ALPL, BGLAP, COL1A1, and RUNX2/PPAR while only 40% of PBMC-derived from diabetic patients (DM-pD) expressed those genes. By using age- and pentosidine-matched NDM-pD as a reference, AGER and BAX/BCL2 expression in PBMC isolated from diabetic patients showing impaired osteoblast-specific gene expression (DM-iD) were 6.6 and 5 folds higher than the reference while AGER and BAX/BCL2 expression in DM-pD were comparable to the reference. AGER expression showed a significant positive correlation with age . The multivariate analysis demonstrated that both age and AGER expression correlated with the potential for osteogenic differentiation in the PBMC isolated from patients with diabetes. In conclusion, this study showed osteogenic differentiation impairment in approximately half of PBMC derived from type 2 diabetic patients receiving metformin monotherapy. Both AGER and BAX/BCL2 overexpression were demonstrated only in PBMC-isolated from diabetic patients with poor osteogenic differentiation. Therefore, this study not only illustrated the existence of RAGE overexpression in PBMC derived from patients with early stages of T2DM but also strengthened the linkage between that RAGE overexpression and the retardation of osteogenic differentiation. Age was also shown to be a positive influencing factor for RAGE overexpression. Furthermore, both age and RAGE overexpression were demonstrated as independent risk factors for determining osteogenic differentiation potential of the PBMC-isolated from T2DM.Preclinical studies have found impaired osteogenic differentiation to be associated with type 2 diabetes (T2DM), which is related to skeletal accumulation of advanced glycation end products (AGEs). Our previous study also showed impaired osteogenic differentiation in peripheral blood-derived mononuclear cells (PBMC) isolated from patients with long-standing T2DM, which is conceivably due to the overexpression of receptor of advance glycation end products (RAGE) and the enhancement of cellular apoptosis. However, the existence of RAGE overexpression in earlier stages of diabetes remains unclear, as do the factors influencing that RAGE overexpression. This cross-sectional study enrolled 40 patients with T2DM treated with metformin monotherapy and 30 age-matched non-diabetic controls (NDM) to investigate the overexpression of RAGE in PBMC derived from patients with earlier stage diabetes, as well as to explore its determining factors. Almost all (90%) PBMC-isolated from NDM (NDM-pD) expressed osteoblast-specific genes including  Type 2 diabetes (T2DM) is a major health issue worldwide. It is a metabolic disorder characterized by insulin resistance and chronic hyperglycemia, contributing to multiple devastating microvascular and macrovascular complications. It is well documented that chronic hyperglycemia accelerates the accumulation of advanced glycation end products (AGEs) –3. TheseT2DM is associated with a decrease in bone turnover , 11, chavia binding to their specific receptor, the receptor of AGE (RAGE). Following binding with AGEs, RAGEs initiate multiple signal cascades including inflammatory and apoptotic pathways. Several in vitro studies in osteoblast lineage cells have demonstrated that AGEs-dependent RAGE activation inhibited osteoblast differentiation -isolated from patients with long-standing T2DM compared to those in a matched non-diabetic control group, suggesting higher cellular RAGE activation in individuals with long-standing T2DM . All participants signed an informed consent agreement before they were enrolled on the study.®) using the Thailand database  was collected from all enrolled participants to isolate the PBMC, and to determine serum levels of pentosidine  and sRAGE . Fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C) and serum creatinine were assessed using standardized procedures at a central laboratory of the Faculty of Medicine, Chiang Mai University. Glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method. Fracture risk estimation was estimated from The Fracture Risk Assessment Tool  and cultured for a further 21 days.PBMC were isolated from the 35-40 mL of peripheral venous blood using density gradient centrifugation as described in our previous study . In brie°C, 10 seconds at 60°C and 30 seconds at 72°C using the Applied Biosystems 7500/7500 Fast Real-Time PCR system. The total RNA extracted from the PBMC, cultured both in non-osteogenic and osteogenic-inducing media, was used to determine: 1) osteoblast-specific genes including ALPL, BGLAP, COL1A1 and RUNX2 for representing osteoblast differentiation and 2) PPAR-γ which is a transcription factor driving towards adipocytes for evaluating signals against osteoblast differentiation. Differentiation towards osteoblasts was defined by the increment of expression of all osteoblast-specific marker genes including ALPL, BGLAP and COL1A1, as well as the increment of the RUNX2/PPARγ ratio. In contrast, the total RNA extracted only from the PBMC cultured in the non-osteogenic-inducing medium was used to determine: 1) AGER expression to elucidate cellular RAGE overexpression, and 2) BAX and BCL2 expression for the evaluation of cellular apoptotic signals. The primers were purchased from Invitrogen  method.To examine gene expression total RNA was extracted using the illutraRNA spin Mini Kit  in accordance with the manufacturer’s instructions. Total RNA (500 ng) of each sample was used for reverse transcription into cDNA using an iScript™cDNA Synthesis Kit  in accordance with the manufacturer’s protocol. Afterwards, the cDNA was analyzed by real-time quantitative polymerase chain reaction . The reaction took place at 45 cycles of 5 seconds at 95t-test was used to compare all continuous parameters while a Chi square test was used to compare binary parameters. Linear regression analysis was used to demonstrate factors correlating with osteoblast differentiation. Pearson’s correlation was used to identify the correlation between parameters, the exception being the correlation between AGER expression and other parameters which was done using Spearman’s correlation. A p-value of less than 0.05 was used as a measure of statistical significance. All statistical analyses were done with SPSS version 23.0.All descriptive data are reported as mean ± standard deviation. An independent ® were comparable in both NDM and DM groups , suggesting accelerated AGEs accumulation in T2DM . Even though FPG, HbA1c and serum pentosidine levels were significantly higher in DM than in NDM group, serum pentosidine level showed no correlation with either FPG  or HbA1c . In addition, serum pentosidine level showed no correlation with other parameters, including age, BMI, eGFR and sRAGE level. Fracture risk as estimated by FRAX using the Thailand database was comparable between DM and NDM groups (The study included 40 patients with T2DM treated with metformin monotherapy (DM) and 30 age-matched participants without diabetes (NDM). All patients with T2DM were diagnosed as DM using the FPG criteria with a cut-off value of 126 mg/dL as recommended by the American Diabetes Association. Age, gender, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), LDL-C, eGFR, and 10-year fracture risk as determined by FRAXALPL, BGLAP, COL1A1 and RUNX2/PPAR; therefore, the isolated-PBMC in this group were classified as DM-pD. The other 60% (24/40) of PBMC-isolated from DM did not express those osteoblast-specific genes, so the isolated-PBMC in this group were classified as DM-iD. While almost all the isolated PBMC from NDM expressed osteoblast-specific genes (NDM-pD), only 40% of the isolated PBMC from DM expressed osteoblast-specific genes (DM-pD) . As shown by the RUNX2/PPAR ratio, the PBMC-derived from DM-pD expressed RUNX2, a master transcription factor for osteogenic differentiation, and PPARγ, a transcription factor driving differentiation against osteoblasts, at a similar extent to that of NDM-pD but at 3.8 times higher than that of DM-iD .The PBMC-derived from diabetic patients showed a reduced potential to differentiate towards osteoblasts compared with those from non-diabetic controls. By using osteoblast-specific gene expression as a marker for osteogenic differentiation potential, the isolated PBMC from DM were divided into 2 groups including DM with preserved osteogenic differentiation potential (DM-pD) and DM with impaired osteogenic differentiation potential (DM-iD). Forty percent (16/40) of the PBMC-isolated from diabetic patients showed expression of osteoblast-specific genes including vs 96.1 ± 9.4 mg/dL, p<0.0001), HbA1c  and serum pentosidine  than those in the NDM-pD group  than those in NDM-pD group  and HbA1c  were comparable in both DM-pD and DM-iD groups. Serum pentosidine level was slightly higher in DM-pD in comparison to those in DM-iD group ; however, the difference did not reach statistical significance  but were at the same age as those in NDM-pD   which did not express osteoblast-specific genes, was excluded from the following analysis. When comparing DM-pD and NDM-pD, patients in the DM-pD group had significantly higher FPG  to explore whether there was: 1) cellular RAGE overexpression in early-stage diabetes, 2) an association between RAGE overexpression with cellular apoptotic signal enhancement and osteogenic differentiation impairment, and 3) factors influencing cellular RAGE overexpression.Our previous study demonstrated higher AGER enhancer, and age was confirmed earlier as an independent risk factor for the determination of osteogenic differentiation potential, the expression of AGER in both DM-iD and DM-pD was compared with the level of AGER expression in age- and pentosidine-matched NDM-pD individuals. This comparison aimed to explore if there was only a higher level of AGER expression in DM-iD, which would in turn suggest a link between cellular RAGE overexpression and defects in osteogenic differentiation. Using NDM-pD as a reference group, AGER expression in DM-iD was 6.6 times higher than that in the reference while the AGER expression in DM-pD was comparable to that in the reference , suggesting cellular RAGE overexpression in DM-iD as well as a connection between that RAGE overexpression and osteogenic differentiation defects in the PBMC. Consistent with higher AGER expression, the BAX/BCL2 expression ratio in DM-iD was 5.0 times higher than that in the reference while the BAX/BCL2 expression ratio in DM-pD was comparable to that in the reference , suggesting higher cellular apoptotic rate only in cases of diabetes with impaired osteogenic differentiation ability. Furthermore, AGER expression showed a strongly positive correlation with the BAX/BCL2 expression ratio , but showed a negative correlation with multiple osteoblast-specific gene expression including ALPL , BGLAP , COL1A1  and RUNX2/PPARγ ratio   . In this study, 40% of cells from diabetic patients expressed osteoblast differentiation markers to a similar extent of those in non-diabetic individuals, suggesting a preserved potential of osteogenic differentiation only in some of the population among the whole diabetic group. Even though being diabetic increases the risk of osteogenic differentiation defects, diabetes at the different stages may have different degrees of that defect. Our previous study, which included long-standing type 2 diabetic subjects with an average of 10.7 ± 7.7 years of diagnosis, demonstrated that only 7.3% of PBMC-isolated from these diabetic patients expressed