Cognitive deficits in Parkinson’s disease typically affect executive functions.Recently, the concept of Mild Cognitive Impairment (MCI) has been related to PD(PD-MCI). PD-MCI is considered a transition phase to Parkinson’s diseaseDementia. Therefore, it is important to identify PD-MCI in a reliable way.Objective: To evaluate the sensitivity and specificity of the INECO FrontalScreening (IFS) in detecting cognitive deficits in PD-MCI. Additionally, wecompare the IFS and the Addenbrook Cognitive Examination Revised (ACE-R) betweenthree groups; PD-MCI, MCI, and controls. Methods: The IFS and ACE-R wereadministered to 36 patients with PD-MCI, 31 with MCI (amnestic-multidomainsubtype) and 92 healthy controls. Sensitivity and specificity were determinedusing ROC analysis. The groups were compared using one-way analysis of variance.Results: The IFS had adequate accuracy in differentiating patients with PD-MCIfrom healthy controls , and goodaccuracy in differentiating PD-MCI from MCI patients . However the IFS had low accuracy indifferentiating MCI patients from healthy controls . On the ACE-R, the PD-MCI group had low performance in Fluencyand Language. Only patients with PD-MCI had difficulties on the IFS,specifically in inhibitory control and visual working memory. This dysexecutiveprofile explains the sensitivity and specificity values found in the IFS.Conclusion: The present study results suggest that the IFS is a suitablescreening tool for exploring cognitive dysfunction in PD-MCI, especially inthose patients with a dysexecutive profile. Mild cognitive impairment (MCI) identifies a transitional phase from cognitive changes ofnormal aging to those typically found in dementia, but with preserved activities ofdaily living.,A few years ago, the concept of MCI was related to Parkinson’s disease (PD-MCI).The study of MCI and PD-MCI poses several challenges from a methodological point of view.Perhaps the most important is related to the presence of common risk factors for bothpathologies. For example, age is one of the most important risk factors for thedevelopment of MCI, ,Usually, the investigations that are carried out in patients with PD-MCI presumethat thepresence of cognitive decline is the result of the PD. However, we should bear in mindthat the person exhibiting cognitive decline (possibly PD-MCI) would show signs ofdeterioration before receiving the diagnosis of PD, especially if the disease isdiagnosed after the age of 60. The current results show that although the cognitivedeficits present in AD and PD are heterogeneous, ,,There is also a need to validate the neuropsychological tests used to diagnose cognitivedeficits associated with PD-MCI.There is currently evidence that the INECO Frontal Screening (IFS) has good psychometricproperties, including high internal consistency, for neurodegenerative pathologies, suchas Alzheimer’s Disease (AD)The IFS is an easy-to-administer instrument for assessing several domains of executivefunction in a short time. The IFS comprises eight subtests arranged in three maindomains of executive functions: 1) response inhibition and set-shifting, 2) workingmemory, and 3) capacity of abstraction.,The IFS had been used previously in PD patients with and without mild cognitiveimpairment .In this study, we evaluate the sensitivity and specificity of the INECO Frontal Screeningfor detecting executive deficits in PD-MCI. Additionally, we compare the INECO FrontalScreening between three groups, PD-MCI, MCI, and controls.A total of 159 participants were evaluated in the period from January toSeptember 2016. The sample was divided into 3 groups, comprising 31 patientswith MCI, 36 patients with PD-MCI and 92 cognitively healthy controls. Theparticipants included in the three groups were selected according to thecriteria outlined below.MCI-PD Group. Diagnosis of Idiopathic Parkinson’s disease, based on the UK PDBrain Bank criteria, MCI Group (amnestic-multidomain subtype). We employed the criteria proposed byPetersen:Control Group. The criteria for the control group were as follows: a score >85on the ACE-R,None of the participants included in the study showed clinical signs ofdepression The Addenbrooke Cognitive Examination Revised (ACE-R)Luria motorseries (3 points), Conﬂicting instructions (3points), Go-no go (3 points), Months backwards(2 points), Backwards digit span (6 points), ModifiedCorsi tapping test (4 points), Proverbinterpretation (3 points) and Modified HaylingTest (6 points). The IFS has a maximum possible score of 30 points.High scores indicate preservation of executive functions.INECO Frontal Screening (IFS)All participants received a full explanation of the research objective andsubsequently signed the informed consent form. The cognitive evaluations werecarried out by two clinical psychologists with neuropsychology training. Thedata were obtained observing the regulations of the Ethics Committee of theUniversidad Central “Marta Abreu” de Las Villas, and in compliance with theHelsinki Declaration for Human Research.partial). Cohen classifies .01 as a small effect, .06 as a mediumeffect and .14 as a large effect.The data were processed using SPSS/Windows, version 21. The three groups werecompared using one-way analysis of variance and post-hoc comparisons using theTukey HSD test. Effect sizes were calculated using partial eta squared (ηp=0.77) or INECO FrontalScreening , whereas years of education had apositive linear influence on the ACE-R and INECO Frontal Screening . The present study included 36 patients with PD-MCI, 31 patients with MCIdiagnosis and 92 cognitively healthy controls. The results of the comparison ofdemographics in the three groups are shown in Go-No go subtest between PD-MCI/MCI patients was 0.66, while the area under the ROCcurve of the Modified Corsi Tapping test was 0.77 . Finally, the area under the ROC curve ofthe Modified Hayling Test was 0.80 .An additional analysis was conducted comparing the IFS subtest between the twogroups. The results showed that the area under the ROC curve of thep<0.001). The MCI group had a significantlylower score on the MMSE compared to the PD-MCI group(p<0.001).The results of the comparison of neuropsychological batteries among the threegroups are shown in Attention and Orientation domain of theACE-R showed significant differences in the MCI patient groups compared to thePD and Control groups (p<0.001). Patients with MCI performedworse than PD-MCI patients and healthy controls on the memory component of theACE-R tests (p<0.001). Fluency scores alsodiffered among the three groups. The mean score for the PD-MCI group differedsignificantly from the score in the MCI group (p<0.001). Thecontrol group also differed significantly from both MCI and PD-MCI groups(p<0.001).The means cores on the p<0.001). Concerning the performance on thevisuospatial component of the ACE-R, patients with PD-MCI and MCI performedworse than healthy controls (p<0.001), although there wereno differences between these two groups . Regarding differences in the ACE-R totalscore, both the PD-MCI and MCI groups performed worse than healthycontrols (p<0.001), but no differences between them werefound .The post-hoc comparisons also revealed differences among the three groups on thelanguage domain. However, patients with PD-MCI had significantly lower scores onthe language domain than MCI patients and cognitively healthy controls andcognitively healthy controls (p=0.03). No significantdifferences between the MCI and control groups were found(p=0.95). On the Modified Corsi tapping test,the PD-MCI group had significantly lower scores than the MCI group and controls(p<0.001). No differences were found between MCIpatients and controls on this subtest (p=0.41). Significantdifferences were found on the Modified Hayling test andTotal IFS between the PD-MCI group and the other twogroups, while no significant differences between the MCI and control groups werefound for these two variables.The PD-MCI patients had significantly lower scores on the In this study, we evaluated the sensitivity and specificity of the INECO FrontalScreening in detecting cognitive deficits in PD-MCI. Additionally, we comparedcognitive performance on the INECO Frontal Screening among the three groups: PD-MCI,MCI, and controls. Concerning the usefulness of the ACE-R and the INECO Frontal Screening, it was foundthat in MCI patients, the ACE-R possessed a high sensitivity and diagnosticspecificity. These results confirm previous findings reporting the clinical utilityof ACE-R in the diagnosis of MCI.-Both the ACE-R and the IFS showed adequate diagnostic sensitivity and specificity forthe detection of the cognitive deficits present in the PD-MCI patients in comparisonwith healthy controls. There is current evidence that Addenbrooke’s CognitiveExamination Revised (ACE-R) and the ACE-III have very good diagnostic sensitivityfor cognitive decline in Parkinson disease.Compared to the ACE-R, the IFS showed better sensitivity and specificity whendiscriminating between the patients from the PD-MCI groups and the MCI patients. Inparticular, the IFS sub-tests that showed the best sensitivity and diagnosticspecificity were those related to the processes of visual working memory andinhibitory control. This result may be related to the fact that cognitivedeterioration in PD begins with impairments on tests that are sensitive to frontallobe dysfunction, and then progresses with deficits on tests that involve moreposterior cortical areas.,In our results, the ACE-R showed low precision for discriminating between PD-MCI andMCI associated with Alzheimer’s ,while the area under the ROC curve of the IFS was 0.80 . Other investigations have indicated that theIFS may be used as a screening test for executive dysfunction in otherneurodegenerative conditions, such as Alzheimer Disease (AD),The tasks that showed the greatest ability to discriminate between PD-MCI and MCIpatients are those that explore inhibitory control (Go-No Go and Modified Haylingtest)and visual working memory (Modified Corsi tapping test). With regard to workingmemory, there are previous studies reporting that patients with mild-to-moderate PDwere impaired on a test of visuospatial WM, while their performance on an analogoustest of verbal WM was unaffected.In the case of the inhibitory control evaluated by the IFS using the Modified Haylingtest, our results confirm the findings obtained by other studies that have exploredpatients with PDD. For example, a recent study investigated inhibitory control inpeople with Alzheimer’s disease dementia (ADD) and patients with Parkinson’s diseaseusing the Hayling Sentence Completion Test (HSCT). According to some authors, theinhibitory control difficulties present in patients with Parkinson’s disease couldbe a characteristic with prognostic