimic the activity of EGF is highly desired in both medical and cosmetic fields. Here, using the modified biosensor system, we observed that natural small-compound isoprocurcumenol, which is a terpenoid molecule derived from turmeric, can activate EGFR signaling. It increased the phosphorylation of ERK and AKT, and upregulated the expression of genes related to cell growth and proliferation, such as c-myc, c-jun, c-fos, and egr-1. In addition, isoprocurcumenol induced the proliferation of keratinocytes in both physical and UVB-induced cellular damage, indicative of its function in skin regeneration. These findings reveal that EGF-like isoprocurcumenol promotes the proliferation of keratinocytes and further suggest its potential as an ingredient for medical and cosmetics use.

HNRNP A1 Promotes Lung Cancer Cell Proliferation by Modulating VRK1 Translation.

THeterogeneous nuclear ribonucleoprotein (HNRNP) A1 is the most abundant and ubiquitously expressed member of the HNRNP protein family. In recent years, it has become more evident that HNRNP A1 contributes to the development of neurodegenerative diseases. However, little is known about the underlying role of HNRNP A1 in cancer development. Here, we report that HNRNP A1 expression is significantly increased in lung cancer tissues and is negatively correlated with the overall survival of patients with lung cancer. Additionally, HNRNP A1 positively regulates vaccinia-related kinase 1 (VRK1) translation via binding directly to the 3' untranslated region (UTR) of VRK1 mRNA, thus increasing cyclin D1 (CCND1) expression by VRK1-mediated phosphorylation of the cAMP response element-binding protein (CREB). Furthermore, HNRNP A1 binding to the cis-acting region of the 3'UTR of VRK1 mRNA contributes to increased lung cancer cell proliferation. Thus, our study unveils a novel role of HNRNP A1 in lung carcinogenesis via post-transcriptional regulation of VRK1 expression and suggests its potential as a therapeutic target for patients with lung cancer.

The RNA-binding protein hnRNP Q represses translation of the clock gene Bmal1 in murine cells.

Most living creatures have a circadian rhythm that is generated by a precisely regulated transcriptional-translational feedback loop of clock genes. Brain and muscle ARNT-like 1 (BMAL1) is one of the core clock genes and transcription factors that represents a positive arm of this autoregulatory circadian clock system. Despite the indispensable role of BMAL1 in the circadian rhythm, the molecular mechanisms underlying translational control of BMAL1 are largely unknown. Here, using murine NIH-3T3 cells, gene constructs, and a variety of biochemical approaches, including RNAi- and luciferase reporter gene-based assays, along with immunoblotting, in vitro transcription, quantitative real-time PCR, and real-time bioluminescence experiments, we show that translation of Bmal1 is negatively regulated by an RNA-binding protein, heterogeneous nuclear ribonucleoprotein Q (hnRNP Q). Interestingly, we found that hnRNP Q rhythmically binds to a specific region of the Bmal1 mRNA 5' UTR and controls its time-dependent expression. Moreover, we demonstrate that knockdown of hnRNP Q modulates BMAL1 protein oscillation amplitude without affecting mRNA rhythmic patterns. Furthermore, hnRNP Q depletion increases the mRNA oscillation amplitudes of BMAL1-regulated target genes. Together, our results suggest that hnRNP Q plays a pivotal role in both Bmal1 translation and BMAL1-regulated gene expression.

A method for measuring spatial effects on socioeconomic inequalities using the concentration index.