osteoblast-specific genes while 86.7% in non-diabetic controls expressed those genes  . The present study showed a much higher number of PBMC with preserved osteogenic differentiation potential than those in the previous study which was done at a later stage of diabetes. However, it remains to be elucidated whether newly diagnosed type 2 diabetes still results in an impaired osteogenic differentiation.In animal models with T2DM, a dramatic decrease in osteoblast/osteoid surface and bone mineral apposition rate has been demonstrated which indicates osteoblast differentiation and function impairment . Consist<0.0001) . HoweverAGER enhancer and age is an independent risk factor for determining osteogenic differentiation as described above, AGER expression in an age- and pentosidine-matched NDM-pD group was used as a reference to compare the level of AGER expression between DM-iD and DM-pD for determining whether higher cellular AGER expression occurred only in the DM-iD group. Interestingly, higher AGER expression was demonstrated in DM-iD group but not in DM-pD, suggesting the existence of RAGE overexpression only in PBMC with poor osteogenic differentiation ability that isolated from diabetic patients. To further explore the association between cellular apoptosis and osteogenic differentiation, BAX and BCL2 expression in DM-iD and DM-pD were compared by using BAX/BCL2 expression in an age- and pentosidine-matched NDM-pD group as a reference. As seen with AGER expression, the ratio of BAX/BCL2 expression was higher only in the DM-iD group, suggesting a link between cellular apoptotic signal enhancement and osteogenic differentiation impairment. Consistent with our previous study . Therefore, the present study not only confirmed the existence of RAGE overexpression in PBMC with poor osteogenic differentiation potential but also strengthened the link between the cellular RAGE overexpression with osteogenic differentiation impairment and cellular apoptotic signal enhancement in the PBMC-isolated from T2DM patients.Our previous study demonstrated cellular RAGE overexpression in type 2 diabetes which may lead to higher cellular apoptosis and poorer differentiation toward osteoblasts in T2DM. Because most PBMC-isolated from diabetic patients lose their ability to differentiate into osteoblasts, no firm conclusion can be made regarding the influence of cellular RAGE overexpression shown in type 2 diabetes on cellular apoptosis and the poorer differentiation found in type 2 diabetes. In this study, we focused on the earlier stage of diabetes and we demonstrated that only 60% (24/40) of the PBMC-isolated from diabetic patients lose their osteogenic differentiation potential (DM-iD). Therefore, we had the opportunity to explore whether there was only cellular RAGE overexpression in PBMC-isolated from diabetic patients showing impaired osteogenic differentiation. As pentosidine is an us study , the expAGER expression was illustrated only in the cells from the group of diabetics with impaired osteogenic differentiation, and that higher AGER expression was shown to be associated with the differentiation potential toward osteoblasts. Therefore, it is conceivable that serum pentosidine level has poor potential for the prediction of osteogenic differentiation in diabetes. Nevertheless, due to a small sample size and the wide standard deviation of serum pentosidine concentration found, the results of our study cannot exclude its potential for predicting osteoblast differentiation ability.Since the hyperglycemic state in diabetes accelerates the accumulation of AGEs in various tissues including those in the skeleton, accumulation of AGEs is one of the factors proposed as being responsible for the impairment in bone quality associated with diabetes and may be a useful predictor of fracture in diabetic individuals. Several studies have shown that the skeletal accumulation of AGEs alters bone mechanical properties, leading to fragility fractures –24. In aAGER expression was also a risk factor for determining osteogenic differentiation, suggesting the contribution of higher cellular RAGE overexpression to the potential of differentiation of the PBMC towards osteoblasts. Interestingly, this study also demonstrated a positive correlation between age and AGER expression. Since age was an independent risk factor for osteogenic differentiation, as well as age showing a positive correlation with AGER expression, age itself is conceivably a contributor to cellular RAGE overexpression which in turn negatively affects osteogenic differentiation. Son and colleagues . Therefore, it is reasonable to state that ACEI and ARB do not contribute to a lower rate of osteogenic differentiation in the diabetic group. In patients with diabetes, ACEI and ARB were used in the DM-pD group at a higher rate than those in DM-iD ; however, the difference was nowhere near statistical significance. Therefore, it is reasonable to state that ACEI or ARB usage is not a contributory factor in the maintenance of osteogenic differentiation shown in DM-pD. Statins have been previously shown to have beneficial effects on bone metabolism and osteoporosis ; however, the difference did not reach statistical significance. Therefore, from these findings the higher usage rate of statins in the diabetic group should not contribute to a lower rate of osteogenic differentiation in diabetic group.Several different types of medication prescribed for participants in this study were shown to influence bone metabolism. Metformin was the only anti-hyperglycemia agent given to all diabetic individuals in this study and it was not taken by non-diabetic controls. Metformin has been shown to promote the differentiation of osteoblasts from mesenchymal stem cells through the activation of the AMPK pathway , 50. Zhooporosis –58. Stat pathway . Zhang M pathway  demonstr pathway . In huma pathway  carried AGER overexpression will not lead to higher RAGE activation. The further studies involving RAGE knock-down would clarify whether cellular RAGE overexpression directly entail an impaired osteoblast differentiation. Second, this study presented data to show the pattern of association between parameters, so the causes and effects of those parameters cannot be definitely concluded. Finally, this study was a cross-sectional study which had several unexpected confounding factors by the nature of this type of study, for examples, AGER polymorphisms. Even though all baseline characters of the enrolled participants were generally comparable, those unexpected confounding factors might influence the results of the study. Multiple single nucleotide polymorphisms (SNPs) of AGER gene have been reported for association with diabetes and chronic diabetic complications (AGER expression in vitro by enhancing the binding affinity of the transcription factor site while the rs207600 SNP was documented for enhancing the affinity of RAGE for its ligands (AGER polymorphism was not determined in this study, the contribution of AGER polymorphism to RAGE overexpression in PBMC was still possible. However, the evidence showing detrimental effects of AGER polymorphism on bone metabolism remains to be elucidated in cases of diabetes. To date, Raska Jr I and colleagues (This study provides evidence to support that cellular RAGE overexpression leads to osteogenic differentiation impairment in early stages type 2 diabetes, and that cellular RAGE overexpression is influenced by age. However, this evidence should be carefully interpreted due to several limitations. First, this study only demonstrated signal activation by mRNA level not protein expression due to the limited number of isolated cells from the relatively small 35-40 mL sample of peripheral blood collected from recruited patients. This raises the possibility the chance that transcription is activated but not translated into proteins. Therefore, it is probable that ications –60. Chenications  showed t ligands . Since AThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Research Ethics Committee of the Faculty of Medicine, Chiang Mai University. The patients/participants provided their written informed consent to participate in this study.MP was involved in conceptualization, funding acquisition, methodology, formal analysis, original draft writing, review and editing of the manuscript. PP was involved in the methodology, original draft writing, review and editing of the manuscript. PK was involved in original draft writing, as well as review and editing of the manuscript. All authors contributed to the article and approved the submitted version.This work is supported by Merck. The funder had no roles in the study design, data collection and analysis, preparation of the manuscript or decision to publish.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Work disability days (long-term sickness absence (LTSA), disability pension (DP)) during the three years before to three years after the cohort’s entry date were identified by generalised estimating equations. LBP-patients undergoing LSDS had higher overall work disability during the three years following surgery  than LBP-patients without LSDS , and those without LBP . Among patients undergoing LSDS, the prevalence of work disability due to dorsopathies increased from 20 days three years before surgery to 70 days in the year after and attenuated to 30 days in the third year following surgery. Work disability for other diagnoses remained stable at a low level in this group . LBP-patients undergoing LSDS have an unfavourable long-term work disability prognosis, primarily due to dorsopathies. Decompression surgery seemed to restrict further inclines in work disability in the long run.Low back pain (LBP) patients undergoing lumbar spine decompression surgery (LSDS) often suffer from multi-comorbidity and experience high work disability. This study aimed to identify diagnosis-specific work disability patterns in all LBP-patients before and after LSDS during 2008–2010, that were aged 19–60 years and living in Sweden ( Low back pain (LBP) is a leading diagnosis for work disability  and disability pension (DP)) ,2,3,4. PMany patients suffering from lumbar spine disorders have various co-morbidities, such as common mental disorders (CMDs) , and in Socio-demographic factors ,14, as wThe aims of the study were to investigate the pattern of diagnosis-specific work disability in patients before and after lumber spine decompression surgery, adjusting for socio-demographic and clinical factors, and to compare these patterns across LBP-patients with LSDS, LBP-patients without LSDS, and individuals without diagnosed LBP. This study utilises nationwide data from five registers which are linked based on the personal identity numbers of all residents in Sweden  and provSpondylopathies: M47.8, M47.9, M47.9K, M48.0, M48.0K, M48.8, M48.8K and M48.8W; Radiculopathies: M51.1, M51.1K, M54.1; and other diagnosis with LBP: M53.8, M53.9, M54.3, M54.4, and M54.5. The LBP-patients were then stratified according to the type of treatment provided: by LSDS  , and treated conservatively . Each patient with LBP was matched (exact matching without any replacement) on age, sex, educational level and region of birth with up to four reference individuals, randomly selected from the general population, who had not been treated at in- or specialised outpatient care during 2001–2013 due to any degenerative spine disease (ICD 10: M40-M54) as the main or secondary