value to determine the risk of dementia.In relation to the second objective of the study, significant differences were foundin MCI group compared with the other groups, in the Attention and Orientationdomains, and Memory. The difficulties found in Language and the global score on theACE-R did not differ from those attained by the PD-MCI group, but were both worsethan the performance shown by the control group. The results obtained support thepresence of a continuum of cognitive function within the concept of MCI, even whenthe main impairment affects memory.In PD-MCI patients, difficulties were detected in the fluency and language domainsevaluated by the ACE-R, results that were significant in comparison with the othergroups. These results support the findings of other studies reporting deficits inlanguage among patients with PD. Previous research indicates difficulties in severalprocesses related to language, such as processing action-related verbs, Regarding the results achieved on the INECO Frontal Screening, difficulties werefound in the executive functions by the PD-MCI groups that were significant incomparison with the other groups included in the study. The executive tasks on whichthe PD-MCI patients had difficulties were related to inhibitory control and visualworking memory. Additionally, total score on the IFS was statistically lower in thePD-MCI group than the MCI or healthy groups. The MCI group presented no difficultieson any of the executive domains evaluated by the IFS, showing similar performancecompared to healthy controls.,,,,,Our results are consistent with other studies assessing the most common MCI subtypesand their associations with later development of dementia in PD.The present study had some limitations. First, our PD-MCI and MCI samples arerelatively small, with only 36 PD-MCI cases, and 31 MCI patients. In future studies,large samples are needed to confirm statistically significant differences betweendiagnostic instruments. Second, we were unable to explore the relationship betweenneuropsychological assessments and other biomarkers in the MCI and PD-MCI patientsbecause of economic and technological limitations. Consequently, the clinicaldiagnosis of MCI and PD-MCI were based on a comprehensive diagnostic procedure asthe ultimate gold standard. In conclusion, this is the first study comparing performance on the IFS in subjectswith MCI related to Alzheimer’s disease, PD-MCI patients, and healthy oldercontrols. Our results showed that the IFS has a low capacity for discriminatingbetween patients with MCI and healthy controls, while the ACE-R possesses a highdiagnostic capacity to differentiate between these groups. In PD-MCI patients, boththe IFS and the ACE-R have high sensitivity and diagnostic specificity when comparedwith healthy controls.The ACE-R did not display discriminatory capacity to differentiate between PD-MCIpatients and MCI related to Alzheimer’s disease. The IFS had adequate capacity todiscriminate between PD-MCI and MCI patients related to Alzheimer’s disease,specifically the subtests of visual working memory and inhibitory control. Theseresults suggest that the joint use of IFS and global screening tools for thecognitive investigation of PD-MCI would allow detection of the cognitive deficitspresent in these patients, facilitating early intervention and preventing MCIconversion to dementia.


P < 0.001). Multivariable analysis determined that hs-CRP/PAB ratio was an independent predictor of MACE . Moreover, the area under the curve value of hs-CRP/PAB ratio for predicting MACE was higher than hs-CRP and equal to PAB. High hs-CRP/PAB ratio was considered as a prognostic parameter of MACE in ACS patients, with the predictive power equal to PAB but greater than hs-CRP.The study aimed to determine whether high sensitivity C-reactive protein to prealbumin (hs-CRP/PAB) ratio could be used to predict in-hospital major adverse cardiac events (MACE) in patients with acute coronary syndrome (ACS). A total of 659 patients with ACS were included in the study. Patients were divided into two groups: high hs-CRP/PAB ratio group (hs-CRP/PAB ≥0.010) and low hs-CRP/PAB ratio group (hs-CRP/PAB <0.010). MACE was defined as death, cardiogenic shock, re-infarction and acute heart failure. Logistic regression was performed and the receiver operating characteristic curve (ROC) was generated to evaluate the correlation of hs-CRP/PAB ratio and MACE in patients with ACS. The occurrence rate of MACE was significantly higher in high hs-CRP/PAB ratio group when compared with that in low hs-CRP/PAB ratio group ( Therefore, it is urgent to find appropriate and effective risk factors to conduct early estimation and disease prevention. Several biomarkers have been investigated for the diagnosis and risk stratification of acute coronary syndrome (ACS): cardiac troponin, creatine kinase-myocardial band and high sensitive C-reactive protein (hs-CRP). The newly discovered nardilysin is a promising biomarker for the early diagnosis of ACS3.Cardiovascular disease is still the leading cause of mortality in the world5. Accumulating evidence suggests that hs-CRP is a useful prognostic indicator for major adverse cardiovascular events (MACE) in patients with heart disease8. Prealbumin (PAB) is synthesized by the liver too and suppressed in the inflammatory environment10. Investigations have shown that PAB in both the acute and chronic heart failure patients could predict mortality13. A recent study demonstrated that the PAB level is inversely related to angiographic severity score in ACS patients14. In our previous study, we found that PAB could independently predict MACE in patients with ACS15.Inflammation plays a vital role in the process of atherosclerosis. As a marker of inflammation, hs-CRP is synthesized by the hepatocytes and mainly regulated by interleukin-6 (IL-6)19. However, up until now, there has been little research focusing on hs-CRP/PAB ratio for the prediction of clinical outcomes in ACS patients. Thus, the purpose of this research was to explore the possibility of using hs-CRP/PAB ratio to predict in-hospital MACE in patients with ACS.Both hs-CRP and PAB are produced by hepatocytes and can be measured in the blood. The newly introduced hs-CRP/PAB ratio reflects the patient’s inflammatory status better than either hs-CRP or PAB alone. Investigations have demonstrated that hs-CRP/PAB ratio is superior to either hs-CRP or PAB alone in assessing not only the severity but the prognosis of patients with acute kidney injury, fistula closure and other critically patientsP < 0.001).A total of 659 patients were enrolled in this study with mean age of 66.5 years and 360 patients (54.6%) were male. The demographic and clinical characteristics of the two groups are shown in Table P < 0.001, respectively). However, there was no significant difference between the two groups in the death rate . The proportion of total MACE and acute heart failure was higher in the high hs-CRP/PAB ratio group as compared to the low hs-CRP/PAB ratio group (P < 0.001). In multivariable logistic regression analysis, adjusted for age, hypertension, previous CAD, glucose, estimated glomerular filtration rate and low-density lipoproteins (LDL) cholesterol, the results showed that hs-CRP/PAB ratio remained independent and predicted MACE , as well as hs-CRP and PAB . The area under the curve (AUC) value of hs-CRP/PAB ratio was significantly higher than hs-CRP  , while no statistically significant difference was found between hs-CRP/PAB ratio and PAB  . The best cut-off value, sensitivity and specificity of hs-CRP, PAB and hs-CRP/PAB ratio for predicting MACE is shown in Table To further investigate the value of hs-CRP/PAB ratio, hs-CRP and PAB in predicting MACE, we performed receiver operating characteristic (ROC) curves Fig. . The besThis study was a proof-of-concept study which served to demonstrate the hypothesis that the ratio of hs-CRP/PAB could be used as an early biomarker, to predict the in-hospital MACE in patients with ACS. In the present study the most interesting finding was the incidence rate of MACE was increased in the high hs-CRP/PAB ratio group. After adjusting for other confounding factors, the association between hs-CRP/PAB ratio and poor outcomes was still evident. Thus, we believe that hs-CRP/PAB ratio could be very helpful to predict MACE in patients with ACS.3. In the past, the role of hs-CRP in cardiovascular disease was controversial as a risk marker. Recent studies showed that hs-CRP plays an important role in the progression of atherothrombosis. Hs-CRP elevation is a marker of inflammation that can induce vascular remodeling and coronary atherosclerotic plaque rupture21. Elevation of hs-CRP levels were also observed and associated with adipocytokine imbalance22, which result in visceral fat accumulation and thereby increase the risk of ACS development. Moreover, elevated hs-CRP levels were associated with reduced abilities in clearance of oxidative stressors and inflammatory mediators, thus increase the incidence of cardiovascular events23. It has been reported that elevated hs-CRP levels were associated with increased risk of adverse cardiovascular outcomes in patients with different CAD phenotypes26. Aguilar et al. focused on stable CAD and enrolled 3319 patients and followed up for 37 months, they found that increased levels of hs-CRP were associated with higher risk of adverse cardiac events24. The FRISC study included 917 patients with unstable coronary artery disease and the investigators found that elevated CRP levels were strongly associated with the long-term risk of death from heart disease25. In the current interventional era, higher hs-CRP levels at admission were associated with lower reperfusion success27. In accordance with these results, we have observed that hs-CRP could predict in-hospital MACE in patients with ACS. Furthermore, elevated hs-CRP levels were associated with the severity of CAD26; similarly, in our study, we also found patients with 3-vessel disease tended to have higher levels of hs-CRP.Many biomarkers were associated with the development and progression of coronary heart disease18. PAB as a parameter in the evaluation of nourishment state was suppressed in an inflammatory environment10. Observations show that PAB is transferred by high-density lipoproteins (HDL); the absence of PAB can affect the stability of the HDL particles, and then reduce its protective effect on the heart28. Low levels of PAB in malnourished patients may parallel with vitamin C deficiency29, which may link with adverse cardiac events, since vitamin C plays a key role in antioxidant and anti-inflammatory process30. Decreased levels of PAB could increase free thyroxine, which was associated with adverse outcomes in patients with acute