BACKGROUND: Although spatial effects contribute to inequalities in health care service utilisation and other health outcomes in low and middle income countries, there have been no attempts to incorporate the impact of neighbourhood effects into equity analyses based on concentration indices. This study aimed to decompose and estimate the contribution of spatial effects on inequalities in uptake of HIV tests in Malawi. METHODS: We developed a new method of reflecting spatial effects within the concentration index using a spatial weight matrix. Spatial autocorrelation is presented using a spatial lag model. We use data from the Malawi Demographic Health Survey (n = 24,562) to illustrate the new methodology. Need variables such as 'Any STI last 12 month', 'Genital sore/ulcer', 'Genital discharge' and non need variables such as Education, Literacy, Wealth, Marriage, and education were used in the concentration index. Using our modified concentration index that incorporates spatial effects, we estimate inequalities in uptake of HIV testing amongst both women and men living in Malawi in 2015-2016, controlling for need and non-need variables. RESULTS: For women, inequalities due to need variables were estimated at - 0.001 and - 0.0009 (pro-poor) using the probit and new spatial probit estimators, respectively, whereas inequalities due to non-need variables were estimated at 0.01 and 0.0068 (pro-rich) using the probit and new spatial probit estimators. The results suggest that spatial effects increase estimated inequalities in HIV uptake amongst women. Horizontal inequity was almost identical (0.0103 vs 0.0102) after applying the spatial lag model. For men, inequalities due to need variables were estimated at - 0.0002 using both the probit and new spatial probit estimators; however, inequalities due to non-need variables were estimated at - 0.006 and - 0.0074 for the probit and new spatial probit models. Horizontal inequity was the same for both models (- 0.0057). CONCLUSION: Our findings suggest that men from lower socioeconomic groups are more likely to receive an HIV test after adjustment for spatial effects. This study develops a novel methodological approach that incorporates estimation of spatial effects into a common approach to equity analysis. We find that a significant component of inequalities in HIV uptake in Malawi driven by non-need factors can be explained by spatial effects. When the spatial model was applied, the inequality due to non need in Lilongwe for men and horizontal inequity in Salima for women changed the sign. This approach can be used to explore inequalities in other contexts and settings to better understand the impact of spatial effects on health service use or other health outcomes, impacting on recommendations for service delivery.

Ligament stabilization improved clinical and radiographic outcomes for individuals with chronic ankle instability and medial ankle osteoarthritis.

PURPOSE: Chronic ankle instability with a long symptom duration is often accompanied by medial compartment ankle osteoarthritis (OA). However, the outcomes of individuals after ligament stabilization have rarely been reported. The radiographic and clinical outcomes after ligament stabilization in individuals with chronic ankle instability and medial compartment OA were investigated. METHODS: The study investigated 27 ankles with chronic ankle instability and medial compartment OA that underwent lateral ankle ligament reconstruction from 2007 to 2015 with a follow-up period of at least 1 year. Ligament stabilization was performed via either the modified Broström procedure (MBP) or lateral ankle reconstruction (LAR) using semitendinosus tendon allografts. RESULTS: The median instability duration was 60 (range 12-480) months, and the median follow-up period was 39 (range 12-108) months. The preoperative Takakura ankle OA stage was predominantly stage I (20 patients (74.1%)), followed by stage II (five patients (18.5%)). Ankle MRI (20 ankles) revealed medial cartilage denudation in three cases (15%), cartilage thinning in nine cases (45%), osteophyte formation in ten cases (50%), and loose body formation in six cases (30%). According to the arthroscopic results, the modified Outerbridge grade was two in nine cases and four in ten cases, so these grades were the most common (37.5% and 41.7%, respectively). The MBP was performed in 14 patients, and LAR was performed in 13 patients (52% and 48%, respectively); the bone marrow stimulation procedure was performed in 15 patients (55%). The visual analogue scale score decreased from 6.0 (SD 1.6) preoperatively to 1.8 (SD 1.6) postoperatively (p = 0.000). The American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score improved from 61.9 (SD 14.2) to 89.7 (SD 6.2), and the Karlsson-Peterson score improved from 54.7 (SD 13.9) to 88.3 (SD 9.0) (p = 0.000). There were no serious complications, and all patients were satisfied. CONCLUSIONS: Ligament stabilization with arthroscopic procedures for individuals with chronic ankle instability and medial ankle OA yielded significant functional outcomes with high patient satisfaction, even without radiographic improvement. LEVEL OF EVIDENCE: IV.

Expression of Genes Involved in Axon Guidance: How Much Have We Learned?