diagnosis . The cohort entry date (CED) for LBP-patients treated by LSDS was considered to be the date of surgery, for LBP-patients not treated by LSDS it was the date of diagnosis. Individuals with no diagnosed LBP were included on the identical CED to that of their matched LBP-patients. Those individuals who died or emigrated during the study period (from three years before inclusion to three years after) were excluded, leaving us with 10,800 LBP-patients with LSDS, 109,179 LBP-patients without LSDS and 472,191 individuals with no diagnosed LBP. All individuals registered in Sweden on 31 December preceding the year of entering the cohort, aged 19–60, with a diagnosis of LBP from in- or specialised outpatient care during 2008–2010 were included. LBP was defined by the following ICD-10 codes : SpondylWork disability was measured as the mean of the annual sum of net days with SA or DP due to a specific diagnosis. Net days considers the grade of SA and DP. As such, if an individual had, for example, 50% SA or DP for two days, this was counted as one net day. Hereafter, ‘work disability net days’ will be regarded as ‘work disability days’. The Swedish Social Insurance Agency keeps records of SA cases with a duration of 14 or more gross days for employed individuals, therefore, our study included SA spells lasting for 14 or more days. SA and DP were measured for three years before, and up to three years after, CED. The underlying main diagnosis for the SA spell or DP was determined by the ICD-10 codes. Diagnosis-specific annual work disability days were categorised as: due to CMDs , due to other mental diagnoses than CMDs , due to degenerative spine diseases (ICD-10: M40-54), due to musculoskeletal diseases other than degenerative spine diseases (ICD 10: M00-99 except M40-54), and due to other somatic diagnoses , external causes of morbidity (V01-X59), factors influencing health status and contact with health services (Z00-Z99) and codes for special purposes (U00-U85)). Additionally, we estimated that the most common reasons for work disability during the three years following CED, measured as first long-term SA (LTSA) spell (more than 90 net days) and DP, were due to: neoplasms (C00-D48), mental disorders (F00-F99), diseases of the nervous system (G00-G99), cardiovascular diseases (I00-I99), musculoskeletal diseases (M00-M99), symptoms, signs and abnormal clinical laboratory findings (R00-R99), injuries/poisoning (S00-T98), and all others. Socio-demographic factors such as sex, age, educational level, living area, region of birth, and family situation were measured on 31 December in the year preceding inclusion. The socio-demographic factors were categorised as mentioned in As clinical covariates, previous in- or specialised outpatient care due to different diagnoses, SA in the year prior to inclusion, and the usage of analgesics, anxiolytics, antidepressants, and sedatives/hypnotics in the year prior to inclusion were used. Previous in- or specialised outpatient care was categorised as common mental disorders , other mental disorders , LBP , degenerative spine diseases other than LBP , and somatic diagnoses other than musculoskeletal diseases , external causes of morbidity (V01-X59), factors influencing health status and contact with health services (Z00-Z99) and codes for special purposes (U00-U85)). Sickness absence in the year prior to inclusion was categorised into four categories: 1–90 days, 91–180 days, 181–365 days, and more than 365 days . Prescribed and dispensed medication for analgesics, anxiolytics, antidepressants, and sedatives/hypnotics in the year prior to inclusion were coded according to the ATC codes: N02A and N02B; N05B, N06A, and N05C, respectively . These wThe differences in clinical factors between the LBP-patients with and without LSDS, and individuals without LBP diagnosis were assessed using the Chi-square test. To adjust for socio-demographic variations between the compared groups, the absolute levels of annual diagnosis-specific mean work disability days were calculated by the least square means over a six-year period. The three years of observation for both before and after the t0 (cohort entry date) comprised t − 3 to t − 1 and t + 1 to t + 3, respectively. To estimate the slope and risk of diagnosis-specific work disability days before (t − 3 to t − 1), around (t − 1 to t + 1) and after (t + 1 to t + 3) the CED, repeated measure regression with a generalised estimating equations (GEE) method with an exchangeable correlation structure was applied in order to produce relative risks (RRs) and 95% confidence intervals (CIs) . The estIn Adjusted mean work disability days due to different diagnoses three years prior to three years after inclusion in the three different groups are shown in Our study showed trends of diagnosis-specific work disability in patients with lumber spine decompression surgery, as well as in LBP-patients without surgical treatment and individuals with no diagnosed LBP, during the three years before and after the cohort entry date. LBP-patients treated by LSDS had high amount of work disability due to degenerative spine diseases throughout the observation period, with a sharp downward trend during the second year following surgery. However, work disability due to degenerative spine diseases was still about 25% higher three years after than surgery than it was three years before surgery. In addition to musculoskeletal diseases, patients with LSDS also had high work disability caused by other somatic and mental diagnoses, before and after the surgery, indicating for many mental and somatic co-morbidities that are not affected by the improvement in degenerative lumber spine disease. Among all three groups, LBP-patients without LSDS had the highest proportion of patients and mean number of days with work disability due to somatic diagnoses other than musculoskeletal, CMDs, or other mental diagnoses throughout the study. The findings show that patients with LSDS, have a relatively poor long-term prognosis in terms of work disability due to degenerative spine diseases, although it seems that the surgery was able to curb the increasing work disability trend from the second postoperative year. In these patients, about one sixth had long term SA or DP due to musculoskeletal diseases in the three years following decompression surgery . Work disability in patients with LSDS was already high at the beginning of the study and was even higher three years following the decompression surgery than three years before the intervention. According to recommendations, LSDS is performed as the primary option of therapy in severe cases of degenerative diseases, such as hernias and stenosis, and in rare acute cases of severe neurological complications ,24, and LBP-patients without decompression surgery had nearly double the amount of mean annual days of work disability due to CMDs and other somatic disorders—rather than musculoskeletal disorders—than the individuals without LBP. Similarly, the prevalence of work disability days due to degenerative spine diseases was three times higher, due to other musculoskeletal diseases was four times higher and due to mental diagnoses other than CMDs was slightly higher among LBP-patients without LSDS than in individuals without LBP. On the other hand, compared to individuals without LBP, LBP-patients with decompression surgery had similar amounts of mean annual work disability days for CMDs and other mental disorders, but six times higher rates of work disability days for degenerative spine diseases, three times higher for other musculoskeletal diseases, and one and a half times higher for other somatic disorders. Interestingly, work disability patterns due to diagnoses other than musculoskeletal diseases remained flat throughout the six observation years and did not show any upwards or downwards slope before or after CED, as it did for work disability due to degenerative spine diseases. Thus, patients with LBP (including those with LSDS) represent a population with many mental and somatic co-morbidities that were already present three years before CED (date of diagnosis/surgery) and did not change much over time. In particular, mental co-morbidities  have been shown to significantly increase work disability when co-occurring with chronic pain ,10 or trAn unexpected result was that work disability due to CMDs or due to other mental disorders was higher in individuals with LBP with no LSDS than it was in patients who had undergone LSDS. A possible explanation could be that the patients who already underwent LSDS and were granted SA or DP anytime during the three years after the surgery were, by default, recorded as SA or DP due to a degenerative spine disease that led to the surgery, although the underlying cause for work disability might have been mental or somatic co-morbidities. Another justification could be the obvious morphological defect and/or functional deficit in patients with LSDS , which eThis study is based on data from Swedish population-based nationwide registers, which have proofed to be of high quality ,19,20,30The study has been approved by the Regional Ethical Committee of Stockholm and by the ethical committees of Statistics Sweden, the National Board of Health and Welfare, and the Social Insurance Agency. After legal review, the data are only made available for researchers in the group who meet the criteria for access to this type of sensitive data. These procedures follow the Swedish Ethical Review Act, the Personal Data Act, and the Administrative Procedure Act. Data are derived from different registers. Therefore, no personal contact with the individuals is established. The integrity of the persons is secured through de-identification of the individual information by the data providing agencies. Results are presented on group level without any possibility of backward identification, as in numerous previous publications derived from this database. The research group applies high standards of data safety.This is the first register-based prospective cohort study on work disability following lumber decompression surgery, covering all individuals living in Sweden aged between 19–60 years.LBP-patients undergoing lumber spine decompression surgery (LSDS) had higher work disability during three years following surgery than patients without surgery and individuals without diagnosed LBP.LBP-patients undergoing LSDS had higher work disability three years following surgery than three years before, indicating unfavourable work disability prognosis, due to degenerative spine diseases.LSDS seems to be able to restrict the increasing work disability trend due to degenerative spine disease in the LBP-patients in the long run.Interventions and disability policy should focus on LBP-patients with degenerative spine disease.Key points:This study showed that patients undergoing lumber spine decompression surgery have an unfavourable work disability prognosis, with already high work disability being primarily due to dorsopathies before surgery. Work disability in patients with LSDS due to other diagnoses is also high, but without clear trends over time from before to after surgery, indicating high mental and somatic co-morbidities. Despite the higher work disability three years following the decompression surgery than three years before, the trend shows that the decompression surgery seemed to restrict a further incline in work disability in the long run.