myocardial infarction31. Clinical studies have revealed that a lower level of serum PAB was associated with prognosis of heart failure13, higher overall mortality in critically ill patients32, and negatively associated with angiographic severity in patients with ACS14. The above research results illustrated that patients with low PAB levels have poor clinical outcomes.However, using of hs-CRP alone to predict MACE in patients with ACS may be limited. Inflammation can induce malnutrition, which may exert a negative effect on the management of inflammationHs-CRP/PAB ratio reveals the balance between hs-CRP and PAB in the body and also assesses inflammatory and nutritional status of a patient’s condition. When the value of either marker changes, the ratio could change accordingly but presented a higher sensitivity than using either marker alone. To the best of our knowledge, the current study is the first time to demonstrate that hs-CRP/PAB ratio is an independent predictor of in-hospital MACE in patients with ACS. Furthermore, the prognostic value of the hs-CRP/PAB ratio for predicting in-hospital MACE is significantly greater than the traditional risk factor, which is hs-CRP. In the present study, the predictive power of hs-CRP/PAB ratio was equal to PAB, further study with more patients and longer follow-up duration may help to evaluate if hs-CRP/PAB ratio is a better index than PAB.This is an observational study; notwithstanding, it offers a rapidly assessable marker for clinical practice. The detection of serum hs-CRP and PAB is quite convenient in recent years, the ratio of hs-CRP to PAB may aid the risk stratification of patients with ACS and have been widely available to clinicians.The present study has several limitations. First, deaths were defined as all-cause deaths in this study and cardiovascular disease-related mortality should be further analyzed. Second, this was a single center study and a relatively small sample was recruited. Third, stable angina pectoris or asymptomatic coronary atherosclerosis patients were not recruited in the study. Fourth, the prognostic and predictive ability of hs-CRP/PAB was only investigated about the in-hospital MACE. So, larger sample size, including patients with stable angina pectoris or asymptomatic coronary atherosclerosis, and multicenter studies are needed to further confirm the initial findings of this study.In conclusion, this study indicates that elevated hs-CRP/PAB ratio is associated with in-hospital MACE in patients with ACS and this ratio may be used as a biomarker, to predict adverse events in patients with ACS with a predictive power equal to PAB but greater than hs-CRP.34. The inclusion criteria were ACS patients with angina occurred in the 24 hours and agreed to participate in this study. The exclusion criteria as follows: chronic heart failure (NYHA class >II), stage V chronic kidney disease or patients on regular dialysis, hepatic cirrhosis, malignancy or valvular heart disease, concomitant acute infection, stroke or venous thromboembolism. All the protocol was approved by the Ethics Committee of Liaocheng People’s Hospital and informed consents were obtained from all participants. All research was performed in accordance with the relevant guidelines/regulations.This cohort study was conducted from March to October 2017, ACS patients consecutively admitted to the Department of Cardiology of Liaocheng People’s Hospital, affiliated with Shandong University were enrolled in this study. Diagnosis and determination of ACS were applied according to AHA or ACCF guidelinesAfter enrollment, venous blood samples were drawn immediately on admission before reperfusion therapy. Clinical presentations were assessed, and characteristic data was collected by the attending physician on admission. Cardiovascular risk factors, including age, gender, diabetes mellitus, hypertension, smoking status and previous CAD were all noted. Hypertension was defined as the use of antihypertensive drugs or blood pressure ≥140/90 mmHg. Diabetes was defined as fasting plasma glucose of at least 7.0 mmol/L or glucose level ≥11.1 mmol/L in 2-hour glucose from an oral glucose tolerance test. Coronary angiography was performed through the femoral or radial approach and the results were interpreted by two experienced interventional cardiologists. Coronary artery with diameter obstruction >50% were considered to exhibit stenosis. Blood biochemical indexes including LDL cholesterol, liver and kidney function and blood glucose were routinely performed at the hospital’s central laboratory using Hitachi 7600–120 analyzer . Hs-CRP and PAB were measured in the clinical laboratory, using a biochemical analyzer , according to the manufacturer’s instructions. They were analyzed by immunoturbidimetry using original reagent which supplied by Beckman Coulter.The endpoint of this study was in-hospital MACE, which included death, cardiogenic shock, re-infarction and acute heart failure during hospitalization. Deaths were defined as all-cause deaths. Cardiogenic shock was defined as a persistent systolic blood pressure less than 90 mm Hg, or signs and clinical manifestations of low perfusion with administration of vasopressor agents subsequently. Re-infarction was diagnosed by recurrent or newly occurring chest pain, with new ST segment changes or cardiac troponin I levels that rose again. Acute heart failure was diagnosed according to clinical signs and symptoms: such as pulmonary edema on physical examination or breathlessness symptoms, subsequent use of intravenous diuretics or positive inotropic agents. The MACE was determined by attending cardiologists who provided the treatment accordingly.t-test was used for comparison of normally distributed continuous variables and the Mann-Whitney U test was used for comparison of values that do not normal distribution. Continuous variables were presented as mean ± standard deviation for normal distribution and median (quartile deviation) for those with non-normal distribution. A chi-square test and Fisher exact test was used to compare categorical data. The variables that may associate with in-hospital MACE were calculated in univariate analysis, those showed a univariate relationship with MACE or clinically relevant were included in the multivariable logistic regression model. Given the number of MACE available, the included variables were carefully chosen, to ensure the final model robust. ROC analysis was carried out to establish the best cut-off value of hs-CRP, PAB and hs-CRP/PAB ratio for predicting in-hospital MACE. The Z-test was used to compare the AUC values of hs-CRP, PAB and hs-CRP/PAB ratio. A P value < 0.05 was determined as statistically significant.SPSS software version 17.0 was used for statistical analysis. The median value of hs-CRP/PAB ratio (0.010) was set as the cut-off point, the patients were divided into the hs-CRP/PAB ratio ≥0.010 (high hs-CRP/PAB ratio) group and the hs-CRP/PAB ratio <0.010 (low hs-CRP/PAB ratio) group for analysis. The Kolmogorov-Smirnov test was used to assess whether continuous data were normally distributed. Student’s


Infants with respiratory distress syndrome, bronchopulmonary dysplasia, patent ductus arteriosus ligation, periventricular leukomalacia, and retinopathy of prematurity were more common in the compliance group. Follow-up rates showed significant differences according to NICU volume. Using multivariate logistic regression, high birth weight, low NICU volume, siblings, foreign maternal nationality and high 5 min APGAR scores were significant independent factors associated with the non-compliance of VLBW infants for follow-up at 18–24 months of age. This is the first nation-wide analysis of follow-up for VLBW infants in Korea. Understanding factors associated with failure of compliance could help improve the long-term follow-up rates and neurodevelopmental outcomes through early intervention.The critical need to emphasize preterm infant follow-up after neonatal intensive care unit (NICU) discharge assures early identification of and intervention for neurodevelopmental disability. The aims of this study were to observe the follow-up rates in high-risk follow-up clinics, and analyze factors associated with non-compliance to follow-up among very low birth weight (VLBW) infants. The data was prospectively collected for 3063 VLBW infants between January 2013 and December 2014 from 57 Korean neonatal network (KNN) centers at a corrected age of 18–24 months. Correlations among demographic data, clinical variables, and neonatal intensive care unit (NICU) volume (divided into 4 quartiles) with the occurrence of non-compliance were analyzed. The overall follow-up rate at the corrected age of 18–24 month was 65.4%. The follow-up rates were inversely related to birth weight and gestational age. Apgar score, hospital stay, maternal age, and maternal education were significantly different between the compliance and non-compliance groups. The follow-up rate was higher for mothers with chorioamnionitis, abnormal amniotic fluid, multiple pregnancy, and  Improvement of survival rates for very low birth weight (VLBW) and extremely preterm infants resulted in advances in perinatal and neonatal care –3. HowevHigh-risk infants who missed follow-up were more likely to present with severe impairment, such as cognitive impairment, or sensory adverse events. Prior research has found many factors to be associated with NICU follow-up appointment compliance ,12–15. TThe Korean Neonatal Network (KNN) was established in 2013 to improve data collection systems in participating facilities and study various factors associated with mortality and morbidity of VLBW infants in Korea. Long-term data were also collected at the corrected age of 18–24 months and postnatal age of 3 years for VLBW infants. A better understanding of long-term outcomes in a national cohort will lead to improved approaches to neonatal care for VLBW infants in Korea. However, successful compliance with appropriate care and presentation to follow-up clinics must be guaranteed first and foremost.The aims of this study were to observe the follow-up rates to high-risk follow-up clinics at the corrected age of 18–24 month, and to identify predictors of non-compliance to follow-up among VLBW infants in the KNN.Data were prospectively collected for 3522 VLBW infants born between January 2013 and December 2014 from 57 KNN centers by local staff using a standardized electronic case report form ,17. The This study was approved by the Samsung medical center institutional review board (2013-03-002). The data registry was approved by each institutional review boards of all 57 hospitals participating in the KNN. Written consent was obtained from the parents of infants during enrollment in KNN.Several