We analyzed the efficacy and toxicity of cabazitaxel (CBZ) at high and low initial doses in Japanese patients with docetaxel-resistant castration-resistant prostate cancer (CRPC).2, n = 36) and low  CBZ doses. Factors associated with survival and grade 4 neutropenia were evaluated.We retrospectively evaluated 118 patients who received CBZ for docetaxel-resistant CRPC in 10 university hospitals in Japan between 2014 and 2016. The rate of decrease of prostate-specific antigen (PSA), adverse events, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving initially high (≥22.5 mg/mP = 0.073). The median PFS time for the all-patient, high- and low-dose groups was 2.8 months , 2.1 months (1.2–5.5), and 3.0 months (2.0–4.4), respectively (P = 0.904). The median OS times were 16.3 months (95% CI 9.7–30.9), 30.9 months (11.8–47.4), and 10.2 months (8.6–20), respectively (P = 0.020). In multivariate analyses, PFS was significantly associated with existing bone metastasis at diagnosis (P = 0.005) and OS with PSA > 100 ng/ml (P = 0.007), hemoglobin < 12 g/dl (P = 0.030), and low initial CBZ dose (P = 0.030). Grade 4 neutropenia occurred in 53 patients (45%) and was associated with a low CBZ dose .PSA values decreased by > 50% in 22 patients (19%), with a higher frequency in the high-dose group than in the low-dose group (29 and 14%, CBZ at a higher initial dose may have similar response rate and response duration, but longer survival duration after treatment with higher toxicity than a lower initial dose for docetaxel-resistant CRPC in Japanese patients. Subsequent reports suggested that 20 mg/m2 CBZ might decrease myelotoxicity without altering efficacy [Prostate cancer is the second leading cause of cancer-related death in men in the USA  and its efficacy . However2  or 20 or 15 mg/m2 . The relative dose intensity (RDI) of CBZ was calculated as the ratio of delivered dose intensity (mg/m2/week) to the planned dose intensity  in the first three cycles of CBZ treatment. PFS was defined as the time from initiation of CBZ to an increase in PSA value > 25% relative to the nadir PSA value, radiological progression, or death after CBZ treatment. OS was defined as the time from initiation of CBZ treatment to death from any cause. The type and incidence of adverse events were also evaluated based on the laboratory data and medical records.This was a retrospective study of 118 patients who received CBZ for docetaxel-resistant CRPC at 10 university and satellite hospitals in Japan between 2014 and 2016. The study was approved by the institutional review board of each university. All patients had pathologically proven adenocarcinoma of the prostate that was progressing according to prostate-specific antigen (PSA) concentrations or radiographic criteria, despite androgen blockade therapy. The data were retrospectively obtained from medical records. CRPC was defined as either an increase in PSA level of > 25% relative to the nadir PSA value or radiological progression after initial hormonal therapy. All CRPC patients had received docetaxel before CBZ treatment. The criteria for decision making about CBZ doses was different between institutions and not determined. The rate of PSA decrease, incidence of adverse events, and duration of progression-free survival (PFS) and OS were compared between patients who received a first course of CBZ treatment of 25 or 22.5 mg/mP values of < 0.05 were considered statistically significant.The data are presented as medians and ranges. PFS and OS times were estimated using the Kaplan–Meier method and compared using the log-rank test. Associations between clinicopathological variables and prognosis were assessed using univariate and multivariate Cox’s proportional hazards regression models. The median values were used as cut-off values of the subgroups. Associations with adverse events were examined using multivariate logistic regression analysis. All statistical analyses were performed with EZR , which is a graphical user interface for R . 2, 7 received 22.5 mg/m2 initially) and 81 (69%) were in the low-dose group . The clinicopathological characteristics for the patients in the high- and low-dose groups are shown in Table P = 0.017), but there were no significant differences in other parameters. Patients were administered one dose of CBZ every 3 to 4 weeks (28 in 3 weeks and 90 in 4 weeks) and the median number of treatment cycles was 4 (range 1–33). During treatment, the CBZ dosage was decreased due to adverse events in 13 patients (35%) in the high-dose group and 6 patients (7%) in the low-dose group. Dosage was increased in 4 patients (5%) in the low-dose group and none in the high-dose group. RDI was calculated in 29 patients (78%) in the high-dose group and 56 patients (69%) in the low-dose group who received three or more cycles of CBZ treatment. The median RDI was 75% (60–100%) in the high-dose group and it was 60% (30–80%) in the low-dose group (P < 0.001)  were in the high-dose group , and this remained the only significantly associated factor after multivariate analysis including low initial CBZ dose . PSA values decreased by > 50% in 22 patients (19%), with a higher frequency in the high-dose group  than in the low-dose group . However, this difference was not statistically significant , PSA > 100 ng/ml , hemoglobin < 12 g/dl , lactate dehydrogenase > 300 U/L , alkaline phosphatase > 350 U/L , initial low CBZ dose , and RDI 60% or lower . In multivariate analyses including these parameters, only the association with PSA > 100 ng/ml  remained significant. Then, using stepwise regression multivariate analyses, PSA > 100 ng/ml , hemoglobin < 12 g/dl  and low initial CBZ dose  were significantly correlated with OS  and grade 3 thrombocytopenia  than the 20 mg/m2 group . However, there was no significant difference in either the median PFS time  or median OS time  between the treatment groups. We found a similar PFS in the two treatment groups even though the PSA decrease rate tended to be lower in the low initial CBZ dose group. In contrast, the high-dose group had a significantly longer OS than did the low-dose group in univariate and multivariate Cox proportional hazard analyses. The RDI was significantly higher in the high-dose group. Based on these results, the initial high-dose CBZ has a potential to enhance the RDI, causing longer survival after treatment. However, our study was retrospective and the CBZ treatment protocol differed between institutes and physicians. The results might be influenced by some selection bias, which suggests that other patient characteristics were likely to explain the difference in OS. Moreover, the RDI of CBZ was smaller than 60% in many patients. In the real world, we had easily decreased the dose of CBZ because of high rate adverse events such as neutropenia. Based on the results of this study, we need to make efforts to increase the RDI so that CBZ can be used effectively. The appropriate dose of CBZ should be determined based on the disease status and characteristics in each patient.Based on the results of the phase III TROPIC trial, CBZ at 25 mg/m2 and 25 mg/m2 CBZ, respectively, which supports the notion that a lower dose of CBZ may decrease the hematological toxicity rate [P < 0.001), which is similar to the results of the PROSELICA study. Moreover, grade 4 neutropenia was not significantly associated with age or PS in our study, which supports the possibility that low-dose CBZ could be safe even for older patients and/or those with low PS. Kosaka et al. reported that the presence of grade 3 or 4 neutropenia after CBZ treatment was significantly correlated with longer OS [In the PROSELICA study, grade 3 and 4 neutropenia was observed in 57.1 and 82.1% of patients treated with 20 mg/mThe PSA response rate in our study was 19%, which is significantly lower than those in the TROPIC and PROSELICA studies. The proportion of patients who received abiraterone or enzalutamide was also different between the studies; i.e., 0, 26, and 79% in TROPIC, PROSELICA, and our study, respectively. We previously reported that patients treated sequentially with abiraterone and enzalutamide showed a poorer response to the second than to the first treatment [Elucidating an appropriate treatment sequence using novel hormone treatments including abiraterone and enzalutamide and taxane chemotherapies including docetaxel and CBZ is important for maximizing clinical benefit in CRPC patients. We previously identified factors predicting efficacy in CRPC patients treated with enzalutamide . We founThere are several limitations to our study. The number of patients is too small to allow precise statistical analyses. In addition, the study was retrospective and lacked a control group, and the treatment protocol differed between institutions. Moreover, we missed some prognostic parameters of the patients, such as metastatic status at the time of CBZ treatment, the efficacy of previous docetaxel, abiraterone, and enzalutamide, and the usage of bone-modifying agents, such as bisphosphonates, denosumab, and alpharadin. However, to our knowledge, this is the largest study (118 patients) of the treatment efficacy and toxicity of CBZ in Japanese patients to date. Further prospective studies are needed to determine the optimal dose of CBZ for Japanese subjects with CRPC.Existing bone metastasis and high PSA levels predicted shorter PFS and OS, respectively, after CBZ treatment. CBZ at higher initial doses may have similar response rate and response duration, but longer survival duration after treatment with higher toxicity than lower initial doses for docetaxel-resistant CRPC in Japanese patients.