P < 0.0001). They were also less likely to develop respiratory complications, such as bronchitis or pneumonia, or organ dysfunction. Four (1.2%) of our COVID-19 patients required respiratory support compared with 14.2% of controls needing respiratory support. COVID-19 cases tended to have lower neutrophil count but higher hemoglobin compared with controls. There were no reported deaths of COVID-19 infection; in contrast, 0.7% of the control group died. In the multivariable analysis, older age, travel history, and close contact with an infected household member were associated with COVID-19 infection. This study shows that the majority of pediatric COVID-19 cases were of lesser severity compared with other community acquired respiratory infections.There is a scarcity of population-level data of pediatric COVID-19 infection from Southeast Asia. This study aims to describe and compare epidemiological, clinical, laboratory and outcome data among pediatric COVID-19 cases versus controls in two neighboring countries, Singapore and Malaysia. We used a test-negative case–control study design recruiting all suspected COVID-19 cases  from January 2020 to March 2021 admitted to two main pediatric centers in Singapore and Malaysia. Data were collected using a standardized registry . The primary outcome was laboratory-confirmed COVID-19. Univariate and multivariable logistic regression analysis was used to determine factors associated with COVID-19. This study included 923 children with median age of 4 (interquartile range 2–9) years. Of these, 35.3% were COVID-19 cases. Children with COVID-19 were more likely to be asymptomatic compared with controls (49.4 versus 18.6%;  These centers are part of the Pediatric Acute and Critical Care COVID-19 Registry of Asia, which is a registry  within the Pediatric Acute and Critical Care Medicine Asian Network. All children and infants from birth to 16 years were admitted fulfilling the suspect criteria , and critical  according to the WHO definition.The primary outcome was laboratory-confirmed COVID-19 infection as defined earlier. Severity of COVID-19 cases were classified into four groups: mild , moderate , severe , which accounts for the dependence among repeated measurements on the same patient. Mixed models for continuous data were used, age and time by case–control categories interaction as fixed effects, and time as a random effect with a variance components variance–covariance matrix. The estimation method was based on a maximum likelihood technique and the variance–covariance matrix of the parameter estimates computed using a sandwich  estimator. Estimates from the model was reported as mean with 95% confidence interval (95% CI). Random effects univariate and multivariable logistic regression model with center as random effects was used to determine exposures present at admission that was associated with the primary outcome; covariates chosen for the multivariable model was determined by univariate P value. A priori–determined year of admission (2020 versus 2021) was also included to assess for any changes in view of increased detection of new circulating COVID-19 variants of concern in 2021. Quantitative association from univariate and multivariable logistic regression analysis was expressed as unadjusted odds ratio (OR) and adjusted OR (aOR) with 95% CI, respectively. All tests were two sided, and P < 0.05 was considered statistically significant. All analysis was performed in SAS v9.4 .All variables were summarized in terms of the aforementioned case–control categories. Categorical and continuous variables were presented as counts (percentages) and median (interquartile range), respectively. Association between case–control categories and other categorical variables were evaluated using the chi-square test, whereas the association between continuous variables were tested using the Mann-Whitney A total of 923 patients meeting suspect case criteria were included in this analysis over the recruitment period. Of these, 326 of 923 (35.3%) were confirmed cases, whereas the remaining were negative controls. There were 213 of 326 (65.3%) cases from Singapore and 113 of 326 (34.7%) cases from Malaysia. The epidemic curve of the pandemic in children in Singapore and Malaysia respectively is shown in Figure P < 0.001  age of COVID-19 cases was older compared with controls: mean 7 (3–12) years versus 3 (1–7) years; P < 0.0001) (Table P = 0.0002) and headache . Vital signs recorded throughout the hospital stay, demonstrate a lower heart rate, higher blood pressure and higher oxygen saturation in COVID-19 cases compared with controls after adjusting for age  , whereas only 0.6% were diagnosed with pneumonia (Table n = 3). In comparison, control cases consisted of viral (157 of 597 [26.3%]) and bacterial infections (32 of 597 [5.4%]) from various sources. In the multivariable analysis, older age , travel history (aOR 1.7  versus 182 of 216 [83.8%]); This test-negative case–control study of COVID-19 in children from two neighboring Southeast Asian countries, Singapore and Malaysia, found that pediatric COVID-19 was mostly mild compared with control cases presenting with suspected SARS-CoV-2 infection. They were more likely to be asymptomatic and less likely to develop lower respiratory/pulmonary disease or require respiratory support, to develop organ dysfunction, or require higher level of inpatient care. Besides the association of a lower neutrophil count, COVID-19 cases were less likely to have derangements in laboratory markers. In the multivariable analysis, older age, travel history, and close contact with an infected household member were associated with COVID-19 infection in Singapore and Malaysia.The proportion of COVID-19 cases in hospitalized children presenting without symptoms (approximately 50%) were consistent with published reports. Some children who met epidemiological criteria were admitted to the hospital for isolation purposes. At the beginning of the pandemic, when the clinical course in children was unknown, patients may have been admitted for monitoring, even though they were asymptomatic. As the pandemic evolved, asymptomatic children were only admitted if they did not have suitable conditions for home isolation. Similar to studies from other regions, the common presenting symptoms of COVID-19 in our cohort were fever 32.8%), coryza (17.5%), and cough (16.9%). In terms of laboratory parameters, when comparing children with COVID-19 with the control group, COVID-19 cases tended to have higher hemoglobin and albumin but lower white cell count—specifically, neutrophil count, total bilirubin, aspartate aminotransferase, and alanine aminotransferase. We found that COVID-19 cases in children tended to have lower heart rate, higher blood pressure, and higher oxygen saturation compared with controls even after adjusting for age , possibly signifying a trend toward greater spread of unlinked cases in the two countries. Another observed trend was the shortened duration of hospitalization in COVID-19 cases in 2021 , reflecting transfer of care to other isolation facilities or isolation at home.,The source of viral exposure in this study was consistent with that reported in the literature, with most cases reported to have had contact with an infected household member (259 or 326 [79.4%]).Four COVID-19 cases had coinfection with rhinovirus (three) and respiratory syncytial virus . In controls, rhinovirus (123) was identified as the main causative viral pathogen. This was followed by RSV (seven), Adenovirus (five), parainfluenza (five), and influenza (two). The decrease in typical viral circulation was likely due to pandemic control measures, including lockdowns and school closures as reported in other countries; however, rhinovirus seems to have persisted. There were three dengue cases detected in the control arm, demonstrating ongoing transmission of vectorborne diseases among children during the pandemic. There have been reports of COVID-19 cases wrongly diagnosed as dengue in adults and clinicians in dengue endemic countries need to remain vigilant of this risk in children. A significant number of bacterial pathogens from various sources were identified in the control arm highlighting the difficulty in distinguishing COVID-19 infections from other infections in children based on clinical presentation alone. Despite the ongoing pandemic, prescription of appropriate antibiotics should not be delayed for suspected unwell pediatric cases while awaiting laboratory confirmation of COVID-19.This study incorporated clinical registry data from the two largest pediatric centers in Singapore and Malaysia. Patient identification was complete and datasets had few missing data; hence, the capture population were representative of these cities’ pediatric population. However, it may not be representative of more rural towns in Malaysia or other countries in Southeast Asia. School closures were not uniform between the two countries and the proportion of children attending school in the weeks preceding admission was undetermined; therefore, this study is unable to provide data on school transmission. We were not able to identify patients according to their admission criteria  or whether COVID-19 diagnosis was incidental. This would have provided clearer information on prognosis/outcomes. Although detailed clinical and laboratory data were available on patients who tested positive for COVID-19, we were not able to determine whether the severe/critical cases were solely due to SARS-CoV2. Moreover, there were rapidly evolving viral factors , host factors , and community-based mitigation measures over the period of study, which we were unable to account for. Another limitation of this study is that the data gathered were limited to the duration of hospital stay without any longer term follow-up. Hence, intermediate to long-term complications were not captured. Lastly, our analysis of differences by year of infections was a proxy measure because we did not have data on individual COVID-19 viral strains.Although some children with COVID-19 could have severe clinical manifestations, the vast majority of pediatric COVID-19 cases in the Singapore and Malaysia within the first 15 months of the pandemic were mild and of lesser severity compared with other common community-acquired infections in children. During the course of infection, pediatric COVID-19 cases consistently trended high hemoglobin and platelets but low neutrophil count compared with controls. Older age, travel history, and household exposure to an infected COVID-19 case were associated with COVID-19 infection.Supplemental materials