Neuronal axons are guided to their target during the development of the brain. Axon guidance allows the formation of intricate neural circuits that control the function of the brain, and thus the behavior. As the axons travel in the brain to find their target, they encounter various axon guidance cues, which interact with the receptors on the tip of the growth cone to permit growth along different signaling pathways. Although many scientists have performed numerous studies on axon guidance signaling pathways, we still have an incomplete understanding of the axon guidance system. Lately, studies on axon guidance have shifted from studying the signal transduction pathways to studying other molecular features of axon guidance, such as the gene expression. These new studies present evidence for different molecular features that broaden our understanding of axon guidance. Hence, in this review we will introduce recent studies that illustrate different molecular features of axon guidance. In particular, we will review literature that demonstrates how axon guidance cues and receptors regulate local translation of axonal genes and how the expression of guidance cues and receptors are regulated both transcriptionally and post-transcriptionally. Moreover, we will highlight the pathological relevance of axon guidance molecules to specific diseases.

Sweroside Prevents Non-Alcoholic Steatohepatitis by Suppressing Activation of the NLRP3 Inflammasome.

Non-alcoholic steatohepatitis (NASH), a type of non-alcoholic fatty liver disease, is characterized as steatosis and inflammation in the liver. NLRP3 inflammasome activation is associated with NASH pathology. We hypothesized that suppressing the NLRP3 inflammasome could be effective in preventing NASH. We searched substances that could inhibit the activation of the NLRP3 inflammasome and identified sweroside as an NLRP3 inhibitor. We investigated whether sweroside can be applied to prevent the pathological symptoms associated with NASH in a methionine-choline-deficient (MCD) diet-induced NASH mouse model. The activation of the NLRP3 inflammasome was determined by detecting the production of caspase-1 and IL-1ß from pro-caspase-1 and pro-IL-1ß in primary mouse macrophages and mouse liver. In a NASH model, mice were fed an MCD diet for two weeks with daily intraperitoneal injections of sweroside. Sweroside effectively inhibited NLRP3 inflammasome activation in primary macrophages as shown by a decrease in IL-1ß and caspase-1 production. In a MCD diet-induced NASH mouse model, intraperitoneal injection of sweroside significantly reduced serum aspartate transaminase and alanine transaminase levels, hepatic immune cell infiltration, hepatic triglyceride accumulation, and liver fibrosis. The improvement of NASH symptoms by sweroside was accompanied with its inhibitory effects on the hepatic NLRP3 inflammasome as hepatic IL-1ß and caspase-1 were decreased. Furthermore, sweroside blocked de novo synthesis of mitochondrial DNA in the liver, contributing to suppression of the NLRP3 inflammasome. These results suggest that targeting the NLRP3 inflammasome with sweroside could be beneficially employed to improve NASH symptoms.

Patterns, trends and methodological associations in the measurement and valuation of childhood health utilities.

PURPOSE: To systematically assess patterns and temporal changes in the measurement and valuation of childhood health utilities and associations between methodological factors. METHODS: Studies reporting childhood health utilities using direct or indirect valuation methods, published by June 2017, were identified through PubMed, Embase, Web of Science, PsycINFO, EconLit, CINAHL, Cochrane Library and PEDE. The following were explored: patterns in tariff application; linear trends in numbers of studies/samples and paediatric cost-utility analyses (CUAs) and associations between them; changes in proportions of studies/samples within characteristic-based categories over pre-specified periods; impact of National Institute for Health and Care Excellence (NICE) guidance on primary UK research and associations between valuation method, age and methodological factors. RESULTS: 335 studies with 3974 samples covering all ICD-10 chapters, 23 valuation methods, 12 respondent types and 42 countries were identified by systematic review. 34.0% of samples using indirect methods compatible with childhood applied childhood-derived tariffs. There was no association between numbers of studies/samples and numbers of CUAs. Compared to 1990-2008, 2009-June 2017 saw a significant fall in the proportion of studies using case series; significant compositional changes across ICD-10 chapters and significantly higher sample proportions using childhood-specific and adult-specific indirect valuation methods, and based on pre-adolescents, self-assessment, self-administration and experienced health states. NICE guidance was weakly effective in promoting reference methods. Associations between valuation method, age and methodological factors were significant. CONCLUSION: 1990-2017 witnessed significant changes in primary research on childhood health utilities. Health technology assessment agencies should note the equivocal effect of methodological guidance on primary research.

A bootstrapping approach for generating an inverse distance weight matrix when multiple observations have an identical location in large health surveys.