Introduction: Cirrhotic cardiomyopathy (CCM) develops in about half of all cirrhotic patients, affecting the long-term morbidity and mortality. Although some studies have shown an increased QT-interval in cirrhotic patients, no evidences of myocardial contractile and QT dispersion (QTd) changes are available. This study aimed to compare myocardial contractile dispersion (MCd), using tissue Doppler imaging (TDI), as well as QTd between cirrhotic patients and healthy individuals, investigating their associations with cirrhosis severity.Methods: This prospective cross-sectional study was conducted on patients with confirmed liver cirrhosis and healthy individuals. Participants with structural heart disease, heart ventricular pacing, electrolyte abnormalities, using drugs affecting QT interval were excluded. All individuals underwent 2D echocardiography, and TDI by vivid E9 echo machine. MCd and QTd were considered as main outcomes. Chi-square, independent-sample t test, and Pearson correlation test, were used for statistical analyses by SPPS version 17.0. P  value <0:05 was considered statistically significant.Results: Sixty participants  with a mean age of 40.1 ± 7.1 years in two groups of cirrhotic patients (n=30) and healthy individuals (n=30) were studied. Both groups were statistically similar in terms of age (P = 0.31) and gender (P = 0.39). MCd and QTd of cirrhotic patients were significantly higher than healthy individuals . Cirrhotic patients with MELD score <15 had a lower MCd in comparison to score ≥15 .Conclusion: Cirrhosis was associated with increased MCd, assessed by TDI. Also, MCd and QTd were associated with a higher MELD score. According to the results, it seems that MCd and QTd might be useful predictor of ventricular arrhythmia and negative prognostic factor in cirrhotic patients. This study was aimed to evaluate MCd tissue study and QTd in cirrhotic patients, investigating their associations with cirrhosis severity.Furthermore, QTc prolongation is a sign of action potential duration prolong which is considered to be associate with a prolonged LV contraction.This prospective cross-sectional study was conducted to on cirrhotic patients and healthy individuals referred to Department of Organ Transplant, Nemazi Hospital, Shiraz, Iran between 2016/July and 2017/May. Patients with a baseline ECG abnormality such as bundle branch block, Wolf-Parkinson-White, left ventricular hypertrophy, and other pathological ECG conditions were excluded from study.Patients with confirmed liver cirrhosis diagnosis were enrolled. Cirrhosis was diagnosed based on the generally accepted criteria: history, physical examinations, laboratory tests, imaging examinations (i.e. panendoscopy), abdominal ultrasound, Doppler ultrasound and computerized tomography. Inclusion criteria were 1) age> 18 years, 2) receiving no treatment for cirrhosis, 3) using propranolol. The exclusion criteria were 1) structural heart disease, 2) heart ventricular pacing, 3) electrolyte abnormalities, 4) using the drugs affecting QTi.Baseline characteristics of the participants including: age, gender, and Model for End-Stage Liver Disease (MELD) score were obtained by a date gathering form. Both groups underwent Twelve-lead ECG, and 2D echo, TDI .© 2005-2018 online calculator, using Bazett’s formula. Lastly, considering the difference between minimum and maximum QTc values in the ECG the QTd was measured in millisecond.Twelve-lead ECG was obtained in both cirrhotic and healthy groups. The QT interval was measured on the basis of millisecond from the beginning of QRS complex into the end of T wave, based. Then, the corrected QT (QTc) was calculated based on heart rate using the MDCalc2D echo and tissue Doppler study by a vivid E9 echo machine was done. Three views of four-chamber, apical three-chamber and two-chamber with color coded TDI study was obtained and saved. Then in an offline mode 12 segments of basal and mid parts of myocardium were evaluated and myocardial contractility duration in each segments was measured. Myocardial contractile duration was calculated from the time of start of QRS wave to the end of S wave (the last positive wave that crosses zero line). Subsequently the minimum and maximum of it in 12 segments were determined and the difference between them was considered as MCd.The main outcome of this study was to compare the MCd in two groups of cirrhosis patients and healthy individuals. The second outcome was to compare myocardial contraction duration between two groups among 12 segments of LV. Lastly, we evaluated QTd between the two groups.t test between two groups. Pearson correlation test was used for investigating any correlation between MELD score and MCd as well as QTd. P value<0:05 was considered statistically significant.All statistical analyses were performed with the Statistical Package for Social Sciences (SPSS) version 17.0 . Data will be presented as mean ± standard deviation (SD). Chi-square tests, or Fisher exact test were used to compare the proportions in two groups. Also, the mean of myocardial contraction duration, MCd, and QTd were compared with independent-sample P=0.31) and gender . MELD score of the cirrhotic patients was 16.4±5.2 (range 8-28). Seven patients (23.4%) had a MELD score ≥20, 21 (70.0%) 9<score<20, and 2 patients (6.6%) score ≤9.Sixty individuals  with a mean age of 40.1 ± 7.1 years were studied in two groups of cirrhotic patients (n = 30) and healthy individuals (n=30). Both groups were statistically similar in terms of age  in cirrhotic group, while it was in the middle of posterior segment (329 ± 48.3 ms) in healthy individuals. No significant differences were reported for myocardial contraction duration between two groups regarding 12 LV segments .P = 0.028) (P = 0.010). MCd was reported to be higher than QTd in both cirrhotic patients (P = 0.06) and healthy individual groups (P = 0.28).MCd of cirrhotic patients was significantly higher than healthy individuals  . MoreoveP = 0.034, P = 0.016). Pearson correlation analysis revealed that MELD score of cirrhotic patients was correlated with MCd  and QTd .Cirrhotic patients with MELD score<15 had a lower MCd in comparison to score ≥15  and the Ethics Committee of Shiraz University of Medical Sciences. The content of the project was explained to all patients before entering the study, and they signed the consent form. Privacy and dignity of patients were also considered in the project. Information on patients was inserted into the statistical analysis software as encoded, and was published as overall results.The present study has been adopted from Specialty thesis written in Cardiology by Dr. Hamed Mirzaee at Shiraz University of Medical Sciences (Code: 9750). This study was conducted with the financial and spiritual supports of the Deputy of Research at Shiraz University of Medical Sciences.


Lymphoma is a malignant lymphoproliferative tumor that can involve the conjunctiva. Approximately 5–15% of all extranodal lymphomas are found in the ocular adnexal region, with approximately 25% of those involving the conjunctiva. Ninety-eight percent of conjunctival lymphomas arise from B-lymphocytes. The most common subtype of conjunctival lymphoma is extranodal marginal zone lymphoma (80%), followed by follicular lymphoma (8%), diffuse large B-cell lymphoma (3%) and mantle cell lymphoma (3%). Natural killer and T cells (NK/T) are rare causes of lymphoma. While most conjunctival lymphomas are localized to the ocular adnexa at the time of presentation, systemic examination and management are of key importance in the long-term care of the patient.This review outlines the classification, etiology, presentation, diagnosis, and management of conjunctival lymphoma. The novel use of high resolution optical coherence tomography, both as a diagnostic tool and as a means for ongoing evaluation during treatment, is illustrated. Treatment options discussed include external beam radiation, chemotherapy, immunotherapy, antibiotic therapy, and combination regimens. Future investigation of the etiology and pathogenesis of conjunctival lymphoma is expected to reveal opportunities for innovative and individualized therapeutic agents. Collaboration between multiple disciplines is key in the advancement of the field. The conjunctiva is an important site of extranodal lymphoma development, which comprises 25–30% of all lymphomatous disease , 2. WhilA thorough PubMed search of articles published between January 1990 and July 2018 on the diagnosis and management of conjunctival lymphoma was performed. Searches included a combination of the following terms: “bendamustine,” “conjunctival lymphoma,” “ocular adnexal lymphoma,” “extranodal marginal zone lymphoma,” “optical coherence tomography,” “radiation therapy,” “chemotherapy,” “Chlamydia psittaci,” “doxycycline,” “interferon-alpha,” and “rituximab.” Pertinent articles were carefully reviewed and referenced in this paper.The histology and clinical stage of conjunctival lymphomas are the most important predictors of disease outcome.(Table ). Conjunctival lymphomas are most commonly extranodal marginal zone lymphoma (EMZL) and follicular lymphoma (FL), both of which are generally low-grade. EMZL, previously known as mucosa-associated lymphoid tissue (MALT) lymphoma, constitutes approximately 80% of conjunctival B-cell non-Hodgkin lymphomas (NHL). EMZL is slightly more common in female patients and typically presents in the patient’s sixties .