factors potentially associated with non-compliance to follow-up clinics for VLBW infants were evaluated. Maternal, demographic, and NICU-related data were obtained through KNN records. Gestational age was determined by obstetric examination with ultrasonography early during the pregnancy or, via obstetric history based on the mother's last menstrual period. Birth weight was recorded for each baby as soon as they arrived at the NICU for admission. Bronchopulmonary dysplasia was defined by NIH classification . NecrotiUnadjusted comparisons of maternal demographics and neonatal characteristics between the compliant and non-compliant groups with high-risk follow-up were performed using a chi-squared or Fisher’s exact test for categorical data and Student’s t-test for continuous data. The correlations between compliance to follow-up clinics, gestational age, and birth weight were evaluated using Pearson’s correlation coefficients. Receiver operating characteristic (ROC) curve analysis with associated area under the curve (AUC) was conducted to explore the discriminate ability of NICU volume, gestational age, and birth weight in predicting compliance to follow-up clinics with the selection of the most suitable cut-off point of each parameter with the best sensitivity, specificity, and overall accuracy. Multivariate analyses of variables found to be significant on univariate analysis were also performed to identify independent predictors of non-compliance to follow-up clinics. All statistical analyses were performed using SPSS software version 25.0  and P values of < 0.05 were considered significant.in vitro fertilization, maternal age, chorioamnionitis, maternal education level, maternal nationality, Apgar score, and siblings.Among 3063 infants survived to discharge, 2003 infants (65.4%) were followed-up at the corrected age of 18–24 months. Significant differences were found for the following factors between the compliant and non-compliant groups, as shown in Follow-up rates were significantly and inversely correlated with gestation and birth weight (P < 0.001) .Neonatal morbidity such as respiratory distress syndrome (RDS), air leak, patent ductus arteriosus (PDA) ligation, periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), and duration of supplement oxygenation showed significant differences between the compliant and not-compliant groups .rd quartile, and the largest NICU volume group showed significant differences in the follow-up rate compared to others  showed an AUC of 0.567 (sensitivity of 55.9% and specificity of 54.4% for a cutoff of 1162.5 g). For gestational age and follow-up (P < 0.001), the AUC was 0.560, with a sensitivity of 54.2% and specificity of 53.5% for a cutoff of 29.2 weeks. For NICU volume and follow-up (P < 0.001), the AUC was 0.612, with a sensitivity 53.0% and specificity of 59.1% for a cutoff of 3In multiple logistic regression, foreign maternal nationality, siblings, 5-min APGAR score, birth weight, and NICU volume were confirmed as significant predictors of non-compliance to follow-up .Preterm infant follow-up clinics after NICU discharge play important roles in monitoring growth and development; provides continuity of medical care; and provides assurance of appropriate therapeutic interventions . High foLack of developmental follow-up has been associated with higher rates of neurodevelopmental impairment. The American Academy of Pediatricians recommends that preterm infants be followed-up by physicians affiliated with a NICU ,23. HowePrior research has identified many factors associated with NICU follow-up appointment compliance. Maternal drug use (odds ratio [OR] = 0.049), multiple gestation pregnancy (OR = 0.163), male sex (OR = 0.308), and greater distance from the hospital (OR = 0.987) ,14,24–28In this study, the compliant group had higher rates of multiple pregnancies. Previous reports showed that non-compliance after a multiple pregnancy might be due to the fact that caring for two sick newborns puts even more stress on the resources and time of a family than caring for one newborn . This diHigher NICU volume was associated with greater odds for high-risk infant follow-up referrals . In thisrd quartile, gestational age ≤ 29 weeks, and birth weight ≤ 1160 g were found to be significantly associated with compliance to follow-up. The parents of infants with a large gestational age and a high birth weight reflects the feeling of decreased need for follow-up.The ranked order of variables for predicting compliance to follow-up, as assessed by AUC analysis is as follows: NICU volume (0.612), birth weight (0.567), and gestational age (0.560) with poor prediction. It may be caused by the fact that compliance to follow-up is related with more than a single birth variable. Multiple variables, such as comorbidities and maternal factors, may exist. NICU volume ≥ 3In order to improve the follow-up rate, it is essential to make an appropriate follow-up appointment at the time of NICU discharge . HoweverVarious interventions could potentially be used to increase the follow-up rate after NICU discharge. To provide patient education through printouts, conversations with primary health care physicians, and videos can help families recognize the importance of follow-up clinics. Reminder letters and phone calls have also been used with success . In partThe limitation of this study was that it narrowly defined compliance to follow-up as collecting the data at the corrected age of 18–24 months. Families ultimately attending a follow-up clinic during a different age window were considered non-compliant. Furthermore, the non-compliant group may also include cases of death after discharge. NICU volume assumed as total number of annual enrollments in KNN during study period, it may have variation within the year and sites. Additionally, regional aspects such as distance, and resources for the hospital were not analyzed.In conclusion, through this first nationwide study, we detected the factors associated with non-compliance to follow-up at the corrected age of 18–24 month. Strategies, such as patient education, reminder phone calls, and an organized system of storing and remembering appointments, should be used particularly targeted to families who may be at risk of non-compliant to follow-up based on the factors we have identified. This could contribute to improve patient care accordingly and long-term outcome through early detection and intervention.


Objective: The US Burden of Disease Collaborators reported that between 1990 and 2016, the top 10 states with increasing probability of death between the ages of 20 and 55 years were all in the South. A recent study of annual surveillance data found that increasing all-cause mortality rates were occurring in middle-age non-Hispanic whites. The vast proportion of all-cause mortality consists of medical causes, not external causes . It has been hypothesized by researchers that the ongoing opioid epidemic has an etiologic role in the trend of increasing medical death, but ecological studies looking for an association have not been published. The objective of this study was to test the hypothesis that hydrocodone and oxycodone sales are temporally associated and correlated with annual NHW45-54 medical-cause mortality rates in the Deep South region comprised of Alabama, Arkansas, Louisiana, Mississippi, Oklahoma, and South Carolina.Methods: Mortality and opioid sales data were obtained from the Centers for Disease Control and Prevention Wonder Detailed Mortality and University of Wisconsin State Health Access Data Assistance Center databases, respectively. Annual, state and regional NHW45-54 medical-cause mortality and opioid sales data were analyzed using Spearman rank correlation (rs) testing, after first and second differencing, in order to achieve stationarity and control for trend similarities.Results: Sales of prescription opioids follow very similar temporal patterns across these six states, with simultaneous increases in 2007 and 2013. With few exceptions, annual opioids sales trends were correlated state-to-state. Two prominent spikes are evident in the aggregated opioid sales trends of the six states, with both sales spikes preceding same-directional fluctuations in medical-cause mortality by ~1 year. After a 1 year adjustment of second-differenced data, population hydrocodone exposure was correlated with female NHW45-54 population medical-cause mortality ; and oxycodone exposure correlated with male NHW45-54 population medical-cause mortality .Conclusions: State sales of prescription hydrocodone and oxycodone in the six states studied follow non-random, systematic trajectories. A strong correlation and temporal association exists between prescription opioid sales and medical-cause mortality in this Deep South NHW45-54 population. Life expectancy worldwide has generally been increasing for more than 100 years . AssociaBetween 1990 and 2016, the top 10 states with increasing probability of death between the ages of 20 and 55 years were all in the South. These states were: Alabama, Arkansas, Kentucky, Louisiana, Mississippi, New Mexico, Oklahoma, South Carolina, Tennessee, and West Virginia. The greatest proportion of all-cause mortality in these states is comprised of medical disease, not external causes  . Given tMost studies measuring associations between prescription opioids and mortality are small, and focus on individual exposure and overdose outcomes. The diversion of prescribed opioids into the broader, non-patient population is commonplace —thus, prThe aim of this study was to determine whether population exposure to prescription opioids in the South is a risk factor for increasing NHW45-54 medical-cause mortality . The objective was to test the hypothesis that aggregated hydrocodone and oxycodone sales are temporally associated and correlated with annual NHW45-54 medical-cause mortality rates in the Deep South region comprised of Alabama, Arkansas, Louisiana, Mississippi, Oklahoma, and South Carolina.P-value >0.05) after first-differencing; therefore, data from these states were dropped from the current study  and V01-Y89 . The following cause-of-death categories were included in the dataset for analyses:Annual medical-cause mortality data were obtained from the publicly accessible Centers for Disease Control and Prevention (CDC) Wonder Detailed Mortality database . The IntA00-B99 (Certain infectious and parasitic diseases)C00-D48 (Neoplasms)D50-D89 (Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism)E00-E88 G00-G98 (Diseases of the nervous system)H00-H57 (Diseases of the eye and adnexa)H60-H93 (Diseases of the ear and mastoid process)I00-I99 (Diseases of the circulatory system)J00-J98 (Diseases of the respiratory system)K00-K92 (Diseases of the digestive