Spatial weight matrices play a key role in econometrics to capture spatial effects. However, these constructs are prone to clustering and can be challenging to analyse in common statistical packages such as STATA. Multiple observations of survey participants in the same location (or cluster) have traditionally not been dealt with appropriately by statistical packages. It is common that participants are assigned Geographic Information System (GIS) data at a regional or district level rather than at a small area level. For example, the Demographic Health Survey (DHS) generates GIS data at a cluster level, such as a regional or district level, rather than providing coordinates for each participant. Moreover, current statistical packages are not suitable for estimating large matrices such as 20,000 × 20,000 (reflective of data within large health surveys) since the statistical package limits the N to a smaller number. In addition, in many cases, GIS information is offered at an aggregated level of geographical areas. To alleviate this problem, this paper proposes a bootstrap approach that generates an inverse distance spatial weight matrix for application in econometric analyses of health survey data. The new approach is illustrated using DHS data on uptake of HIV testing in low and middle income countries.

Short-Latency Positive Peak Following N20 Somatosensory Evoked Potential Is Superior to N20 in Predicting Neurologic Outcome After Out-of-Hospital Cardiac Arrest.

OBJECTIVES: The absence of N20 somatosensory evoked potential after cardiac arrest is related to poor outcome. However, discrimination between the low-amplitude and the absence of N20 is challenging. P25 and P30 are short-latency positive peaks with latencies between 25 and 30 ms following N20 (P25/30). P25/30 is evident even with an ambiguous N20 in patients with good outcome. Therefore, we evaluated the predictive value of P25/30 after cardiac arrest. DESIGN: A retrospective observational study. SETTING: University-affiliated hospital. SUBJECTS: Comatose survivors after out-of-hospital cardiac arrest treated by hypothermic targeted temperature management. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The specificity and the positive predictive value of P25/30 and N20 in predicting poor outcome were the same, showing a rate of 100%. The sensitivity of P25/30 in predicting poor outcome (90.12% [95% CI, 81.5-95.6%]) was higher than that of N20 (70.37% [95% CI, 59.2-80%]). Also, the negative predictive value of P25/30 in predicting poor outcome (81.4% [95% CI, 69.4-89.4%]) was higher than that of N20 (59.3% [95% CI, 51-67.1%]). The P25/30-based adjusted model showed a larger area under the curve (0.98 [95% CI, 0.95-1]) compared with the N20-based adjusted model (0.95 [95% CI, 0.91-0.98]) (p = 0.02). CONCLUSIONS: The absence of P25/30 is related to poor outcome with a higher sensitivity, negative predictive value than the absence of N20.

CT arthrography visualizes tissue growth of osteochondral defects of the talus after microfracture.

PURPOSE: Little is known about the arthroscopic or radiographic outcomes after arthroscopic microfracture of osteochondral lesions of the talus (OLTs). The purpose of this study was to investigate tissue growth after arthroscopic microfracture of OLTs using computed tomography arthrography (CTA) and to identify the relationship between CTA findings and clinical outcomes. We hypothesized that the morphology of the repaired tissue would be similar to that of normal anatomy and correlate with the clinical outcomes. METHODS: Forty-two ankles treated using arthroscopic microfracture of OLTs between 2009 and 2014 were monitored. CTA was performed post-operatively at 6 months and at 1 and 2 years after surgery. The post-operative thickness of the repaired tissue associated with OLT (grade) and the volume of the subchondral cystic lesions were evaluated using CTA. Clinical outcomes, including the pain visual analog scale (VAS) and American Orthopaedic Foot and Ankle Society (AOFAS) ankle functional scores, were evaluated and correlated with CTA. RESULTS: The proportion of fully grown tissue (grade 3) increased over time; specifically, the rates were 12/40 (33.3%) at 6 months, 11/18 (61.1%) at 1 year, and 8/10 (80%) at 2 years after surgery (p = 0.005). The VAS pain (p < 0.001) and AOFAS scores (p < 0.001) were also improved at the final follow-up; however, they were not associated with repaired tissue thickness as shown by CTA (n.s.). CONCLUSIONS: After microfracture of OLTs, tissue growth in the osteochondral defects was well visualized using CT arthrography and was observed in most cases. However, the CTA findings were not related to the clinical outcomes. LEVEL OF EVIDENCE: IV.