–50.(Tabl(Table ) , 51, 52.(Table ) , 88(Tabl(Table ) , 89. A w(Table ) , 90–92  with a median age at diagnosis of 38 years. Local control after 26 Gy radiation therapy was 98.1%. The 5-year survival rate was 100%; all but one of the relapsed cases were treated with re-radiation therapy. In this study, the radiation was delivered with five 2 Gy fractions per week .Several studies have found associations between the site of disease, tumor grade, or histopathology of the lesion and long-term outcome of EBRT. In one retrospective study, relapse at distant sites after treatment completion was significantly higher in patients with lacrimal and soft tissue disease (51%) than in those with only conjunctival lesions (11%) . Bolek eEarly minor complications of local radiation treatment include eyelid irritation and mild conjunctivitis. Long-term complications, which occur in up to 50% of patients, include dry eye syndrome (which can be severe), cataract formation, retinopathy, orbital fat tissue atrophy, and corneal ulceration , 98, 102Current literature reports possible therapeutic success with much lower doses of radiation than previously used. A recent retrospective review of 22 patients with EMZL, FL, or MCL of the ocular adnexa who underwent ultra-low-dose EBRT, 4 Gy delivered to the orbit(s) in two 2-Gy fractions on two consecutive days, revealed an overall response rate of 100%, after a median time of 3.73 months following treatment. Local control was 75% after 2 years . FurtherInterferon-alpha is a family of cytokines with anti-viral, anti-proliferative, and immunomodulatory functions. Interferons aid in cancer treatment by enhancing the immune response and directly affect tumor cells by increasing transcription of tumor suppressor gene p53, inducing apoptosis, and inhibiting angiogenesis . CelliniLocal side effects to interferon-alpha include temporary conjunctival chemosis at the site of injection and transient flu-like symptoms including fever, myalgia, and headache that may last for several hours after injection during the initial weeks of treatment , 75, 104Rituximab is a chimeric human-rodent monoclonal antibody that targets the surface antigen CD20, which is overexpressed on CD20-positive NHL B cells. Rituximab binding mediates complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, and induces cellular apoptosis . It is fNo significant adverse ocular events have been reported secondary to administration of intralesional rituximab in the treatment of OAL. Some patients experience mild pain and local inflammation lasting less than 24 h after injection .C. psittaci, antibiotic therapy has been found to have variable efficacy and requires further investigation [C. psittaci infection. Typical dosing of doxycycline is 100 mg twice daily by mouth for 3 or 6 weeks.Despite the suspected link between OAL and tigation , 86. DoxC. psittaci infection [C. psittaci infection, and treatment with a double course of doxycycline [P = 0.038). In addition, the 2-year time to treatment failure (TTF) was 88% for conjunctival lymphoma, compared to 64% for non-conjunctival tumors [In several Korean and Italian studies, doxycycline was shown to be a viable treatment option for T1N0M0 OAL, with two of the largest studies claiming 5-year progression-free survival (PFS) rates of 55 and 60.9% , 112–114nfection , 87. Staycycline , 114. Ofl tumors .The use of clarithromycin in the treatment of extranodal lymphoma has also been explored but reports are scarce , 85, 115(Table ).Systemic treatment is reserved for aggressive bilateral disease or conjunctival lymphoma accompanied by active systemic involvement. The recommended treatment for this is intravenous rituximab in combination with chemotherapy or other immunotherapeutic agents Table .Table 4OCommonly used chemotherapeutic agents are chlorambucil and combined regimens such as CHOP , 92. Due. Data on the use of chemotherapy in patients with conjunctival lymphoma is limited. When used as a single agent or as part of combined therapy, it has produced varied results [Chemotherapy can be used as an adjunct to local treatment or as the sole therapy for OAL. It is the treatment of choice, typically in combination with rituximab, in cases of systemic disease, resistance to radiation, or contraindication of radiation therapy  Fig. 5). results , 132.Bendamustine is a chemotherapeutic drug with alkylating and antimetabolic properties. In 2008, it was approved for the treatment of both indolent and aggressive B-cell NHL after it was found to successfully treat NHL that had relapsed after primary treatment with rituximab or a rituximab-containing regimen in three independent phase II trials , 134. AlChlorambucil, which is frequently used in combination chemotherapy regimens such as CVP  and CHOP , has a highly favorable toxicity profile. Complete response to chlorambucil has been observed in 67–100% of patients with OAL, but local relapse occurs in up to 29% of cases . A study2. It is very well tolerated. Most case reports in which rituximab was delivered in this manner in the treatment of newly diagnosed OAL revealed a 100% overall response rate [As discussed above, rituximab has cytotoxic effects on CD20-positive B cells and is the most commonly used immunotherapeutic agent for the treatment of lymphoma . It is tnse rate , 140. Honse rate . Althougnse rate . Celikernse rate . These rnse rate .Sullivan et al. demonstrated the usefulness of systemic rituximab treatment in OAL patients with preexisting or concurrent systemic disease. In this study, seven of eight patients responded to rituximab therapy. One of those had relapse of orbital disease at 26 months while the rest remained free of disease recurrence at a median of 17.5 months of follow-up. The eighth patient did not respond to rituximab treatment and passed away after progression of systemic disease . Other cp = 0.0119) than those patients who were treated with chlorambucil or rituximab alone [Rituximab is theorized to sensitize B cells to the effects of systemic treatment, and combination therapy with rituximab and conventional chemotherapy have been associated with higher response rates than chemotherapy alone in the treatment of NHL , 124. Riab alone .90Y-ibritumomab tiuxetan is well tolerated in patients. Transient pancytopenia often occurs in patients during the first 3 months following drug administration, sometimes necessitating transfusions. The estimated absorbed radiation to orbital soft tissues with 90Y-ibritumomab tiuxetan use is less than 3 Gy. Its use has not resulted in any of the ocular toxicities associated with external beam radiation treatment [90Y-ibritumomab tiuxetan use in conjunctival and OAL are limited but have shown excellent response rates [2 prior to Indium total-body imaging. One week after this, patients are given a second dose of rituximab 250 mg/m2 IV, followed by 90Y-ibritumomab tiuxetan. Typically, patients with a platelet count of 100,000 – 149,000/mm3 are given 0.3 mCi/kg 90Y-ibritumomab tiuxetan, while patients with a platelet count above 150,000/mm3 are given a dose of 0.4 mCi/kg [.Radioimmunotherapy, in which monoclonal antibodies are used to deliver radioisotopes to the site of disease, has shown a better response than rituximab alone in some studies . Yttriumreatment . Other creatment . Studiesse rates , 142. An4 mCi/kg  Fig. 5)90Y-ibritOcular adnexal lymphoma has an overall 5-year survival rate ranging between 50 and 94%, depending on the grade of histologic subtype, TNM stage at diagnosis, and age of the patient . ConjuncThe most important prognostic factor in conjunctival lymphoma is histological subtype of the lesion. Isolated cases of low-grade EMZL and FL are associated with the best outcome after treatment , 143. A Other clinical, laboratory, and various tumor biomarkers have been associated with prognostic effect. Established negative prognostic factors in the outcome of OAL include: age greater than 60–64 years , 147, elAdvanced stage at the time of diagnosis also correlates with worse long-term prognosis of OAL , 147. LyVariation on outcome based on the site of OAL is debated. Many studies have found significantly better outcomes, including progression-free survival and overall survival, in patients with conjunctival lymphoma as compared to other ocular adnexal sites , 150. HoLymphoma is among the most common malignant conjunctival tumor. As the symptoms are often minimal, it is imperative for the general ophthalmologist to be alert for the characteristic “salmon patch” appearance of these neoplasms or to suspect lymphoma in individuals with unexplained chronic follicular conjunctivitis. Diagnosis is established via surgical biopsy with proper fresh tissue immunohistochemical studies. New imaging techniques with high resolution OCT can also help identify possible lymphoproliferative lesions as well as assist in the ongoing clinical evaluation during and after treatment. Systemic work-up and staging are critical to formulating the correct treatment plan. Both local and systemic treatments are available. The ophthalmologist should remain active in the management of possible ocular complications during lymphoma treatment. Long-term follow-up is necessary as systemic lymphoma may develop after many years.