system)L00-L98 (Diseases of the skin and subcutaneous tissue)M00-M99 N00-N98 (Diseases of the genitourinary system)O00-099 P00-P96 Q00-Q99 R00-R99 U00-U00 By de-selecting the two broad categories of external-cause mortality from the dataset , overdoses, depression, suicide, homicide, and other unintentional traumatic deaths were excluded from the data analyses. The categories of 45–54 years of age and non-Hispanic white mortality were selected in the CDC database. Mortality rates are presented as deaths per 100,000. All data were anonymized by the database owners prior to this project. Mortality data were not used in the final models if suppressed by CDC, due to sparseness.Annual hydrocodone and oxycodone sales data in kilograms per 100,000 persons were collected from the publicly accessible University of Wisconsin State Health Access Data Assistance Center (SHADAC) database; the data of which originated at the US Drug Enforcement Agency's Automated Reports and Consolidated Ordering System (ARCOS) Retail Drug Summary Reports .P-value < 0.05); after first-differencing. All individual state hydrocodone sales datasets, after first-differencing, failed to meet criteria for stationarity using ADF testing ; but after second-differencing, criteria for stationarity were met by all except Arkansas and Oklahoma. The six-state aggregated hydrocodone sales dataset also required second-differencing to achieve stationarity. State oxycodone sales datasets, after first-differencing, failed to meet criteria for stationarity using ADF testing ; therefore, second-differencing of the datasets was undertaken; with all but Mississippi and Oklahoma datasets meeting criteria for stationarity. The six-state aggregated oxycodone sales dataset also required second-differencing to achieve stationarity.All data collected were trending upward from 2000 to 2017 . Augmented Dickey-Fuller (ADF) tests were performed with trend in the regression and a lag of one. Aggregated state medical-cause mortality datasets met criteria for stationarity using ADF testing  testing, after second differencing, in order to achieve stationarity and control for increasing trend similarities. Mortality time series graphs were generated to demonstrate trend and period effect comparisons between populations. Graphs that compare mortality and opioid sales time series period effects utilize a dual-Y-axis format automatically produced by Stata 15.1, in order to compare period effects of variables with different measurement units.(16) = 0.701, P = 0.001], using first-differences  = 0.3298, P = 0.168], whereas female mortality rate continued to climb.The six-state-aggregated medical-cause mortality time series increased during the first 10 years for both females and males ; however, the gender-specific trends diverged after 2008 . Male me(16) = 0.954, P < 0.001] , and an overall upward trend was demonstrated [rs< 0.001] . In the State sales of prescription hydrocodone followed very similar, upward trends in all six states , with siSales of prescription oxycodone also had similar period effects across the six states, but with greater variability . Common (15) = 0.655, P = 0.003] and , respectively. Hydrocodone sales spiked in 2007 and 2013, and oxycodone sales also spiked in 2007  = 0.540; P = 0.038] ((13) = 0.607; P = 0.016] ((13) = 0.257; P = 0.355], or oxycodone sales and female mortality .After 2nd differencing both datasets , and adjusting the medical-mortality datasets 1 year back , population hydrocodone exposure was correlated with female NHW45-54 medical-cause mortality [rs= 0.038] ; and oxy= 0.016] . CorrelaThis is the first study that attempts to demonstrate a correlation between population exposure to prescription opioids and population medical-cause mortality. The time series correlations, and temporal association of period effects between opioid sales and NHW45-54 medical-cause mortality rates indicate that prescription opioids are a risk factor for rising medical-cause mortality in this population. This study controls for trend in the exposure and outcome variables, and it is therefore unlikely that the correlations are coincidental or spurious. Individual-level studies will be necessary to determine whether the rising medical mortality in the South exists due to actual medical disease, and which diseases; or represents misclassification of death .The United States is in the midst of an historic opioid epidemic that began in the 1990s –14, drivVarious medical co-morbidities at the individual-level are known to be associated with opioid abuse and addiction: infections  , immune Opioid use disorder is defined as a problematic pattern of opioid use leading to clinically significant impairment or distress , 27, andSales of hydrocodone, and to a lesser extent oxycodone, in the six study states have simultaneous spikes, and appear to have been systematic across the region. All but one state pair in the six states exhibited strong correlations in hydrocodone sales—clear indication that these fluctuations are non-random. Determining the cause of these non-random sales patterns will be important in the planning of future health care policies in the US. An examination of government policies, healthcare management plans, and prescribing practices in these Deep South states will give more information on the systematic nature of sales across the states.Major fluctuations in opioid sales are closely followed by same-directional trajectory changes in medical-cause mortality, by ~1 year. The first two spikes in NHW45-54 medical-cause mortality occurred during a rapid escalation in Medicaid opioid prescribing, which could have modified the effect between overall opioid sales and mortality prior to 2006. It has been demonstrated that prescription opioid use is more prevalent in patients with public insurance . ResearcThis study demonstrates that hydrocodone sales are associated with female medical-cause mortality, and oxycodone sales are associated with male medical-cause mortality. After 2008, female mortality in the study population continued to increase while male mortality remained stable and then decreased. In 2013, another prominent spike in hydrocodone sales is observed, but not oxycodone sales, when female mortality rates continued to rise. It has been shown that prescription opioid use is more common in females , 32, andSeveral other known mortality risk factors have been hypothesized to be etiologic of increasing mortality in the US. Smoking, obesity, and poverty all have known associations with population mortality, but these risk factors have not been linked to the current increasing mortality or the time series period effects. Poverty in the deep South has been rising, but not with great variability. One must also consider the possibility that prescription opioids are an upstream determinant of unemployment and poverty.Smoking is well-known to be associated with poverty and mortality, and has been hypothesized to be a possible cause of rising mortality. But, smoking rates have not increased in the past 20 years, and dramatic year-to-year fluctuations certainly not reported. The delayed uptake  of smoking decades ago by women could be one reason medical-cause mortality is increasing in women, but this would not hold true for rising male mortality from 1999 to 2008. Southern states have seen an increased prevalence of obesity in the last 20 years, and increasing morbidity and mortality of obesity-related diseases might follow. However, once again, the impact of obesity on population mortality will not likely lead to mortality time series period effects with such non-random variability, as seen between categories of mortality, states, and genders. The dissemination of massive quantities of prescription opioids into this region is the most plausible risk factor, as it is without the aforementioned arguments.No doubt, the etiology of increasing middle-age mortality in the US is multifactorial. Epidemiologists must consider the analytical challenges of confounding and effect modification. This ecological study is no exception, and certainly cannot draw conclusions about causality. Moreover, with the well-known public health issues of smoking and obesity in the Deep South, the population burden of prescription opioids is likely to be one of a few risk factors associated with increasing mortality. However, it is also possible that smoking and obesity are confounders or even upstream determinants of an association between opioids and population mortality. Indeed, smoking, obesity, and poverty are all upstream determinants of health care exposure; and prescription opioids are disseminated into the population through the healthcare system. Large, detailed, case-control and cohort studies in the future will be necessary to better understand the interaction and confounding between these known risk factors.Measurement error in this study could be responsible for the association between population opioid exposure and medical-cause mortality. Cause of death determinations are often made by primary care physicians, and it is plausible that information bias (physician reporting error) might lead opioid-prescribing physicians to report medical-cause of death determinations when in fact overdoses or other opioid-associated illnesses are responsible for patient death. This direction of misclassification is a particular concern in the current climate of physician arrests for over-prescribing opioids , 34. If,Specifically, individual data on opioid prescribing, gender, medical examiner reports, and more specific geographical locations of the deceased would allow for case-control and cohort studies that could corroborate ecological study results and better characterize increasing all-cause mortality. More precise measurements could also be made using individual data in cohort studies of opioid prescriptions and mortality. Prescribing data from the state Medicaid programs, Medicare, Drug Enforcement Agency, and Medical Examiner's Offices, would allow closer examination of physicians who are overprescribing opioids to see if they are associated with geographic hotspots of mortality.Opioid sales across the six states of Alabama, Arkansas, Louisiana, Mississippi, Oklahoma, and South Carolina have very similar period effects, with strong correlations between most state pairs. Sales of prescription hydrocodone and oxycodone across these six states were systematic, and not random. A strong temporal association exists between population exposure to prescription hydrocodone and oxycodone and NHW45-54 medical-cause mortality. Hydrocodone exposure is associated with female NHW45-54 medical-cause mortality, and oxycodone exposure with male NHW45-54 medical-cause mortality.https://wonder.cdc.gov/controller/datarequest/D76 (http://statehealthcompare.shadac.org/ (The datasets generated for this study are available online: uest/D76 , http://dac.org/ .MB is the sole researcher and author of this paper, and conceived of the project design, conducted the background work, collected the data, performed all statistical analyses, and wrote the manuscript. This work is an extension of his Masters in Epidemiology research project while at the London School of Hygiene and Tropical Medicine, but is not the original project submitted.