What are the underlying factors associated with disparities between California Latino and non-Latino White smokers with Medicaid insurance who receive advice and assistance from health professionals regarding smoking cessation?In this cross-sectional study of 1861 patients, Latino smokers were less likely to receive advice from clinicians in the unadjusted model. When adjusted for sociodemographic factors, smoking behavior, health care factors, and acculturation measures, the difference was not statistically significant.Efforts to eliminate disparities for Latino smokers might consider community engagement and population health outreach strategies outside the clinical encounter. This cross-sectional study uses the California Health Interview Survey to investigate disparities in receipt of smoking cessation advice and assistance between Latino and non-Latino White smokers. Nationally, Latino smokers are less likely than non-Latino White smokers to receive advice and assistance from health professionals to quit smoking. California’s Medicaid expansion included the Patient Protection and Affordable Care Act’s comprehensive tobacco cessation benefits; however, it is unknown whether expanded coverage helped resolve this disparity.To examine the association between race and ethnicity (Latino and non-Latino White) and health professional cessation advice and assistance among smokers with Medi-Cal insurance in the post–Affordable Care Act period.This repeated cross-sectional study was conducted with the 2014 and 2016-2018 California Health Interview Survey. A total of 1861 Latino and non-Latino White current smokers aged 18 to 64 years who had Medi-Cal insurance and consulted a health professional in the past 12 months were included. Data were analyzed between December 1, 2019, and April 30, 2021.Race and ethnicity classified as Latino or non-Latino White.The outcomes were receipt of health professional advice to quit smoking or assistance to quit in the past 12 months. Logistic regression was used to examine the association between race and ethnicity and each outcome, adjusted for sociodemographic factors, smoking behavior, health care factors, and acculturation measures. All estimates were weighted to adjust for the complex survey design.Among 1861 participants, 44.8% were Latino, 53.8% were aged 40 years or older , 54.1% were male, and 59.9% had less than a high school education. Latino smokers were less likely than non-Latino White smokers to receive health professional advice (38.3% Latino smokers vs 55.3% non-Latino White smokers) or assistance (21.8% Latino smokers vs 35.7% non-Latino White smokers). In the unadjusted model, compared with non-Latino White smokers, Latino smokers were less likely to receive advice  and also less likely to receive assistance . However, in the adjusted model, race was no longer significant. Smokers with more office visits  and those with at least 1 chronic disease  were more likely to receive advice from a health professional. Additionally, daily smokers compared with nondaily smokers  were more likely to receive assistance.In this cross-sectional study, more office visits, having a chronic disease, and daily smoking were associated with an increased likelihood of receiving smoking cessation advice or assistance. Use of strategies to engage tobacco users outside of the clinic, such as proactive outreach and community-based engagement, may help address this disparity. A better understanding of Latino tobacco use and cessation behaviors is needed to inform prevention, screening, and treatment strategies.Tobacco use is still a major cause of morbidity and mortality in the United States.5 but through the Patient Protection and Affordable Care Act (ACA), many of them gained health care access. Few studies have examined whether tobacco treatment disparities persist in the post-ACA era, or specifically between Latino and non-Latino White smokers. Pre–Affordable Care Act studies reported that Latino smokers were less likely than non-Latino White smokers to receive advice to quit and cessation assistance from a health professional9; these studies examined racial and ethnic differences across the overall population. Only 1 national post-ACA study has explored how these trends compare among Latino and non-Latino White adults, which reinforced findings of previous studies that reported continued disparities between Latino and non-Latino White adults in advice from health professionals to quit.10 A regional post-ACA study of newly enrolled Kaiser Permanente patients in Northern California11 reported that Spanish-speaking, light/nondaily smokers had significantly lower rates of advice from a health professional to quit (56%) compared with English-speaking patients who were light/nondaily smokers (84%). Similarly, Spanish-speaking daily smokers reported lower rates of advice from a health professional to quit (70%) compared with English-speaking daily smokers (84%). The study findings highlight the importance of assessing language and smoking intensity among Latino populations to provide comprehensive services.Access to health insurance coverage and health care services, including tobacco cessation treatment, is a known barrier among Latino individuals,12 and the percentage of smokers covered by Medi-Cal increased substantially, from 19.3% before the ACA to 41.5% afterward.13 Therefore, there is a need to assess smoking intensity, access to cessation advice, and acculturation measures to better understand Latino tobacco use and treatment in Medi-Cal. Acculturation describes the process of acquiring cultural elements  of the host culture.14 Survey studies show that Latino individuals with a higher level of acculturation (as measured by US birthplace or English-language proficiency) are more likely to be daily smokers and smoke more cigarettes per day than foreign-born Latino individuals.18 Latino individuals also have the highest rates of nondaily smoking,15 which is associated with being less likely to be advised or assisted by health professionals to quit.19In California, the ACA expansion increased access to Medi-Cal insurance to 2.8 million people by the fall of 2014; of these, 41% were newly insured nonelderly Latino individuals,This study compares health professional advice and assistance in the post-ACA period among Latino and non-Latino White smokers with Medi-Cal and investigates associated factors. California provides a unique setting to examine Latino tobacco use, screening, referrals, and cessation behaviors because it has approximately 3 million smokers, one-third of whom are Latino. We hypothesized that race and ethnicity, lower acculturation, and lower smoking intensity  may be associated with receiving less health professional advice and cessation assistance.AAPOR) Transparency Initiative and follows their reporting guidelines as outlined in their methodology report.20 This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. The need for informed consent was waived by the University of California, Davis institutional review board because this study was approved as exempt from human subjects review.Data from the 2014 and 2016-2018 California Health Interview Survey (CHIS), a population-based survey that is representative of the California population, were analyzed as a repeated cross-sectional study. Primary outcomes were not included in CHIS 2015, 2019, or 2020, and therefore these years were not included in this secondary analysis. The CHIS is a stratified random-digit-dial telephone survey of landline-only and cell phone–only households, with more than 20 000 participants each year. The survey is conducted in English, Spanish, Chinese (Cantonese and Mandarin), Korean, and Vietnamese. The overall adult survey response rate was 44.8% in 2014, 41.5% in 2016, and 42.3% in 2017 and 2018. The CHIS is certified by the American Association for Public Opinion Research , who self-identified as Latino or non-Latino White, had a clinician visit in the past 12 months, and currently smoked cigarettes (N = 1861). Current smokers were defined as ever having smoked 100 cigarettes in their lifetime and smoked every day or some days in the past 30 days.To assess advice to quit smoking and assistance from a health professional with referral or cessation information, smokers were asked the following: “In the past 12 months, did a doctor or other health professional advise you to quit smoking?” and “In the past 12 months, did a doctor or other health professional refer you to, or give you information about, a cessation program?” These questions were administered only to current smokers in the survey.13 The health care factor variables included number of office visits to a “medical doctor” in the past 12 months (1-4 vs ≥5), having