To identify the incidence of, risk factors for, and outcomes associated with postoperative delirium (POD) in older adult patients who underwent noncardiac surgery.This prospective study recruited patients aged ≥ 60 years who were scheduled to undergo noncardiac surgery at Siriraj Hospital . Functional and cognitive statuses were assessed preoperatively using Barthel Index (BI) and the modified Informant Questionnaire on Cognitive Decline in the Elderly, respectively. POD was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition criteria. Incidence of POD was reported. Univariate and multivariate analyses were used to identify risk factors for POD.p < 0.001) and age ≥ 75 years  to be independent risk factors for POD. Median length of hospital stay was 10 (range: 3–36) days for patients with POD versus 6 (range: 2–76) days for those without delirium (p < 0.001).Of the 249 included patients, 29 (11.6%) developed POD. Most patients (61.3%) developed delirium on postoperative day 1. Univariate analysis showed age ≥ 75 years, BI score ≤ 70, pre-existing dementia, preoperative use of opioid or benzodiazepine, preoperative infection, and hematocrit < 30% to be significantly associated with POD. Multivariate logistic analysis revealed pre-existing dementia (adjusted risk ratio [RR]: 3.95, 95% confidence interval [CI]: 1.91–8.17; multidisciplinary team consisting of anesthesiologists and geriatricians should implement perioperative care to prevent and manage POD.POD remains a common surgical complication, with an incidence of 11.6%. Patients with pre-existing dementia and age ≥ 75 years are the most vulnerable high-risk group. A  Delirium has been associated with adverse outcomes, such as functional decline [Delirium is a common postoperative complication that occurs in 5 to 52% of older adult patients after noncardiac surgery , 2. Deli decline , 5, deme decline , 7, incr decline , 9, incr decline , and inc decline .patients that present for anesthesia and surgery. The development of delirium following surgery has some significant potential effects on patient outcomes; however, POD is often underdiagnosed. Some studies reported that more than 50% of patients with delirium were undiagnosed by medical teams [As the population of older adults increases, so too with the number of older adult al teams –13. Moreal teams . DeliriuThe gold standard diagnostic criteria for delirium is the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) from the American Psychiatric Association . DefinitAccordingly, the aim of this study was to enlist anesthesiologists and geriatricians to collaboratively investigate the incidence of, risk factors for, and outcomes associated with POD among older adult patients who underwent noncardiac surgery.After receiving Siriraj Institutional Review Board (COA no. Si 718/2015) approval, a prospective cohort study was conducted at a large university-based national tertiary referral center during the March 2017 to December 2017 study period. Patients aged 60 years or older who were scheduled to undergo noncardiac surgery were eligible for inclusion. Patients were excluded if they refused to participate in the study or required postoperative intensive care unit admission. The protocol for this study followed all of the guidelines outlined in the Declaration of Helsinki and all of its later amendments. Written informed consent was obtained from all study participants.Preoperatively, all patients were assessed for functional and cognitive status by the clinical researcher or a trained research assistant. Functional status was assessed using the Barthel Index of Activities of Daily Living . The BarCognitive status was measured using the modified Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), which is based on information elicited from a close relative or caregiver of each patient. The modified IQCODE for detection of dementia in Thai older adults  consists of 32 items designed to assess cognitive changes over the previous 10 years . ScoringDaily patient assessment for POD was performed during the daytime for 7 consecutive days after surgery. The occurrence of POD and delirium onset time was documented.POD was diagnosed by one of three geriatricians based on the DSM-5 criteria . All thrThe surgical procedures and anesthetic techniques were carried out with no specific intervention from the research team. Patient demographic data, comorbidities, type and duration of surgery, anesthesia technique, intraoperative hypotension, intraoperative hypoxemia, and length of hospital stay were recorded. Intraoperative hypotension was defined as either systolic blood pressure less than 90 mmHg for more than 5 min or the use of vasopressor to treat hypotension . Intraopnumeric rating scale (NRS) on a 10-point scale. Pain intensity was classified as mild (NRS = 1–3), moderate (NRS = 4–7), or severe (NRS = 8–10) pain.Medications used within 3 months before surgery were also recorded, including opioids, benzodiazepines, statins, anticonvulsants, and psychotropic drugs . Preoperative laboratory values, including hematocrit (Hct), sodium, and ratio of blood urea nitrogen to creatinine (BUN/Cr ratio), were measured and recorded. Maximum pain scores on the first postoperative day were determined using a The sample size was estimated based on multiple logistic regression analysis . Based ot-test, or Mann-Whitney U test, as appropriate. Seven risk factors with univariable p-value less than 0.05 including preexisting dementia, age ≥ 75 years, hematocrit < 30%, preoperative opioid use, preoperative benzodiazepine use, preoperative infection, and Barthel index score ≤ 70 were entered into multiple regression model. Risk ratios and adjusted risk ratios with their respective 95% confidence intervals were reported. A p-value less than 0.05 was considered to be statistically significant for all tests. Receiver operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff age for developing delirium. The results of that analysis are reported as Youden’s index, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, and area under curve.All statistical analyses were performed using PASW Statistics version 18.0  and MedCalc Statistic Software version 17.6 . Continuous data are presented as mean ± standard deviation (SD) for normally distributed data, and as median and interquartile range for non-normally distributed data. Categorical data are presented as frequency and percentage. All variables in patients without POD versus those with POD were analyzed by univariate logistic regression analysis using chi-square test, Fisher’s exact test, independent During the study period, a total of 269 patients were assessed for eligibility. Of those, 20 patients were excluded for the reasons showed in Fig. p < 0.001), had a greater prevalence of pre-existing dementia (p < 0.001), had a lower Barthel Index score (p = 0.001), and had a higher rate of preoperative opioid (p = 0.001) or benzodiazepine (p = 0.022) relative to those patients without delirium. In addition, among patients with delirium versus those without delirium, hematocrit less than 30%  and preoperative infection  were significantly associated with the development of delirium. Median length of hospital stay was 10 (range: 3–36) days for patients with delirium versus 6 (range: 2–76) days for those without delirium (p < 0.001). In multivariate analysis, only pre-existing dementia  and age ≥ 75 years  remained significantly associated with POD in patients undergoing noncardiac surgery  developed delirium on postoperative day 1, followed by 16.1% on day 2, 12.9% on day 3, 6.5% on day 5, and 3.2% on day 6. As shown in Table % developadmitted to the surgical ward after noncardiac surgery. Pre-existing dementia and age 75 years or older were the independent risk factors for POD in these patients. In terms of outcome, patients who developed delirium had longer hospital stay than those without delirium. There was no in-hospital mortality in this study.Based on DSM-5 criteria, this prospective cohort study found an 11.6% incidence of postoperative delirium among the older adult patients The 11.6% incidence of POD in the present study was similar to the 13.2% incidence reported in a previous study . This isRegarding onset time of POD, most patients in this study (61.3%) developed POD on postoperative day 1, whereas those in previous studies , 23 deverecent study of non-surgical patients also reported pre-existing dementia to be the main risk factor for delirium [In the present study, pre-existing dementia was the strongest risk factor for POD, with an adjusted risk ratio of 3.95 (95% CI: 1.91–8.17). This finding is consistent with previous studies , 8, 26 tdelirium . Deliriudelirium . The predelirium , and 1.4delirium . The occdelirium , 32. Givdelirium .years or older, with an adjusted risk ratio of 2.54 (95% CI: 1.11–5.80). From previous studies, there were different age groups of patients  that were identified as groups at high risk for delirium [years or older. Although age is a fixed risk factor that cannot be modified, the delirium prevention and management strategies may be of benefit via their effects on intensity and duration of delirium.Older age is also an important risk factor for delirium. The present study showed a significant association between POD and age 75 delirium . In the Previous studies revealed that delirium may be preventable in 30–40% of hospitalized older adult patients , 34. IdeStrengths of the present study include its prospective design, the fact that we used the DSM-5 for diagnosing delirium, and that delirium diagnosis was made by experienced geriatricians. Some limitations must also be mentioned. First, this study was conducted at a single institution. Therefore, our results may not be generalizable to other care settings. Second, the sample size may be too small to identify all significant differences and associations that relate to POD. Third, delirium assessment was only performed once daily, so the incidence of POD may have been underestimated. Finally, some relevant information was not obtained, such as prior postoperative delirium and intraoperative medication usage, and this could have had a confounding effect on our analysis and findings.years or older were found to be the independent risk factors for development of POD. Collaborative approach to identify patients at risk for delirium and provide perioperative management strategies may help to prevent POD or reduce its severity. Further studies that focus on multidisciplinary collaboration are needed to improve delirium care.This prospective study found an 11.6% incidence of postoperative delirium among patients undergoing noncardiac surgery. Pre-existing dementia and age 75