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Randomized controlled clinical trials (RCTs) in oncology enroll patients who meet strict protocol-specified criteria. Many of these criteria overlap across multiple RCTs. A vast proportion of patients with metastatic cancer do not meet such criteria. Hence, patient populations encountered in clinical practice are essentially different from RCT-populations, questioning the representativeness of these trials. A real-world evidence approach, using data from clinical practice, is increasingly employed to complement the information on drug safety and efficacy obtained from traditional clinical trials. The application of novel treatments to the broad real-world population of patients with a certain cancer disease often results in poorer outcomes than expected from pivotal clinical trials. In extreme cases, evidence from randomized controlled trials (RCT) , 2 appeaGiven these important differences between RCT and real-world populations, the recent approval of numerous new treatments—with their associated high monetary costs and risks of toxicities—have led to a quickly increasing interest in the real-world evidence of the efficacy and safety of such therapies. Currently, a growing number of regulatory bodies, professional societies, and patient organizations support the use of real-world evidence for post-approval recommendations, health technology assessment, reimbursement policies and development of treatment guidelines. Currently, the broadest real-world evidence can be obtained from geographically defined whole population-based studies. These conditions may be satisfied by whole-population retrospective studies conducted within entire countries or regions with proven quality of data registration, such as those that are commonly carried out in Denmark .p = 0.0013) or 2012 , with no major differences in 2014 versus 2012  , early-modern era  and modern era  . Despite 0.0935) . ImportaIn conclusion, although RCTs are still the gold-standard practice to evaluate the efficacy (and safety) of a given treatment intervention versus the standard-of-care, real-world studies are critical for understanding whether the results from such RCTs are applicable to the broader population of patients affected by a certain disease. This is particularly true in oncology, where up to two-thirds of real-world patients –7 are no


Daily iron-folic acid supplementation reduces anemia and various adverse obstetric outcomes such as preterm delivery, low birthweight, hemorrhage, and perinatal and maternal morbidity and mortality. However, its supplementation has not been successful that attributed to several determinants including poor adherence. Therefore, we aimed to conduct a systematic review and meta-analysis on the prevalence and determinants of adherence to prenatal iron-folic acid supplementation in low- and middle-income countries. In addition, we will develop a conceptual framework in the context of low- and middle-income countries (LMIC).Q χ2 statistics and Higgins (I2 statistics) method. The result will be presented using forest plots and Harvest plots when necessary. Furthermore, we will perform Jackknife sensitivity and subgroup analysis. Data will be analyzed using comprehensive meta-analysis software (version 2).We will search PubMed, MEDLINE, EMBASE, EBSCO, Web of Science, SCOPUS, WHO Global Index Medicus, and African Journals Online (AJOL) databases to retrieve relevant literatures. Observational  and quasi-randomized and randomized controlled trial studies conducted in LMIC will be included. The Newcastle-Ottawa Scale (NOS) and Joanna Briggs Institute (JBI) critical appraisal checklist will be used to assess the quality of observational and randomized controlled trial studies respectively. The pooled prevalence and odds ratio of determinants of adherence will be generated using a weighted inverse-variance meta-analysis model. Statistical heterogeneity among studies will be assessed by Cochran’s Contemporary evidence about the prevalence and determinants of adherence in LMIC will be synthesized to generate up-to-date knowledge. To our knowledge, this is the first systematic review. It would have substantial implications for researchers, clinicians, and policymakers for optimizing maternal and child health outcomes in LMIC.https://www.crd.york.ac.uk/), registration number CRD42017080245.The protocol has been registered on International Prospective Register of Systematic Review (PROSPERO), University of York Center for Reviews and Dissemination (The online version of this article (10.1186/s13643-018-0774-x) contains supplementary material, which is available to authorized users. Anemia is a global public health problem affecting nearly two billion people . DespiteA systematic review and meta-analysis of maternal anemia in lower and middle-income countries (LMIC) showed that 12, 19, and 18% of low birthweight, preterm births, and perinatal mortality are associated with maternal anemia respectively . AccumulIn LMIC, high proportion of pregnant women suffered from anemia mainly due to poor adherence to the daily iron-folic acid regimen , 8. FurtGenerally, pregnant women living in LMIC need a support for initiating and maintaining optimal adherence to the recommended iron-folic acid supplementation . Therefohttps://www.crd.york.ac.uk/], registration number CRD42017080245. Preferred Reporting Items for Systematic review (PRISMA-2009) statement will be used to report the findings. Furthermore, PRISMA flow diagram will be used to illustrate study screening and selection process.This protocol has been written in accordance with the recommendation of Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA-P) 2015 statement . The PRIP-population: pregnant mothers who have received prenatal iron-folic acidE-exposure: determinants of adherence  and interventions and intervention characteristics/components  that are associated with prenatal iron-folic adherence. PRECEDE-PROCEED conceptual framework  will be C-comparison: the reported reference group for each determinant in each study O-outcome: adherence to iron-folic acid supplementationhttp://www.who.int/hinari/en/), Carolina digital repository (https://cdr.lib.unc.edu/), and SpringerOpen-Open repository (https://www.springeropen.com/get-published/indexing-archiving-and-access-to-data/open-repository). Medical subject headings (Mesh), keywords, and free-text words were identified for selected PECO components. “OR”, “AND”, and “NOT” Boolean operators were used to combine search terms. Moreover, we will contact Cochrane Pregnancy and Childbirth Group, WHO headquarters and regional offices, the nutrition section of the United Nations Children’s Fund (UNICEF), the World Food Program (WFP), and US Agency for International Development (USAID) micronutrient program to identify additional studies [PubMed, MEDLINE, EMBASE, EBSCO, Web of Science, and SCOPUS databases will be searched to retrieve all available studies. We will also extend our searching to WHO Global Index Medicus and African Journals Online (AJOL). Cross-references of included studies will be hand-searched as well to access additional relevant articles that may have been missed in the search. In addition, we will search existing reviews and perform citing studies/snowballing search in PubMed and SCOPUS databases to screen all studies that cited included studies. Likewise, a search for gray literature will be conducted using Google Scholar and through browsing Hinari ( studies . The sea studies .The inclusion criteria are (1) observational  and quasi-randomized and randomized controlled trial studies, (2) studies conducted in LMIC, and (3) studies that reported the prevalence and/or least adjusted determinants of adherence. The most up-to-date World Bank country classification, when our review is published, will be used to categorize LMIC . The seaCovidence web-based software will be used to remove duplicated articles and carry out all of the screening processes. First, articles will be assessed for inclusion through a title and abstract review by two independent reviewers. Disagreement will be solved by consensus; a third reviewer will be invited in case of persistent contradiction. Second, potentially eligible studies will undergo full-text review to determine if they satisfy the criteria set for inclusion. We will do a full-text review in duplicates and clearly document reasons for inclusion and exclusion. Finally, data will be extracted from all articles that meet the inclusion criteria.Data will be extracted using the Joanna Briggs Institute (JBI) data extraction form for experimental/observational studies  will be used to assess the quality of cohort and case-control articles . SimilarQ χ2 statistics and Higgins (I2 statistics) method [I2 describes the percentage of total variations across the studies due to heterogeneity rather than chance. I2 value greater than 80% will be indicative of considerable heterogeneity [Data will be analyzed using comprehensive meta-analysis software (version 2) . Funnel ) method . I2 descogeneity . In addiogeneity . The resogeneity  and Harvogeneity  when necogeneity . PRECEDEogeneity .Leave-one-out Jackknife sensitivity analysis will be used to stabilize the variance of studies with very low or very large prevalence estimates , 31. If Subgroup analysis will be carried out based on epidemiological and/or clinical covariates that can impact estimates such as study design, measures of adherence, age of women, residence of women, and geographical distribution.If protocol modifications are required, we will include the detailed description of any changes along with a justification during the publication of the review results.The protocol has been registered and written in accordance with a standardized guideline which is helpful to replicate methods in other nations. Contemporary evidence on the prevalence and determinants of adherence in LMIC will be synthesized using an appropriate statistical method and qualitatively using PRECEDE-PROCEED conceptual framework . Given tAdditional file 1:PRISMA-P  2015 checklist: recommended items to address in a systematic review protocol*. (DOCX 22 kb)Additional file 2:PubMed search string. (DOCX 16 kb)Additional file 3:JBI Data Extraction Form for Experimental/Observational Studies. (DOCX 80 kb)