at least 1 chronic disease (yes vs no), and experiencing psychological distress in the past year (yes vs no). Participants were classified as having at least 1 chronic disease if they were told by a physician that they had 1 or more of these conditions: heart disease, hypertension, diabetes, or current asthma. The 6-item Kessler Psychological Distress Scale was used to classify adults as experiencing psychological distress. Scores on the 6 dimensions were coded and summed to produce a total score of 0 to 24, with a 0 indicating no distress at all and 24 indicating extreme distress. Scores of 13 or greater were considered as indicating severe psychological distress. The survey year variable was included to assess trends in each outcome during the 2014 and 2016-2018 periods. These variables were selected according to previous study findings.21Covariates reflect 4 domains that may influence health professionals’ advice and assistance: sociodemographic factors, smoking behavior, measures of acculturation, and health care factors. Sociodemographic variables included age , sex , education (less than high school education or high school graduate vs any college), and race and ethnicity (Latino and non-Latino White). Smoking behavior variables included smoking intensity (daily or nondaily smoking), stopped smoking in the past year for 1 day or longer (yes vs no), and thinking about quitting in the next 6 months (yes vs no). The measures of acculturation included birthplace (the United States or foreign born) and English-language proficiency . The health care factors reclassification of the chronic health conditions, frequency of physician visits, and psychological distress variables were modeled after the variable categories chosen in a previous CHIS Medicaid smoker study.2 tests. In addition, the prevalence of each outcome was estimated for all covariates, and differences were assessed with χ2 tests. Statistical significance was set at 2-sided P = .05. Unadjusted and adjusted logistic regression was used to examine the association between race and each outcome. Adjusted models included all covariates described earlier. All estimates were weighted to adjust for the complex survey design, using SAS survey procedures such as survey logistic regression. The CHIS uses replicate weights to adjust for both the weighting and the stratum. Data were analyzed between December 1, 2019, and April 30, 2021. All analyses were conducted with SAS version 9.4 (SAS Institute Inc).The prevalence of each covariate was estimated for Latino and non-Latino White smokers, and differences were assessed with χAmong adult smokers with Medi-Cal who had a clinician visit in the past year, more than half had not received advice, and almost three-quarters had not received assistance to quit smoking . CompareResults from the unadjusted logistic regression analysis revealed that race and ethnicity were significantly associated with both outcomes . CompareIn this study, there was no statistically significant difference in the final adjusted model for the likelihood of receiving smoking cessation advice from a health care professional between Latino and non-Latino White smokers enrolled in Medi-Cal. Five or more visits to a physician, having at least 1 chronic disease, and daily smoking were significantly associated with advice and assistance, suggesting that these factors help explain outcome differences among Latino and non-Latino White Medi-Cal beneficiaries. This research contributes to the understanding of the outcome differences between 2 groups having Medi-Cal and who consulted a health professional in the last year.10 Although this national study did not account for any of the health care factors in our study, similarly, the findings from our study confirm there were no significant changes in advice or assistance to Latino smokers over time.Despite an increase in health insurance coverage, there was no change in the percentage of smokers with Medi-Cal who received cessation advice or assistance from 2014 to 2018. This finding is consistent with 1 national post-ACA study that compared Latino and non-Latino White smokers’ receiving advice from health professionals to quit, noting there was no change over time (2000-2015).11 that adjusted for factors similar to those used in our study, including preferred language. They found that Spanish-speaking nondaily smokers had significantly lower rates of advice (56%) compared with English-speaking smokers and Spanish-speaking daily smokers. Some research suggests there could be a patient-level misconception that infrequent nondaily tobacco use does not qualify one as a tobacco user and may not prompt a physician to provide advice.22 However, nondaily, light use could present a long-term elevated risk of tobacco-related illness. A meta-analysis23 found that no safe level exists for cardiovascular disease and that even 1 cigarette per day carries risk. Health care systems can implement screening protocols that ask about use in the past 30 days to capture nondaily smokers.Our finding that daily smoking, compared with nondaily smoking, was associated with receiving smoking cessation assistance is consistent with a regional post-ACA study of newly enrolled Kaiser Permanente patients in Northern California24 to help direct individuals to evidence-based state quit-line services. Less than one-fifth of Latino individuals (19.5%) are enrolled in quit-line services, yet they make up more than one-third (34.2%) of all smokers in California.25We found that visiting a physician more often was associated with an increase in receiving cessation advice and assistance. In the study, Latino individuals who smoked had slightly lower rates than non-Latino White smokers for consulting a health professional in the past year, and, among those who did so, non-Latino White individuals who smoked were nearly twice as likely to have at least 5 office visits as Latino smokers were. For populations who are less likely to visit a physician, such as Latino individuals, Medicaid plans and health care systems might consider proactive outreach strategies19 Leveraging community leaders and promotoras  can be an effective channel for conveying health messages.26Use of communication messages and channels that consider the Latino community and culture can help address Latino smoking behavior. Community-based messaging strategies that focus on how secondhand smoke harms the family are motivating messages. Messages should address smoking risk, racial and ethnic differences, and smoke-free homes, and address situational triggers through brief interventions.27 Spanish-speaking Latinx individuals had a higher engagement with the California Smokers’ Helpline through in-home mailings .28 Once engaged with the helpline, Spanish-speaking Latinx individuals had higher rates of completing counseling and receiving nicotine therapy than White individuals. Targeted Spanish language–designed media can increase calls to the helpline and improve quit outcomes. Greater awareness and research are necessary to improve tobacco cessation advice and assistance in younger, healthier patients and nondaily smokers.Broader and simultaneous strategies to promote cessation services outside of the clinical encounter, which include written materials  with information about nicotine replacement therapy, are proven strategies and necessary to address higher smoking rates among California’s Medi-Cal population.29 Additionally, these responses regarding clinician visits may have been influenced by recall bias and potential misclassification also owing to self-report. This study did not examine cessation outcomes, but advice and assistance from health professionals are important process measures toward quitting. Latino tobacco use and cessation behaviors in California may vary from that of other Latino subgroups and Latino individuals in other geographic areas in the United States; therefore, generalizability may be limited. The use of ORs in our analysis may have overestimated the strength of the association when the outcome of interest was not rare (>10%).30The study has several limitations. Survey response was below 50%, which may lead to nonresponse bias. To help address this bias, CHIS survey weights include an adjustment for nonresponse. The repeated cross-sectional study design precludes causal inferences. There may be misclassification owing to self-report of smoking intensity, which is likely nondeferential. Although the data rely on smokers’ self-reports, which were not biochemically verified with cotinine levels, a meta-analysis comparing self-reported smoking status with results of biochemical validation suggested generally high levels of sensitivity and specificity for self-report.To our knowledge, this is the first study to examine factors associated with Latino vs non-Latino White smokers receiving Medicaid and reporting less advice and assistance from health professionals in the post-ACA era. More office visits, having a chronic disease, and daily smoking were associated with an increased likelihood of receiving smoking cessation advice or assistance. Use of strategies to engage tobacco users outside of the clinic, such as proactive outreach and community-based engagement, may help address this disparity. Future Latino tobacco interventions and population health strategies need to understand the unique smoking behaviors and health care use practices of low-income Latino individuals. The findings may be useful in promoting awareness of these patient-level differences to health care and in informing the design of more targeted studies that can examine the health care system–, clinician-, and patient-level factors in more detail.