Background and objectives: The percutaneous route is an interesting and inventive investigation field of drug delivery. However, it is challenging for drug molecules to pass through the skins surface, which is a characterized by its permeability barrier. The purpose of this study is to look at the effect of some penetration enhancers on in vivo permeation of insulin and insulin sensitizers (curcumin and rutin) through diabetes-induced mouse skin. Materials and Methods: Sting crude extracts of Dendrocnide meyeniana, Urtica thunbergiana Sieb. and Zucc, and Alocasia odora (Lodd.) Spach were used as the penetration enhancers. Mouse skin irritation was tested by smearing the enhancers for the measurements at different time points and the cell viability of the HaCaT human skin keratinocytes, which was determined by Trypan blue exclusion and MTT assays to evaluate human biosafety for these extracts after the mouse skin permeation experiments. Results: All enhancers induced a slight erythema without edema on the mouse skin that completely recovered after 6 h from the enhancer smears as compared with normal mouse skin. Furthermore, no damaged cells were found in the HaCaT keratinocytes under sting crude extract treatments. The blood sugar level in the diabetic mice treated with the insulin or insulin sensitizers, decreased significantly (p < 0.05) in the presence of enhancers. The area under the curve (AUC) values of transdermal drug delivery (TDD) ranged from 42,000 ± 5000 mg/dL x min without enhancers, to 30,000 ± 2000 mg/dL x min in the presence of enhancers. Conclusions: This study exhibited that natural plant extracts could be preferred over the chemically synthesized molecules and are safe and potent penetration enhancers for stimulating the transdermal absorption of drugs. Transdermal drug delivery (TDD) has been recognized as a promising and painless approach with advantages such as favorable reception by patients (noninvasiveness), enhancing bioavailability, minimal toxic side effects, and ease of access ,2. HowevCurcuma longa (Zingiberaceae) plant which has been reported to adequately sensitize insulin by inhibiting ATPase activity for mitochondria [Carpobrotus edulis (Aizoaceae) and Ruta graveolens (Rutaceae). These plants have been found to play a critical role in sensitizing insulin by downregulating the expression level of the protein-tyrosine phosphatase 1B [Diabetes mellitus (DM) is the result of insulin deficiency or insensitivity and shows the multiple complications in diabetic patients . Althougchondria . Rutin iatase 1B . One vitatase 1B  or suffeDendrocnide meyeniana  and Urtica thunbergiana Sieb. and Zucc  are species with nettle stings at leaf blades formed by cells with high Si/Ca ratio [Alocasia odora (Lodd.) Spach  is a traditional herbal medicine for treating abdominal pain, cholera, hernias, stomach aches, heals wounds, and fungi [Capsicum annuum (Solanaceae) was used as a positive control for the penetration enhancer since it has been shown to have analgesic advantages in post-therapeutic neuralgia, painful polyneuropathies, and surgical neuropathic syndromes [Ca ratio ,15. HistCa ratio ,17. Alocnd fungi ,19. The nd fungi ,21. Fromyndromes . Furtheryndromes .General chemicals used in this study, including rutin (R5143), curcumin (C1386), capsaicin (M2028), DMSO (D2650), trypan blue , and 3--2, 5-diphenyltetrazolium bromide , were purchased from Sigma-Aldrich . Reagents and mediums for cell culture were obtained from Thermo Fisher Scientific . Hand cream  was purchased from Neutrogena .Dendrocnide meyeniana  and Urtica thunbergiana Sieb. and Zucc , and Alocasia odora (Lodd.) Spach  were from different localities: Dm from the riverside of the Mugua River , Ut from the lakeside of Liyu Lake , and Ao from the National Dong Hwa University (NDHU) . After collections, all plants were identified according to their morphology and their features were used to confirm species. Fresh leaves of Dm, Ut, and Ao were dried at room temperature (RT), cut into pieces, ground using a mill, sieved through a no. 40 mesh, and extracted by soaking with 50% ethanol/H2O at RT for one week. The extracts of Dm, Ut, and Ao were collected by filtration and vacuum evaporation. All extracts were stored at 4 °C and avoided exposure to light. In all performed experiments, the crude extracts and rutin were dissolved in the distilled water while curcumin was dissolved in ethanol. Capsaicin was solubilized in 10% Tween 80, 10% ethanol, and 0.9% saline. The prepared samples were filtered by sterile syringe filter with a 0.45 µm pore size. A voucher specimen (No. 106012-1) was deposited in the Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan.Collections of 2). All experiments were carried out within 10 passes for consistency and accuracy.Human skin keratinocyte cells HaCaT were obtained from the Bioresource Collection and Research Center . Cells were grown in high-glucose Dulbecco’s modified eagle’s medium with 10% fetal bovine serum (FBS) and 1% antibiotic-antimycotic supplementation under culture condition . For the MTT experiment, cells were added with 30 μL/well MTT solution (25 μg/mL) and incubated for additional 4 h. Then the medium was removed, formazan was solubilized by the addition of 100 μL/well dimethyl sulfoxide (DMSO), and OD value was measured at 570 nm using α-screen multiplate reader . The percentage of viable cells was determined by comparing with an untreated control.The cell viability test was carried out in two different methods: TB exclusion and MTT assays. HaCaT cells were seeded at 5 × 10BALB/c male mice (8 weeks old) and ICR male mice (6 weeks old) were obtained from BioLASCO  and housed in a pathogen-free environment under a constant room temperature of 25 °C, humidity of 50 ± 5%, and on a 12 h dark/light cycle. Mice had free access to water and food during the study period. All procedures were carried out in accordance with the “Guide for the Care and Use of Laboratory Animals” of NDHU and approved by the NDHU Animal Ethics Committee (Relevant permit number: NSCB04-001).v/v) fructose for 14 weeks. At week 10, ICR mice fasted for 10 h prior to oral gavage 4 g/kg body weight of D-glucose. Blood from the tail vein was collected, and then the blood sugar level was analyzed using an EasyTouch® GCU glucose analyzer  for 120 min every 30 min. When blood sugar levels were higher than 160 mg/dL at 120 min postprandial, mice were defined as glucose intolerant.After one week of adaptation, ICR mice were fed with a high-fat diet  and 60%  injected with 4.25 U/kg body weight of insulin solution . If the blood sugar level was higher than 126 mg/dL at 120 min after insulin injection, mice were considered as diabetic.Diabetes-induced ICR7 mice were shaved on the neck and back followed by fasting for 10 h. After determining preprandial blood sugar level, diabetes-induced ICR7 mice were smeared with Dm (2 mg/mL), Ut (2 mg/mL), Ao (2 mg/mL), or Ca (0.25 mg/mL) with/without insulin , curcumin (20 μg/mL), or rutin (80 μg/mL), respectively; followed by the oral gavage of glucose. Blood from the tail vein was collected, and then the blood sugar level was analyzed by glucose analyzer for 120 min at an interval of every 30 min. The area under the curve for blood sugar (AUC) was calculated using the trapezoidal method .BALB/c mice were shaved on their neck and back, and then smeared with 100 µL of Dm (2 mg/mL), Ut (2 mg/mL), or Ao (2 mg/mL), respectively. The skin was then examined for erythema/edema based on Draize dermal irritation scoring system , and treDiabetes-induced ICR mice were shaven on their neck and back and smeared with 100 µL of Dm (2 mg/mL), Ut (2 mg/mL), or Ao (2 mg/mL) together with hand cream , respectively. After 30 min, mice skin was cut and fixed in 4% paraformaldehyde (PFA) solution. The fixed skin was embedded by paraffin followed by hematoxylin and eosin (H&E) staining according to standard procedures. Images were acquired using a Nikon digital camera .p-value less than 0.05 was considered to be statistically significantly different (* p < 0.05) using one-way ANOVA with Dunnett’s test.Data were shown as mean ± standard deviation (SD) of three independent experiments. A When the skin contacts the natural crude extracts, it is strikingly crucial to fortify so that Dm, Ut, and Ao will not cause serious contact sensitization responses. For this reason, a skin-irritation test was performed on mice by smearing mouse skin with 100 µL of Dm, Ut, or Ao at a concentration of 2 mg/mL, respectively. The outcome has been graded depending upon the degree of erythema caused as follows: 0—no erythema, 1—very slight erythema, 2—well-defined erythema, 3—moderate to severe erythema, and 4—severe erythema . Table 1Dendrocnide meyeniana (Dm), Urtica thunbergiana Sieb. and Zucc (Ut), and Alocasia odora (Lodd.) Spach (Ao) are tested in mouse skin. 0—no erythema, 1—very slight erythema, 2—well-defined erythema, 3—moderate to severe erythema, and 4—severe erythema [erythema .The elevation of stratum corneum (SC) permeability plays a key role in increasing transdermal drug delivery. To investigate the effect of the sting crude extracts Dm, Ut, and Ao on the structure of the mouse skin, diabetes-induced ICR mice were exposed to 100 µL of Dm (2 mg/mL), Ut (2 mg/mL), or Ao (2 mg/mL) mixed with hand cream (20 mg) for 30 min and then examined histologically to image the appearance of the mouse skin. Skin irritation and cell damage are among the most important standards to evaluate whether or not the penetration enhancers could be approved for clinical use in spite of their adequately sufficient fulfilment in enhancing the permeation of drug molecules. Hence, the cell viability evaluation of the sting crude extracts was studied using trypan blue and MTT assays. p > 0.05). When checking the positive control, intraperitoneal injection of insulin (10 pM) produced a significant decrease in serum glucose (p < 0.05). Skin permeation of the insulin without the enhancers (direct smear insulin) was negligibly proven by the elevated blood sugar level with similar concentrations as compared with untreated skin. However, the addition of the crude extracts or capsaicin as the enhancers increased the skin permeation of the insulin as compared with the control groups (untreated skin or insulin treated without enhancers) demonstrated by the strongly decreasing blood sugar levels (p < 0.05).To investigate the effect of the sting crude extracts as the enhancers on the in vivo skin permeation of the insulin and insulin sensitizers, diabetes-induced ICR7 mice were smeared with Dm, Ut, or Ao at 2 mg/mL or Ca at 0.25 mg/mL with/without insulin , curcumin (20 μg/mL), or rutin (80 μg/mL), respectively; followed by the oral gavage of glucose and blood sampling. The results showed that applying individual crude extracts Dm, Ut, or Ao or the capsaicin compound to the mouse skin were found to have no effect on the reduction of the blood sugar level A as revep < 0.05). This indicates that curcumin and rutin cannot easily penetrate the intact skin; whereas, the transdermal treatments of curcumin or rutin with induvial enhancer Dm, Ut, or Ao, respectively, were more efficient than transdermal treatments of curcumin or rutin without the enhancers in reducing blood sugar concentration (p < 0.05).Curcumin and rutin are well-known insulin sensitizers that improve insulin resistance and lower blood sugar levels by oral administration ,27. FiguTaken together, smearing with the sting crude extracts Dm, Ut, or Ao was found to cause increases in skin penetration of the insulin and insulin sensitizers (curcumin and rutin), which, consequently, affected the blood sugar level to meet non-invasion demands.For decades, the use of skin as a target for drug transfer has been a fascinating preference to traditional approaches including intravenous and oral administration. However, human skin has a superior permeability barrier to prevent entry of nearly all but small molecules . TherefoIt has been shown that the stings of Dm are found to cause the acute dermatitis by its component formic acid via contact . The forThe skin, especially the SC layer, provides a serious barrier to drug permeation and restricts percutaneous bioavailability. Previous studies have shown that the skin permeability was further increased by an order of magnitude of 1 or 2 upon removal of the full epidermis as compared with removal of SC only . Our datp < 0.05, The administration route of the insulin via injection is a common approach to reduce blood glucose for diabetic patients. However, this needle-based method requires remarkable training and assiduous care by patients, which usually leads to a poor impact . Transdep < 0.05, Diabetes could increase plasma free fatty acid, cholesterol, and triglyceride concentrations and cause stroke or myocardial infarction . As we kp < 0.05; Rutin also inhibited the generation of advanced glycation end products (AGEs), and improved liver protection . PreviouAltogether, the data of the present investigation show that the sting plant extracts Dm, Ut, and Ao as the penetration enhancers may alter the skin epidermis morphology to facilitate passive diffusion of insulin, curcumin, and rutin into the skin and blood vessel to efficiently moderate the blood sugar levels. Moreover, based on our findings, diabetes-induced mice are found to be an appropriate model organism used for imitating human diabetes for investigating whether the transdermal drug delivery is feasible and worth using as a diabetic remedy per se. Lastly, the application of the sting plants as a permeation agent for dermal medicine delivery may provide a new clue and an alternative approach as a non-invasion route for drug administration.