There were no between-group differences for shoulder extension (p = 0.531) and adduction (p = 0.340). Adding IFT electro-massage to usual care, including manual therapy and exercises, revealed greater positive effects on pain, upper limb function, and mobility in adults with SAPS after acromioplasty.Subacromial pain syndrome (SAPS) is a prevalent condition that results in loss of function. Surgery is indicated when pain and functional limitations persist after conservative measures, with scarce evidence about the most-appropriate post-operative approach. Interferential therapy (IFT), as a supplement to other interventions, has shown to relieve musculoskeletal pain. The study aim was to investigate the effects of adding IFT electro-massage to usual care after surgery in adults with SAPS. A randomized, single-blinded, controlled trial was carried out. Fifty-six adults with SAPS, who underwent acromioplasty in the previous 12 weeks, were equally distributed into an IFT electro-massage group or a control group. All participants underwent a two-week intervention (three times per week). The control group received usual care . For participants in the IFT electro-massage group, a 15-min IFT electro-massage was added to usual care in every session. Shoulder pain intensity was assessed with a 100-mm visual analogue scale. Secondary measures included upper limb functionality (Constant-Murley score), and pain-free passive range of movement. A blinded evaluator collected outcomes at baseline and after the last treatment session. The ANOVA revealed a significant group effect, for those who received IFT electro-massage, for improvements in pain intensity, upper limb function, and shoulder flexion, abduction, internal and external rotation (all,  Shoulder complaints are a common musculoskeletal disorder. The one-year prevalence of shoulder pain in the general population ranges from 5% to 47%, while the lifetime prevalence has been estimated up to 67% . Work-reA great diversity of conservative interventions, combining pharmacological and physical therapy treatments, is often used to decrease pain and enhance function in SAPS . There eInterferential therapy (IFT) is a highly popular treatment modality in the clinical setting, which involves crossing two medium frequency currents to generate a low-frequency beating effect in the deep tissues , and canThe study aim was to investigate the effects of adding IFT electro-massage to a two-week usual care protocol, compared with the usual care protocol alone, on pain intensity, upper limb functionality, and shoulder passive range of motion in adults with SAPS who underwent acromioplasty. It was hypothesized that adding IFT electro-massage to the usual care intervention would achieve higher effectiveness than the sole use of the usual care regime. A single-blinded  randomized controlled trial was carried out. The Consolidated Standards of Reporting Trials (CONSORT) statement and checklist were followed. The research protocol was conducted in accordance with the Declaration of Helsinki statement of ethical, legal, and regulatory principals to provide guidance for health-related research involving human subjects. The study was approved by the Ethical Research Committee of the Hospital Universitario Virgen del Rocío, Sevilla, Spain , and prospectively registered . All participants provided written informed consent.Adult patients with shoulder pain, who underwent acromioplasty in the 12 weeks before data collection, were referred by an orthopedic surgeon at a large public hospital in Southern Spain. Before surgery, SAPS was diagnosed following a positive response to clinical examination  and radiologic diagnostic criteria to differentiate SAPS from other conditions  . A detaihttp://www.randomization.com) was used to complete the randomization schedule for treatment order, considering a 1:1 ratio distribution of participants in the study groups (IFT electro-massage and control group). An external assistant safeguarded the randomization sequence and prepared sealed opaque envelopes concealing the treatment order allocation. Following baseline allocation, demographic and clinical data were initially collected. A blinded evaluator collected all measurements at baseline and immediately after the last treatment session. The treatment protocol consisted of a two-week intervention regime. Three treatment sessions, each lasting around 70–85 min, were made per week and supervised by a physiotherapist with more than 15 years of clinical experience.An external website , good (65–79), medium (50–64), and bad (<50) . The minThe Simple Goniometer iPhone® app  was used to assess the shoulder pain-free passive range of movement. An iPhone® 3GS, iOS 4.3.5  was fixed to the participants’ arm with an armband bracelet . The recordings of shoulder range of motion were made twice (2-min break between assessments), using the average value of the two measures for further analysis. Before assessments, participants were asked to stop the evaluator when they started to feel low-intensity pain during movement (below 20 mm in the VAS). To evaluate shoulder flexion and extension, participants were seated with back support and no armrests, and the iPhone® was fixed on the lateral side of the arm . For shoulder abduction, participants kept the same position, and the iPhone® was placed on the ventral side of the arm . Shoulder adduction was assessed with the participant lying supine, with 90 degrees of shoulder flexion (or the maximum possible pain-free flexion), and with the iPhone® placed on the ventral side of the arm. Internal and external rotation were evaluated with participants in supine, with 90 degrees of shoulder abduction (or the maximum possible pain-free abduction), 90 degrees of elbow flexion, forearm in neutral position, and the iPhone® was placed in the ventral side of the arm . During all assessments, the evaluator applied gentle pressure to the arm or forearm until the edge of movement was reached , and max2 head, and using a frequency of 3 Mhz and a power of 1.2 w/cm2. For participants in the IFT electro-massage group, a 15-min IFT electro-massage over the neck-shoulder and the glenohumeral joint was added in every treatment session to the usual care treatment previously described. A bipolar application, using a carrier frequency of 4000 Hz at constant voltage and an amplitude-modulated frequency of 100 Hz, was administered. The current intensity was set at a medium-high level, but always adapted to individual tolerance, to achieve a “strong but comfortable tingling” without evoking visible muscle twitches [Participants in the control group underwent an usual care protocol involving: Fifteen minutes of transcutaneous infrared thermotherapy  ; 35 min twitches . Two rubtwitches . Some neThe sample size calculation was based on detecting: (1) a 15% change in self-reported pain intensity ; and (2)2) was used to calculate the effect size . Statistical significance was set at a p value < 0.05.Statistical processing of the data was carried out using the PASW Advanced Statistics , version 24.0. Data were reported as mean (standard deviation), and confidence intervals (95% CI). The Shapiro–Wilk test was used to test the normal distribution of the study variables. Differences in the outcome measures were detected using a repeated measures analysis of variance (ANOVA), with the group (IFT electro-massage or control) as the between-subjects factor, and time (baseline or immediately after intervention) as the within-subjects factor. Post-hoc comparisons (Bonferroni) were performed for significant effects. Eta-squared , aged between 23 to 76 years , met the eligibility criteria and were recruited. There were no adverse reactions or dropouts during the study protocol . p > 0.05), except for participants’ height (p = 0.029).p < 0.001). For the between-group analysis of the mean score changes after intervention, the ANOVA revealed a significant group effect, for those included in the IFT electro-massage group, for the decrease in shoulder pain intensity , the improvement in the Constant-Murley score , and the increase in pain-free passive shoulder flexion , abduction , internal rotation , and external rotation . There were no differences between groups for shoulder extension  and adduction .The present findings demonstrated that including IFT electro-massage in a two-week usual care protocol, combining manual therapy, exercises, thermotherapy, and ultrasound, achieved better immediate results on shoulder pain intensity, upper limb function, and pain-free passive range of movement (except for shoulder extension and adduction), compared with the sole use of the usual care regime, in adults with SAPS who underwent recent shoulder surgery. The decrease in shoulder pain intensity and the improvement in upper limb functionality was significantly higher, with a high effect size, for participants who received IFT electro-massage, although individuals in both groups reduced their shoulder pain after the two-week protocol above the minimum clinically important difference for the VAS ,43. On tThere is a huge debate about the clinical impact of including IFT and other electrotherapeutic modalities for the management of chronic shoulder pain. Conflicting to the current results, the addition of IFT to exercise and/or manual therapy did not demonstrate greater clinical effects on shoulder pain and disability, compared to the use of exercise and/or manual therapy alone, in individuals with non-specific soft-tissue shoulder disorders , or withThis inconclusive evidence about the impact of using IFT, alone or in addition to other conservative approaches, persists when considering other chronic musculoskeletal pain conditions, such as neck or low-back pain . There aSome potential study limitations should be mentioned. First, the study did not include a sham IFT electro-massage group. Second, only immediate results after the last session of the two-week intervention protocol were collected, thus it would be highly relevant to investigate the medium and long-term follow-up effects of IFT on post-operative pain in further studies. Third, the therapist in charge of the interventions was not blinded to participants allocation group. Finally, further research is warranted to investigate if different results could be expected using different current parameters.Adding IFT electro-massage to a two-week supervised usual care protocol combining manual therapy, exercises, ultrasound, and infrared thermotherapy achieved better results on decreasing shoulder pain, and improving upper limb functionality and shoulder pain-free passive range of motion, compared to usual care alone, in adults with SAPS who underwent recent acromioplasty.