To report a case of unilateral acute posterior multifocal placoid pigment epitheliopathy (APMPPE) in a Hispanic convalescent COVID-19 female patient.Case presentationA 35-year-old Hispanic female with exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was evaluated due to unilateral visual loss. Ophthalmic examination and diagnostic tests were consistent with APMPPE.Ocular changes can be observed in patients with COVID-19. A complete ophthalmic evaluation must be performed in patients with low vision after SARS-CoV-2 infection. In February 2020, the International Committee on Taxonomy of Viruses (ICTV) announced the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a new virus. This name was chosen because the virus is genetically related to the coronavirus responsible for the SARS outbreak of 2003. The World Health Organization (WHO) named this new disease as "COVID-19" in February 2020. The disease quickly reached the size of a pandemic on March 11, 2020, due to the speed and scale of the transmission [There are basically 3 stages or phases in the natural history of COVID-19, regarding disease severity. The first phase is related to the onset of the disease and is generally characterized by the development of influenza-like symptoms from mild to moderate. Some individuals recover and some progress to the second phase. During the second phase, it is possible to detect pneumonia-like symptoms. Depending on the severity of phase two, patients can improve, or worsen with the necessity of intubation and ventilation. The phase three is characterized by hyper inflammation and sepsis of lungs. Patients often require intensive care unit and most of them unfortunately cannot overcome the infection and eventually die .Ocular manifestations in COVID-19 patients may include conjunctivitis, chemosis, and epiphora. Higher neutrophil counts, procalcitonin, C-reactive proteins, and lactate dehydrogenase are factors associated with such signs .Posterior segment manifestations may include retinal hemorrhages, cotton wool spots, and dilated retinal vessels. Higher veins diameter has been positively correlated with disease severity . InteresWe present a case of a convalescent COVID-19 female patient with acute posterior multifocal placoid pigment epitheliopathy (APMPPE).A 35-year-old Hispanic female presented blurred vision, central scotoma and photopsia in her right eye. She had experienced fever, headaches and myalgia 6 weeks before initial consultation. The patient had past history of Diabetes mellitus diagnosed 3 years before, and good glucose control was obtained with insulin. She tested positive for SARS-Cov-2 IgG antibody 2 weeks before ophthalmic examination. Previous ocular history was unremarkable.A complete ophthalmological exam was performed. Best-corrected visual acuity (BCVA) was 20/400 in the right eye (RE) and 20/20 in the left eye (LE). Biomicroscopy of the anterior segment, pupillary reflexes, and intraocular pressure were normal in both eyes (OU). At fundus examination, multiple yellow-white placoid lesions were evident at the posterior pole in the RE Fig. a. LE posComplete blood count with differential and tests for infectious disease  were requested—the results obtained were negative. Routine blood tests were normal.Based on imaging and clinical features, the patient was diagnosed with APMPPE.More commonly ocular manifestations have been reported in patients with COVID-19 such as conjunctivitis, chemosis, and epiphora in patients with severe systemic disease or abnormal findings on blood tests .Our patient started with unilateral macular dysfunction 6 weeks after the onset of influenza-like symptoms. Laboratory tests found positive IgG antibody for SARS-CoV-2, showing serological evidence of past infection for COVID-19. Fundus photographs, FA, FAF, and OCT findings correlate well with previous descriptions of APMPPE lesions , 15. APMUp to one third of APMPPE cases worldwide have been described as related to a viral prodromic period. While viruses as type five Adenovirus and B4 Coxsackievirus have been typically associated with white dot syndromes, there have been reports of post vaccination disease. Its cause has not been clearly elucidated yet since the incidence of these syndromes is very low. However, Coxsackie antibody titers in acute and treated cases seem to correlate in some series .Using multimodal imaging in APMPPE, some authors have found choroidal inflammation as a preceding and necessary factor for RPE, and subsequent damage in cones . This chDetection of SARS-CoV-2 has been confirmed by Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in human retinal biopsies (RB) of deceased COVID-19 patients. Although ocular symptoms or changes in the posterior segment were not analyzed in these patients, important information about virus presence in the retina was confirmed .ϒ (IFN-ϒ) and retinal damage in BALB/c mice after inoculation of JHM strain in the vitreous cavity [Experimental coronavirus retinopathy (ECOR) occurs after intravitreal inoculation of murine coronavirus  in BALB/c and CD-1 mice. In BALB/c mice, JHM strain induces a biphasic retinal disease characterized by retinal vasculitis observed one to seven days after inoculation (early phase) followed by retinal degeneration in the absence of inflammation (second phase) . The virs cavity .There is uncertainty if retinal changes  or changes on OCT (hyper reflective dots at the level of inner plexiform or ganglion cell layers) appear days or weeks after the onset of COVID-19 and its relation to the severity of the disease or symptoms , 6, 7.To the best of our knowledge, this is the first case of APMPPE in a convalescent COVID-19 patient. Understanding of the physiopathology is still needed15.


Treatment guidelines for generalized anxiety disorder (GAD) are based on a relatively small number of randomized controlled trials and do not consider patient-centered perceptions of treatment helpfulness. We investigated the prevalence and predictors of patient-reported treatment helpfulness for DSM-5 GAD and its two main treatment pathways: encounter-level treatment helpfulness and persistence in help-seeking after prior unhelpful treatment.Data came from community epidemiologic surveys in 23 countries in the WHO World Mental Health surveys. DSM-5 GAD was assessed with the fully structured WHO Composite International Diagnostic Interview Version 3.0. Respondents with a history of GAD were asked whether they ever received treatment and, if so, whether they ever considered this treatment helpful. Number of professionals seen before obtaining helpful treatment was also assessed. Parallel survival models estimated probability and predictors of a given treatment being perceived as helpful and of persisting in help-seeking after prior unhelpful treatment.The overall prevalence rate of GAD was 4.5%, with lower prevalence in low/middle-income countries (2.8%) than high-income countries (5.3%); 34.6% of respondents with lifetime GAD reported ever obtaining treatment for their GAD, with lower proportions in low/middle-income countries (19.2%) than high-income countries (38.4%); 3) 70% of those who received treatment perceived the treatment to be helpful, with prevalence comparable in low/middle-income countries and high-income countries. Survival analysis suggested that virtually all patients would have obtained helpful treatment if they had persisted in help-seeking with up to 10 professionals. However, we estimated that only 29.7% of patients would have persisted that long. Obtaining helpful treatment at the person-level was associated with treatment type, comorbid panic/agoraphobia, and childhood adversities, but most of these predictors were important because they predicted persistence rather than encounter-level treatment helpfulness.The majority of individuals with GAD do not receive treatment. Most of those who receive treatment regard it as helpful, but receiving helpful treatment typically requires persistence in help-seeking. Future research should focus on ensuring that helpfulness is included as part of the evaluation. Clinicians need to emphasize the importance of persistence to patients beginning treatment.The online version contains supplementary material available at 10.1186/s12888-021-03363-3. Generalized Anxiety Disorder (GAD) encompasses a variety of symptoms including excessive worrying, restlessness, irritability, difficulties in concentration, and constantly feeling on edge. Among the anxiety disorders, GAD is perhaps the least well researched or understood in part because of multiple revisions of the diagnostic criteria, consideration of the diagnosis as a “wastebasket” category when other anxiety diagnoses could not made, and because worrying was assumed a part of everyday life and associated with minimal impairment. However, GAD is now known now to be a significant disorder with high prevalence and significant impairment and disability , 2. WorlRandomized controlled trials (RCTs) have identified effective pharmacological and psychosocial treatments –7. HowevPerceived helpfulness of treatment is a key construct that may capture whether patients achieve personally meaningful goals through treatment. Helpfulness is important in its own right, but also has a critical role in treatment in that perceived helpfulness relates directly to treatment adherence as well as to critical processes that span diverse forms psychotherapy  –16. HelpThe likelihood of a help-seeking individual ever obtaining helpful treatment is a joint function of two treatment pathways: 1) the probability that a given treatment provider will be helpful, and 2) the probability that a patient will persist in help-seeking after prior unhelpful treatment encounters. Research on these processes for depression and posttraumatic stress disorder found that the majority of patients who persisted after previous unhelpful treatments eventually obtained helpful treatments, but that only a minority persisted in help-seeking after more than a few unsuccessful treatment encounters , 21. It The present study evaluated the helpfulness of treatment encounters and predictors and pathways leading to helpfulness in national community epidemiological samples that included respondents with a history of GAD who sought treatment for their GAD. The data come from the World Mental Health (WMH) Survey Initiative . This ishttps://www.hcp.med.harvard.edu/wmh/)  ever got helpful treatment”. Respondents who said they never received helpful treatment were asked how many professionals they ever talked to about their worry or anxiety.Respondents who met lifetime criteria for GAD were asked whether they had ever “talk [ed] to a medical doctor or other professional about their worry or anxiety” and, if so, how old they were the first time they did so. “Other professionals” were defined broadly to include “psychologists, counselors, spiritual advisors, herbalists, acupuncturists, and other healing professionals.” Respondents who had ever spoken to a professional about their GAD were asked whether they ever received treatment they “considered helpful or effective”  at the time of first treatment, and education (in quartiles defined by within-country distributions) at the time of first treatment. Lifetime comorbid conditions included other lifetime anxiety disorders , major depressive disorder, broadly defined bipolar spectrum disorder [Treatment type was defined as a cross-classification of (i) whether the respondent reported receiving medication, psychotherapy, or both, as of the age of first GAD treatment; and (ii) the types of treatment providers seen as of that age. Types of providers included mental health specialists , primary care providers, human services providers , and