Opportunistic infections (OIs) are the leading cause of morbidity and mortality among children living with human immunodeficiency virus (HIV). For better treatments and interventions, current and up-to-date information concerning occurrence of opportunistic infections in HIV-infected children is crucial. However, studies regarding the incidence of common opportunistic infections in HIV-infected children in Ethiopia are very limited. Hence, this study aimed to determine the incidence of opportunistic infections among HIV-infected children on antiretroviral therapy (ART) at Debre Markos Referral Hospital.A facility-based retrospective cohort study was undertaken at Debre Markos Referral Hospital for the period of January 1, 2005 to March 31, 2019. A total of 408 HIV-infected children receiving ART were included. Data from HIV-infected children charts were extracted using a data extraction form adapted from ART entry and follow-up forms. Data were entered using Epi-data™ Version 3.1 and analyzed using Stata™ Version 14. The Kaplan Meier survival curve was used to estimate the opportunistic infections free survival time. Both bi-variable and multivariable Cox proportional hazard models were fitted to identify the predictors of opportunistic infections.This study included the records of 408 HIV-infected children-initiated ART between the periods of January 1, 2005 to March 31, 2019. The overall incidence rate of opportunistic infections during the follow-up time was 9.7  per 100 child-years of observation. Tuberculosis at 29.8% was the most commonly encountered OI at follow-up. Children presenting with advanced disease stage (III and IV) , having “fair” or “poor” ART adherence , not taking OI prophylaxis , and CD4 count or % below the threshold  were at a higher risk of developing opportunistic infections.In this study, the incidence rate of opportunistic infections among HIV-infected children remained high. Concerning predictors, such as advanced disease stage (III and IV), CD4 count or % below the threshold, “fair” or “poor” ART adherence, and not taking past OI prophylaxis were found to be significantly associated with OIs. The epidemic of Human Immunodeficiency Virus (HIV) remains a serious public health concern . In 2018OIs are the leading causes of morbidity and mortality among HIV-infected children contributing to 94.1% of HIV-related deaths –13. UnleThe World Health Organization (WHO) recommends a range of medical interventions to reduce the occurrence of OIs among PLHIV. These interventions include reduction of exposure, chemoprophylaxis (primary/secondary), immunization, and early initiation of ART . The useDespite the dramatic decline in the incidence OIs after the introduction HAART, they remain a major cause of morbidity and mortality among these vulnerable population . Most HIA facility-based retrospective cohort study was conducted at Debre Markos Referral Hospital. Debre Markos town is located 300 km far from Addis Ababa, the capital city of Ethiopia and 265 km far from Bahir Dar, the capital city of Amhara Region. According to the 2007 national census, Debre Markos has a total population of 62,497, of whom 29,921 were men and 32,576 were women . Debre MThe source population for this study were all HIV-infected children (aged < 15 years) ever initiated on ART at Debre Markos Referral Hospital, with the study population including those HIV-infected children started on ART between January 1, 2005 to March 31, 2019. HIV-infected children who had incomplete baseline information  and/or who had OIs at the time of ART initiation were excluded from the study.The records of all HIV-infected children ever started on ART (466) at Debre Markos Referral Hospital were recruited. After excluding incomplete records, records of 408 HIV-infected children met the criteria and were included in the study. Data were extracted from the charts of 408 HIV-infected children on ART.The dependent variable for this study was the occurrence of any type of opportunistic infections during follow-up. The independent variables included: Socio-demographic characteristics ; Clinical and laboratory predictors  level, underweight, wasting, stunting, history of Prevention of Mother to Child Transmission (PMTCT), prior history of OIs, functional status, and developmental status); and ART and other medication-related predictors , ART side effects, and ART treatment failure).In this study, an event was considered when HIV-infected child developed any form of OIs after ART initiation during the follow-up period.Censored was recorded when HIV-infected children dropped or transfer out  to other health institutions or are still on active ART follow-up, but did not develop any OIs by the end of the study.ART adherence was classified as good, fair, or poor, according to the percentage of drug dosage calculated from the total monthly dose of ART drugs. Good was reported with compliance equal to or greater than 95% or ≤ 3 missed doses per month; fair reflected 85–94% compliance and between 4 and 8 missing doses per month); and poor reflected less than 85% compliance or ≥ 9 missed dose per month) .Child developmental status was classified as appropriate (able to attain milestones for age), delayed (failure to attain milestones for age); and regression (loss of what has been attained for age) .Children with weight/age Z-score < − 2 SD, height/age Z-score < − 2 SD, and weight/height Z-score < − 2 SD were considered to be underweight, stunted, and wasted respectively , 25.OIs are infections, which occur more frequently and severely among individuals with weakened immune systems, including People Living with Human Immunodeficiency Virus (PLHIV) . Accordi3 or 25% for age < 12 months, CD4 cell counts < 750/mm3 or < 20% for age 12–35 months, CD4 cell counts < 350/mm3 or < 15% for age 36–59 months, and CD4 cell counts < 200/mm3 or < 15% for age ≥ 60 months [CD4 counts or percentage (%) below the threshold was considered if the child had CD4 cell counts < 1500/mm0 months .The data extraction form was based on the federal Ministry of Health’s HIV-care/ART follow-up and intake forms, which are used in the ART clinics of Ethiopian hospitals. The data extraction form included the following variables: socio-demographic characteristics, ART and other medication, clinical, and laboratory-related information. Data were collected by three BSc prepared nurses working in the ART clinic of Debre Markos Referral Hospital. To assure data quality, a data extraction checklist was carefully adapted from a standardized ART intake and follow up forms, nurses currently work in the ART clinic and who took ART training were recruited as data collectors, a one-day training was given for both data collectors and supervisors, completeness of the recorded variables were double checked by taking some randomly selected cards, and the supervisor as well as principal investigators carefully monitored the entire data collection process. Subsequently, all relevant data were retrieved through reviewing of HIV-infected children’s cards. The occurrence of OIs during data extraction was ascertained by reviewing the health professionals’ reporting on patient charts. Any laboratory tests obtained at the time of ART initiation were considered as a baseline data. However, if laboratory tests were not done during ART initiation, any lab tests done within a month of ART initiation were considered as the baseline.p-values ≤0.25 were selected for the multivariable analysis [p-values < 0.05 were considered as statistically significant predictors of OIs.Before entry, data were checked for its completeness and consistency. We used Epi-data™ Version 3.1 for data entry and STATA™ Version 14 for data analysis. Besides, Emergency Nutritional Assessment (ENA) and WHO AnthroPlus software were used to analyze the nutritional status  of HIV-infected children. Descriptive statistics were summarized as percentage, mean, and median, and visualized using tables and charts. The OIs free survival time was estimated using the Kaplan-Meier survival curve. Besides, the OIs free survival time between different categorical explanatory variables were compared using generalized log rank test. A life table was constructed to estimate probabilities of OIs at different time intervals and cumulative survival probabilities. The common assumptions of Cox proportional hazard regression model were checked using Schoenfeld residuals test. In the bi-variable analysis, variables with analysis , 28. In (Table ).A total of 466 HIV-infected children’s medical records were retrieved. Of these, 58 were excluded from the analysis due to incompleteness. The remaining 408 HIV-infected children on ART were included in this study. The median age of the study participants was 7 years IQR = 4, 10). About 42.9% of the children were in the age group of 5 to 9 years. Slightly more than half (54.7%) of the children were male, and more than two thirds (72.1%) were from urban areas. More than half (53.7%) of the parents were both alive and the majority (85.3%) of children were living with their biological parents 0. About (Table 2).About half (51.9%) of children were classified as WHO clinical stage I and II and almost two third (67.9%) of the children had CD4 counts or percentage (%) above the threshold. About 10.3% of participants had < 10 mg/dl hemoglobin level with a median of 12.3 (IQR = 11.3–13.3) mg/dl, with 49.3, 23.8, and 51.7% of participants being underweight, wasted and stunted respectively. More than half (60.8%) of children had taken past OI prophylaxis. Children exhibiting a good adherence level to ART and nevirapine baseline ART regimens were 78.7 and 66.7%, respectively and 56.1% had no history of PMTCT The study participants were followed for a minimum of 2 months and a maximum of 132 months. The total person months of the cohort was 16, 024 child-months of observation. During the follow-up time, almost one third (31.6%) of the study participants developed OIs. This study found that the incidence rate of OIs among HIV-infected children was 9.7  per 100 child-years of observation. From all types of OIs occurring during the follow-up time, TB (29.8%) was the most common, followed by bacterial pneumonia (27.7%), and non-Hodgkins lymphoma or Kaposi’s sarcoma (11.3%) . Figure . Furthermore, children who did not take past OI prophylaxis had less OIs free survival time as compared to the past OI prophylaxis user cohort .In this study, the median