Due to its readiness to convert stem volumes (V) into biomass, national and regional aboveground biomass estimates and greenhouse gas reporting are generally based on biomass conversion and expansion factors (BCEFs). BCEF-based biomass (Ŵ) is computed by the following regression through the origin (RTO): Ŵ = BCEF × V. However, the regression slope (BCEF) is not obtained using least squares (LS); it is obtained as the ratio of observed biomass and stem volume. Therefore, the sum of squares of the residuals is not minimum. This may lead to strongly biased biomass estimates. Furthermore, in this case, the biomass is not modelled. In the present study, it was suggested that BCEFs should be obtained using LS through RTO. The objective of this study was to compare LS-based and ratio-based BCEFs with regard to predictive accuracy and ability. A dataset of 75 trees from 4 species was used for the comparisons.•LS-based BCEFs were associated with higher predictive accuracy and ability than ratio-based ones.•It was proved that RTO is appropriated for estimating BCEFs, as the intercept α was consistently not significant.•Ratio-based BCEFs may lead to seriously biased biomass and carbon stocks estimates.•BCEFs should be estimated using least squares. Forest biomass is a crucial ecological variable for understanding the evolution and potential future changes of the climate system . TherefoForest biomass can be estimated non-destructively using biomass equations. When biomass equations are fitted using least squares they are called biomass regression equations. Biomass regression equations are developed as linear or non-linear functions of one or more tree-level dimensions. When biomass equations are fitted in such a way that they specify tree component biomass as directly proportional to stem volume, the ratios of proportionality are then called biomass conversion and expansion factors (BCEFs) .National and regional aboveground biomass (AGB) estimates and greenhouse gas (GHG) reporting are generally based on BCEFs , mainly BCEF-based biomass is computed by the following equationEq. The assumption behind Eq. The objective of this study was to compare LS-based and ratio-based tree component BCEFs with regard to predictive accuracy and ability. The study addressed the following research question: do LS-based- and ratio-based BCEFs differ in terms of predictive accuracy and ability? It was hypothesized that LS-based tree component BCEFs provide most accurate and reliable estimates.Colophospermum mopane Kirk ex J. Leonard, Afzelia quanzensis Welw., Millettia stuhlmannii Taub., and Pterocarpus angolensis DC.The study was conducted in Mozambique , in Gaza, Inhambane and Sofala provinces. Seventy five (75) trees from four valuable timber species were destructively sampled for biomass and volume estimation, namely: C. mopane was harvested in Mabalane district, Gaza province. Other three species  were harvested in Funhalouro district (Inhambane province) and Cheringoma district .C. mopane, A. quanzensis, M. stuhlmannii, and P. angolensis (C. mopane was harvested from Mopane woodlands and the remaining tree species from Miombo woodlands.Seventeen (17), 24, 15, and 19 sample trees of golensis , respectAfter measuring the diameter at breast height (DBH), the trees were felled considering a predefined stump height of 20 cm. The aboveground portion of the tree was divided into following biomass components: stem, branches, foliage, and crown (branches + foliage).The stem was divided into 5 segments equal in length and the diameter of each segment was measured at the midpoint. The volume of the stem was determined using Hohenadl’s formula . Each seAfter removing the leaves, each primary branch  was fresh-weighted in the field. A sample composed by a disc removed from the primary branch, samples of secondary and higher-order branches and twigs were taken from each primary branch. Dry mass of each primary branch was obtained similarly to that of each stem segment.All the foliage from the crown was measured in the field and a sample of approximately 5% of the fresh mass collected for oven-drying. The dry mass of the foliage was obtained similarly to that of each stem segment.Before computing the BCEFs, the Shapiro-Wilk normality test and normal Quantile–Quantile (Q-Q) plots were used to detect departures of each tree component biomass (the response variable) from normality . Shapiro-Wilk normality test and residual Q–Q plots were also used to diagnose the residual distribution  using ordinary linear regression .Thus, LS-based BCEFs were obtained using generalized linear model if the response variable (biomass) was found to have a residual distribution other than a normal distribution; and using ordinary linear regression if the residual distribution was normal.A. quanzensis and P. angolensis and AGB of P. angolensis.All the residual of all tree components of all species were found to be normally distributed, except the foliage biomass of Ratio-based- and LS-based BCEFs were compared with regard to predictive accuracy and ability.The predictive accuracy was determined by the following sources of errors in model prediction: (1) error due to model misspecification, (2) error due to uncertainty in the model parameter estimates, and (3) error due to residual variability around model prediction.Error due to model misspecification is here expressed by Akaike Information Criterion (AIC) , as it ii2 is the square of model residual and Hii is the diagonal element of the projection matrix H.The predictive ability is expressed by the mean quadratic error of prediction (MEP) , and modMPE was estimated by K–fold cross-validation (K = 10) using cvFit function from the package “cvTools”  of R sofThe lower the MEP and MPE, the better the models in terms of predictive ability.P. angolensis, ratio-based BCEFs were found not to be statistically significant , denoting thus, smaller error due to residual variability around model prediction for LS-based biomass models when compared to ratio-based biomass models (ratio-based BCEFs).The three sources of errors in model prediction prove that biomass estimates obtained from LS-based BCEFs are more accurate than those obtained from ratio-based BCEFs; e.g. LS-based BCEFs were associated with higher predictive accuracy than ratio-based BCEFs.M. stuhlmannii (3), respectively; whilst LS-based BCEFs indicate that stem biomass and AGB (in Mg) are 0.73- and 0.98-fold larger than stem volume (in m3), respectively.Note that, on average, ratio-based BCEFs were larger than LS-based BCEFs; i.e. LS-based BCEFs indicates lower dry weight per unit of stem volume than ratio-based BCEFs. For example, the ratio-based BCEF for stem and AGB for hlmannii  indicateThe mean quadratic errors of prediction (MEP) of LS-based BCEFs were up to 100% (range: 15–100%) smaller than those of ratio-based ones , Table 3a priori reason why the regression was forced to pass through the origin is that if stem volume is zero, then concurrently, tree component biomass is zero. However, this fact is not enough to justify the use of RTO since, as argued by Wooldridge [one serious drawback of RTO is that, if the intercept is different from zero, then the LS estimators of the slope will be severely biased”. Therefore, it was tested whether the hypothesis of the intercept being equal to zero (α = 0) is data admissible , yield the most accurate estimates , provideLS-based BCEFs, to a certain extent, combine the advantages of biomass regression equations and ratio-based BCEFs. However, it should be noted that LS-based BCEFs might not provide biomass estimates as accurate as biomass regression equations. This is because BCEF-based biomass is dependent on stem volume which, in turn, is dependent on DBH, stem height and, sometimes, form factor, if the volume is computed based on form factor instead of a volume equation. All these variables have their own sources of errors which are propagated when estimating biomass. When using biomass regression equation, however, the biomass is, most of the time, dependent only on DBH alone or on DBH and tree height, minimizing the sources of errors.3/ha of stem volume, ratio-based BCEFs estimates up to 75 Mg ha −1 (76%) larger biomass than LS-based BCEFs. In this context, ratio-based BCEFs will lead, on average, to overestimation of emission factors (EFs), forest reference and emission levels (FRELs), and will compromise the reliability of the estimates of carbon stock changes. Consequently, with unreliable FRELs, the country or REDD+ projects contribution in mitigating climate change through forest related actions cannot be properly assessed and, moreover, the contributions will be unreliable as well.The choice of an appropriate biomass equation (e.g. BCEF) is decisive for reducing uncertainties in forest biomass stock estimates , especiaA. quanzensis, M. stuhlmannii and P. angolensis [One of the most important drivers of forest-cover change and forest degradation in Mozambique is selective forest logging , which igolensis , 3 of thAccurately estimating biomass is a critical step in quantifying carbon emission from deforestation and forest degradation and in reducing uncertainties of those emissions. At local and global level, emissions related to forest degradation are poorly quantified . At loca“emissions resulting from conversion of the log to wood products and the subsequent emissions from retired wood products”. Accurate estimates of branches, foliage and crown BCEFs of the concerned species will provide better estimates of LDF, defined as emission resulting from decomposition of all the dead wood produced as a result of felling the tree(s) [Accurate estimates of stem BCEFs of those species will lead to better estimates of ELE, which, according to Pearson et al. , are “em tree(s) , which iOverall, when compared to ratio-based BCEFs, LS-based BCEFs are a potential tool for better estimating biomass and carbon stocks, emission factors and FRELs, while reducing their uncertainties. Specifically, at local context, since LS-based were developed for tree species that are most selectively harvested thus top responsible for forest degradation caused by logging, LS-based BCEFs of these species may contribute in (better) estimating the country-specific emissions from forest degradation.In this study, ratio-based- and LS-based BCEFs were compared in terms of predictive accuracy and ability. LS-based BCEFs were associated with extremely lower (1) error due to model misspecification, (2) error due to uncertainty in the model parameter estimates, and (3) error due to residual variability around model prediction, when compared to ratio-based ones; leading to higher predictive accuracy. LS-based BCEFs had lower values of (1) mean quadratic error of prediction, and (2) model prediction error; leading to higher predictive ability than ratio-based BCEFs.