complementary-alternative medicine . Treatment timing included a continuous variable for length of delay in years between age of onset of GAD and age of initially seeking treatment, and a dichotomous measure for whether the respondent’s first attempt to seek treatment occurred before or after the year 2000. The year 2000 was the typical midpoint between the start of observations and survey field dates. Childhood adversities included retrospective reports of significant stressors experienced during childhood, including family dysfunction  and other adversities .In addition to age of onset of GAD (continuous), we considered 5 classes of predictors of helpful treatment: disorder , alcoholn = 30 respondents received treatment. However, in low/middle-income countries (LMICs), we followed respondents only up through 3 professionals seen because this was the last number where at least n = 30 respondents received treatment.The sample was limited to respondents with a history of DSM-5 GAD treatment who sought treatment for the disorder at some time in their life. Cases were limited to those who first sought GAD treatment in 1990 or later to reduce the potential effects of recall bias. To investigate the two pathways of helpful treatment separately, we used discrete-event survival analysis to calculate the conditional and cumulative probabilities of: (i) obtaining helpful treatment after seeing between 1 and 10 professionals; and (ii) persisting in help-seeking after obtaining prior unhelpful treatment . We follWe then carried out parallel survival analyses of the predictors of these two decomposed, encounter-level outcomes using standard discrete-time methods and a logistic link function , followe2 tests based on design-corrected coefficient variance-covariance matrices. Statistical significance was evaluated using two-sided, design-based .05 level tests.We also investigated possible interactions of each significant person-level predictor with country income group and historical time (beginning treatment in 1990–1999 vs. 2000+) in an effort to examine the generalizability of the findings. Because the WMH sample design used weighting and clustering in all countries, all statistical analyses were carried out using the Taylor series linearization method , a desig21 = 63.6, p < 0.001), but probability of treatment being perceived as helpful did not differ significantly by country income level .Lifetime prevalence (SE) of GAD was 2.8% 0.1) in LMICs, 5.3% (0.1) in HICs, and 4.5% (0.1) across all WMH surveys  of respondents who received treatment said they were helped by the first professional they saw  of respondents persisted in seeing a second professional after initial unhelpful GAD treatment , comorbid panic/agoraphobia , and childhood adversities . The association with treatment type was because respondents who received treatment from a mental health specialist in combination with medication had significantly increased relative-odds of obtaining helpful treatment than those who received treatment in the human services sector . Decomposition showed that this person-level association of treatment from a mental health specialist in combination with the outcome was due to lower relative-odds of encounter-level helpfulness , but higher relative-odds of treatment persistence . Comorbid panic/agoraphobia was associated at the person-level with having significantly increased relative-odds of obtaining helpful treatment  due to increased relative-odds of treatment persistence .At the person-level, significant predictors of obtaining helpful treatment were treatment type , whereas a history of other childhood adversities was significantly associated with increased relative-odds of obtaining helpful treatment . Decomposition showed that the person-level association of family dysfunction with the outcome was due to significantly reduced relative-odds of treatment persistence , whereas the person-level association other childhood adversities with the outcome was due to significantly increased relative-odds of treatment persistence . It is noteworthy that the zero- Pearson correlation between the two CA measures is too low (r = 0.23) to create an opposite-sign pattern as a methodological artifact. Consistent with this observation, the same opposite-sign pattern was also observed in models where only one of the two CA measures was included.2 tests for treatment timing and treatment delay were not significant, there were significantly increased relative-odds of both predictors with significantly decreased relative-odds of with persistence in help-seeking after an initial unhelpful treatment, were found for both beginning treatment in more recent years (2000 or later) and longer treatment delays in obtaining helpful treatment from a given professional, resulting in nonsignificant associations at the person-level.Although the omnibus χWe found significant interactions of treatment type and childhood adversities with country income level eTable . These iThe main findings of the study are as follows. First, only about one-third of people with GAD reported ever obtaining treatment, with a lower proportion in LMICs than HICs (19.2% vs. 38.4%). Second, 70% of those who received treatment perceived the treatment to be helpful. This did not vary by country income level. Third, persistence in help-seeking was required to obtain helpful treatment, as only about one-fourth of patients were helped by the first professional they saw and about half by the first two professionals. Projections from our survival models suggest that up to 10 professionals might be needed to have a 90% probability of being helped, but that only 29.7% of patients would persist that long in the face of repeated unhelpful treatment encounters. Fourth, only relatively modest predictors were found of obtaining helpful treatment at the person-level, most of which were important because they predicted persistence rather than encounter-level treatment helpfulness.It is encouraging that the large majority (70.0%) of respondents with lifetime DSM-5 GAD who sought treatment eventually obtained treatment they considered helpful. This means that the majority of patients persisted up to 3–4 professions in the face of initial unhelpful treatment. This is a lower persistence rate than found in a parallel analysis of specific phobia , but a hOur data on the predictors of helpfulness are useful in beginning to delineate pathways. Patients who received treatment from a mental health specialist in combination with medication had significantly increased relative-odds of obtaining helpful treatment at the person-level than those who received treatment in the human services sector. This was due to lower relative-odds of encounter-level helpfulness, but higher relative-odds of treatment persistence. Patients who receive medication in addition to seeing a mental health specialist may have been more severe than other patients, resulting in lower relative-odds of encounter-level helpfulness due to the severity of their illness, but also more motivation to persist in help-seeking because of that high severity. Likewise, panic/agoraphobia was also associated with having significantly increased relative-odds of obtaining helpful treatment at the person-level due to increased relative-odds of treatment persistence. These individuals may have more chronic and impairing courses of illness  which maThe relationship between childhood adversity and treatment helpfulness was less straightforward. Family dysfunction was associated with lower relative-odds of obtaining helpful treatment due to lower relative-odds of treatment persistence. In contrast, other childhood adversities were associated with greater relative-odds of obtaining helpful treatment due to increased relative-odds of treatment persistence. One possible explanation for this difference is that the family dysfunction category included violent and traumatic forms of adversity, whereas the other childhood adversities category did not . If thisImportant limitations of this study should be noted. First, there was limited information about the precise nature of the interventions that respondents received and no information about sequencing of treatments across types of providers. Moreover, the treatments were not randomized nor evaluated in relation to quality of delivery (treatment integrity) or compliance on the part of the patient (adherence). Consequently, the relation of critical dimensions of treatment to helpfulness could not be discerned. Second, the sample was limited to respondents with onset of GAD treatment after 1990. Recall may have been biased and influenced evaluations of the treatments and helpfulness . It is uRCTs are clearly required to determine the efficacy and effectiveness of GAD treatments –7. AlthoOur findings suggest that treatment guidelines should not only encourage evidence-based interventions, but also should emphasize the value of treatment persistence. Our data do not allow us to study new treatments from the same provider. The persistence we examined was across providers. It should be noted, though, that evidence is clear in showing that patients can also be helped by new treatments from the same provider . FurtherAdditional file 1: Table 1. WMH sample characteristics by World Bank income categoriesa. Table 2. Conditional and cumulative probabilities of obtaining helpful treatment for generalized anxiety disorder after each professional seen, among respondents with lifetime DSM-5 generalized anxiety disorder who obtained treatment in low/middle-income and high-income countries. Table 3. Conditional and cumulative probabilities of persistence in help-seeking after previous unhelpful treatment, among respondents with lifetime DSM-5 generalized anxiety disorder who obtained treatment in low/middle-income and high-income countries. Table 4. Predictors of obtaining helpful treatment (person-level), among people with lifetime DSM-5 generalized anxiety disorder who obtained treatment. Table 5. Interactions between main effects and country income group to predict obtaining helpful treatment (person-level composite outcome) and the decomposed encounter-level outcomes of helpful treatment and persistence, among people with lifetime DSM-5 generalized anxiety disorder who obtained treatment. Table 6. (Low/middle-income countries): Predictors of obtaining helpful treatment (person-level composite outcome) and of the decomposed encounter-level outcomes of helpful treatment and persistence, among people with lifetime DSM-5 generalized anxiety disorder who obtained treatment. Table 7. (High-income countries): Predictors of obtaining helpful treatment (person-level composite outcome) and of the decomposed encounter-level outcomes of helpful treatment and persistence, among people with lifetime DSM-5 generalized anxiety disorder who obtained treatment. Table 8. Interactions between main effects and historical time to predict obtaining helpfulness of treatment (person-level composite outcome) and the decomposed encounter-level outcomes of helpful treatment and persistence, among people with lifetime DSM-5 generalized anxiety disorder who obtained treatment. Table 9. (Started GAD treatment in 2000 or later): Predictors of obtaining helpful treatment (person-level composite outcome) and of the decomposed encounter-level outcomes of helpful treatment and persistence, among people with lifetime DSM-5 generalized anxiety disorder who obtained treatment. Table 10. (Started GAD treatment 1990 to 1999): Predictors of obtaining helpful treatment (person-level composite outcome) and of the decomposed encounter-level outcomes of helpful treatment and persistence, among people with lifetime DSM-5 generalized anxiety disorder who obtained treatment.