OIs-free survival time was 103 months ure Fig. . Furtherort Fig. .Fig. 2K(Table 3).Weight for age Z-scores, history of past OIs, Hgb levels, WHO clinical staging, CD4 counts or %, taking past OI prophylaxis, ever taking IPT, and ART drug adherence were variables for multivariable analysis Of these, WHO clinical staging, CD4 counts, ART drug adherence, and past OIs prophylaxis were found to be significant predictors of OIs. Children presenting with WHO clinical stage III and IV were nearly 2 times (AHR (adjusted hazard ratio): 1.8, 95% CI: 1.2, 2.7) more likely to develop OIs as compared to those children in WHO clinical stages I and II. This study also found that HIV-infected children on ART who had “fair” or “poor” ART adherence were 2 and half fold  more likely to develop OIs as compared to those children who had “good” ART adherence. The risk of developing OIs among children with CD4 count or % below the threshold was 1.7 times  higher as compared to those children with CD4 counts or % above the threshold. Lastly, the risk of developing OIs among children who did not previously take OI prophylaxis was 1.6 times  higher to those who took past OI prophylaxis This facility-based retrospective cohort study was undertaken to determine the incidence of common OIs among HIV-infected children on ART at Debre Markos Referral Hospital. Almost one third (31.6%) of the study participants developed OIs, yielding an incidence rate of OIs 9.7  per 100 child-years of observation. This finding is comparable with an Asian-based study reporting 10.5 per 100 person-years . SimilarLiterature also showed that HIV-related OIs remain high in resource limited settings; especially with SSA being disproportionately affected . DevelopCryptococcus neoformans is not a common cause of meningitis in children.Among all types of OIs, TB is the most common 29.8%) during the follow-up time. This finding is consistent with a study conducted in India, which documented that TB is the most 34.6%) commonly diagnosed OI among HIV-infected individuals .However,.8% durin.6% commoIn this study, children who started ART as WHO clinical stage III and IV were more likely to develop OIs as compared to those children who started ART as WHO stage I and II. This finding aligns with studies done in India , 37, andThis study also found that ART drug adherence is an important predictor for OIs. Children who had “fair or poor” ART drug adherence were more likely to develop OIs as compared to those who had good ART drug adherence. A study conducted in Cameron found that HIV-infected patients who were not adhered to the ART therapy were more prone to develop OIs. This study also documented that OIs significantly increased the risk of non-adherence .HIV-infected children with CD4 count or % below the threshold at the time of ART initiation were more likely to develop OIs as compared to those children with CD4 counts or % above the threshold). A 10 year retrospective study conducted in Uganda  documentLastly, this study found that the risk of developing OIs among HIV-infected children who took past OI prophylaxis was low as compared to those HIV-infected children who did not take past OI prophylaxis. Previous Ethiopian studies revealed that prophylaxis has a significant effect in reducing the occurrence of TB –45. AnotThe current study has some limitations, which must be considered before interpreting results. The data for this study was obtained from charts of HIV-infected children. Therefore, we were unable to get some variables including viral load, income, micronutrient deficiency, and immunization status of the children. At times, OIs might be underestimated due to excluded charts with incomplete data and unrecorded by health professions. Although the data are not always complete, the longitudinal data set may have corrected for some of these limitations.In this study, the incidence rate of opportunistic infections among HIV-infected children remained high. Concerning predictors such as advanced disease stage (III and IV), CD4 count or % below the threshold, “fair” or “poor” ART adherence, and not taking past OI prophylaxis were found to be significantly associated with OIs. Therefore, based on the above findings, we recommend consideration should be given to early screening and treatment of OIs. Besides, adherence support through phone calls and case managers could be strengthened. Furthermore, children presented with severe immunodeficiency and advanced disease stage during the ART initiation should be closely monitored and deeply investigated for the occurrence of OIs in each successive follow-up.


To investigate the changes of retinal nerve fiber layer (RNFL) in patients after an attack of primary acute angle closure glaucoma (PAACG) and to assess the impact of attack time on prognosis of retinal changes.  cross-sectional study. n = 13), while eyes with PAACG attack time more than 1 day constituted the group B (n = 13). All patients received phacoemulsification and viscogoniosynechialysis after intraocular pressure (IOP) lowering. All patients underwent ophthalmic examinations including IOP, best-corrected visual acuity (BCVA), and visual field (VF). Optical coherence tomography angiography (OCTA) was used to obtain circumpapillary RNFL vessel density (cpVD). Spectral domain optical coherence tomography (SD-OCT) was used to examine the peripapillary RNFL and macular ganglion cell complex (GCC). All patients accepted 2 assessments before and 1 month after the procedure.  Twenty-six patients with unilateral PAACG attack and cataracts from 2017 to 2019 were enrolled. Eyes with PAACG attack time less than 1 day constituted the group A (p=0.834) after the procedure. Patients in the group A had better BCVA improvement than those in the group B , as well as better mean defect (MD) values from VF . Compared with group B, patients in the group A had thicker macula , thicker GCC , and thicker RNFL . Higher blood flow density in all-plexus peripapillary retina was observed in the group A eyes compared with group B . In both groups, the association between average RNFL thickness and cpVD as well as MD values and pattern standard deviation (PSD) values from VF was stronger  than the association between GCC thickness and cpVD, as well as MD values and PSD values .  The IOP of all patients recovered to normal (12.77 ± 2.65 mm Hgvs. 12.77 ± 3.85 mmHg,  Patients with attack time less than 1 day had better retinal thickness and all-plexus peripapillary retina blood flow density. Controlling the attack time could decrease retinal damage by PAACG. Primary acute angle closure glaucoma (PAACG), an acute ocular hypertension disease that may lead to irreversible damage to the optic nerve and other ocular tissues, is one of the most common types of glaucoma, especially among Asians . Ocular The shallow anterior chamber depth is a common feature of glaucoma patients . PAACG phttp://www.ClinicalTrials.gov (ChiCTR1800017849). Written informed consent was obtained from each patient in this study prior to enrollment. The inclusion criteria for PAACG patients were as follows: (1) IOP > 21 mmHg with ≥2 following symptoms: visual blurring, ocular pain, headache, nausea, and vomiting; (2) the presence of any following signs on silt-lamp examination: conjunctival congestion, a middilated unreactive pupil, corneal edema, and a shallow anterior chamber; (3) a closed angle observed by gonioscopy; (4) duration of PAACG attack < 120 hours; (5) IOP < 21 mmHg after medical therapy and surgery. The exclusion criteria were as follows: (1) bilateral attack; (2) secondary angle closure caused by phacomorphic angle closure, subluxed lens, and neovascularization; (3) a history of vitreoretinal or corneal surgery in the attack eye; (4) refraction > 5.0 D (sphere) and/or 3.0 D (cylinder); (5) incomplete clinical data, poor-quality OCT scans, the ratio of false negative or false positives in VF examination > 30%, or fixation loss of >20%; (6) Severe corneal edema after IOP control.Study subjects were recruited from patients with an episode of unilateral PAACG attack and cataracts at the Division of Glaucoma, Department of Ophthalmology, Zhongnan Hospital of Wuhan University, China, between January 2017 and April 2019. The study protocol was approved by the Institutional Review Board of Zhongnan Hospital of Wuhan University and adhered to the Declaration of Helsinki. The study protocol was registered on Patients were divided into 2 groups according to their attack time: <1 day (group A) and ≥1 day (group B). All subjects underwent ophthalmic examinations including best-corrected visual acuity , IOP measurement, slit-lamp examination, fundus examination, and gonioscopy. IOP was measured by iCare tonometry or Goldmann applanation tonometry. Gonioscopy was examined with a Goldmann 2-mirror lens at high magnification (×16). VF testing was performed using 24–2 pattern Swedish interactive threshold algorithm on the Humphrey Field Analyzer . VF indices included mean defect (MD) and pattern standard deviation (PSD). Normal VF was defined as MD and PSD within 95% confidence intervals and a glaucoma hemifield test result “within normal limits.” RNFL images were obtained using the stratus OCT 3000 (Carl Zeiss) with peripapillary RNFL thickness calculated automatically, including average, superior, nasal, inferior, and temporal quadrants. Only high-quality images with 3 ≤ signal strength ≤ 10 were included. Macular thickness in scans with a 512 × 128 mm field and ganglion cell complex (GCC) thickness were also assessed with SD-OCT. Vessel perfusion density was measured within the cpVD in scans with a 6 × 6 mm field centered on the optic nerve head. Vessel density within the superficial retina layer was measured using the ZEISS CIRRUS™ OCT Angiography systemRTVue-XR Avanti.All patients underwent phacoemulsification and viscogoniosynechialysis. Two scheduled ophthalmic examinations were performed after IOP controlling: the first one before the procedure and the second one 1 month after the procedure. The patients with IOP > 21 mmHg 1 day after these procedures were further treated with IOP-lowering drugs, such as (1) beta-blockers, (2) carbonic anhydrase inhibitors, (3) pilocarpine, and (4) adrenergic agonists. Additional clinic visits and investigations were scheduled when required.T test was used for the significance of differences between IOP, VA, OCT parameters, vessel flow density, and VF indices including MD and PSD. Pearson correlation was used to evaluate single correlation between average RNFL thickness, average GCC thickness, cpVD, and VF indices. The significance was set as a two-sided p < 0.05.All data were analyzed using the SPSS version 20.0. Independent-sample p=0.092) and gender (p=0.855) were comparable between groups. The mean duration of the PAACG attack was 10.0 ± 6.2 hours (range 2 to 19 h) and 79.3 ± 24.7 hours (range 28 to 120 h), respectively. The mean cpRNFL thickness, baseline vertical cup-to-disc ratio, mean GCC thickness, cpVD, and MD value from VF had no significant differences in the 2 groups . The BCVA before and after surgery in both groups is listed in A total of 26 eyes from 26 patients with unilateral PAACG were enrolled in this study. The characteristics of all the patients are listed in p < 0.001; −2.75 ± 1.10 vs. 9.43 ± 2.93, p < 0.001; As VF was measured 1 month after surgery, the MD and PSD values were significantly lower in patients from the group A than those from the group B . The inner circle of macular thickness was higher in the group A . The outer circle of macular thickness was also higher in the group A . These results indicated that the changes of macular thickness were correlated with attack time. Longer attack time indicated thinner macula. The average thickness of GCC was significantly higher in the group A than those in the group B 1 month after surgery .The fovea and inner circle and outer circle thicknesses of macula were significantly different between groups 1 month after surgery . One monμm vs. 77.69 ± 20.23 μm, p < 0.001). Quadrants analyses showed higher superior  and inferior quadrants  in the group A but comparable thickness in the temporal and nasal quadrants .The superior, temporal, inferior, nasal, and average peripapillary RNFL thickness 1 month after surgery were listed in p=0.002), in the inner area , in the outer area , and in the full area .The OCTA-derived vessel blow densities from both groups are presented in r > 0.4, p < 0.05). In both groups, the association between the average RNFL thickness and cpVD, as well as MD values and PSD values from VF, was stronger  than the association between the GCC thickness and cpVD, as well as MD values and PSD values .The correlation coefficients between VF parameters, average RNFL thickness, and cpVD in both groups 1 month after surgery are summarized in The fundus conditions of 2 representative patients from both groups are shown in In our study, we used the diagnostic ability of BCVA and structural and vascular changes from macula and RNFL to detect retinal changes in PAACG patients. Most patients had good visual outcomes after surgery, and patients with shorter attack time (less than 1 day) got better BCVA. Patients with shorter attack time had thicker macula, GCC, and RNFL. Moreover, the retinal vessel densities in the peripapillary areas were significantly greater in the patients with shorter attack time.SD-OCT and OCT-A were recently developed to observe the retinal function in glaucoma patients in both the foveal and disc areas, in an accurate, convenient, and noninvasive way , 14. RedIn our studies, the thickness of the retina was significantly reduced on the superior and inferior areas, while the changes of nasal side and temporal side in the RNFL were lighter. These results were consistent with the findings of Igarashi et al. , who repp < 0.001), suggesting that reduced vessel flow density was associated with more advanced stages of glaucomatous VF damage. Moreover, we also found that changes in RNFL and RGC thickness often occurred later than changes in VF and blood flow density [In this study, we also evaluated the relationship between VF and fundus changes. There was a strong correlation between the VF loss and cpVD (all,  density , 26. The density . In addi density , 27. Thu density . In otheOur research had several limitations that need to be considered. All patients were selected from a single institution; therefore, a recommendation bias might exist. The number of patients enrolled in this study was limited, and this study lacked long-term follow-up of this series of data on the fundus, such as macular/GCC/RNFL thickness, VF, and cpVD, which might result in further fundus changes to the PAACG patients. However, from our current research data, it was enough to show that for PAACG patients, the attack time and retinal changes were clearly correlated.According to our results, cpVD had more obvious changes than RNFL thickness, macular thickness, and GCC thickness. We considered that OCT-A vessel indicators may be more sensitive than SD-OCT at the early stage of PAACG. Therefore, OCT-A is a promising technology for clinical monitoring of vascular changes in glaucoma. Its application may help the ophthalmologist further understand the pathophysiology of glaucoma and its underlying vascular mechanisms.In summary, longer attack time indicated longer periods of high IOP and perfusion damage to the retinal vessels. It not only caused short-term damage to the fundus but also played a negative role in subsequent fundus change process. Therefore, it is importantly necessary to control the IOP in time once the PAACG patients had the relevant symptoms.


Sir, Takayasu arteritis (TAK) is a rare autoinflammatory disease, characterized by aortitis affecting the aorta and its major branches, coronary arteries and pulmonary arteries [arteries . Long-tearteries , 2. The Tofacitinib (TOF) is an oral Janus kinase inhibitor, which blocks cytokine-mediated inflammatory signalling through the suppression of Janus kinase 1 and 3 . HoweverTofacitinib in combination with MTX is a possible treatment strategy in refractory Takayasu arteritis.A 26-year-old man, diagnosed with TAK at the age of 24 years and treated with prednisolone (16 mg/day) in combination with infliximab (400 mg/8 weeks), ciclosporin (200 mg/day) and AZA (50 mg/day), was admitted to our hospital owing to a relapse of the disease. He was treated with prednisolone (30 mg/day) in combination with TCZ (162 mg/week), followed by oral CYC (100 mg/day) for the induction of remission. However, neither TCZ nor CYC was effective in tapering prednisolone to <25 mg/day, owing to aggravation of his chest pain. A CT scan revealed the worsening of arterial wall thickness of both the left common carotid artery and the descending aorta, with pleural effusion . In viewA recent randomized, placebo-controlled, double-blind, parallel-group, comparative study demonstrated that TCZ is effective in patients with refractory TAK, leading to clinical application . HoweverIn conclusion, our report provides new clinical insight into the role of TOF for refractory TAK and expands the concept that TOF in combination with MTX might be effective in other autoinflammatory diseases caused by multiple cytokines.Funding: This work was not supported by any agency grants except for the cost of tofacitinib, which was supported by the Okayama University Hospital.Disclosure statement: The authors have declared no conflicts of interest.


The etiology of Juvenile Idiopathic Arthritis (JIA) is poorly understood. The purpose of this study was to examine the possible influence of early nutrition on later development of JIA.In a population-based prospective birth cohort of 15,740 children we collected nutritional data, including fish consumption, and biological samples during pregnancy, at birth and at different ages. 16 years after study inclusion we identified 42 children with JIA, of whom 11 were positive for Antinuclear Antibodies (ANA). Heavy metals were analysed in cord blood of all 42 JIA patients and 40 age and sex-matched controls. A multivariable logistic regression model, adjusted for relevant factors, was used as well as Mann-Whitney U-test.p < 0.001 and aOR 5.1 (2.1–12.4) p < 0.001) and of ANA-positivity (aOR 2.2 (1.4–3.6); p = 0.002 and p < 0.001). Concentrations of Al, Cd, Hg and Li in cord blood were significantly higher in the JIA-group than in controls. The ANA-positive, all of whom had consumed fish >once/week their first year, had significantly higher concentrations of Al (p < 0.001), Cd (p = 0.003), and Li (p < 0.001) in cord blood than controls. Frequency of fish consumption correlated with concentrations of Cd (p = 0.003), Li (p = 0.015) and Hg (p = 0.011).Fish consumption more than once a week during pregnancy as well as during the child’s first year of life was associated with an increased risk of JIA (aOR 4.5 (1.95–10.4); Moderate exposure to heavy metals, associated with fish consumption, during pregnancy and early childhood may cause effects on the immune system of the offspring, resulting in ANA positivity and JIA. Juvenile idiopathic arthritis (JIA) is the most common chronic childhood rheumatic disease. It is a heterogeneous autoimmune disease comprising seven categories with onset before 16 years of age , 3. The We have performed a prospective study focusing on environmental factors during pregnancy and childhood in a general population. The aim is to explore environmental factors, such as early feeding, in relation to risk of later development of JIA. Breastfeeding seems to be associated with JIA, as described in a previous paper . Increashttp://www.socialstyrelsen.se/english). More than 99% of all somatic and psychiatric hospital discharges, as well as outpatient visits from both private and public caregivers, are recorded in this population-based register. Several items are recorded, including International Classification of Diseases (ICD) codes and the personal identity number  [The Swedish National Patient Register, launched in 1964, is maintained by the Swedish National Board of Health and Welfare (sidents) .The Swedish JIA-registry started in 2009. In 2014, there were 1700 patients included and coverage was almost complete. Through the unique PIN, information on each individual patient can be linked to other registers.In Sweden, all children aged 0–18 years diagnosed with JIA or RA are treated at paediatric clinics in hospitals or at paediatric rheumatology clinics.n = 21,700) were asked to participate in the study. 17,055 (78.6%) of the families gave their informed consent to participate. According to the ABIS-protocol the children were monitored by biological samples taken at birth and then at the ages 1, 2.5, 5, 8, 10–12 and 13–16 years as well as questionnaires about life-style and environmental factors. A detailed diary was used for daily registration of certain facts related to nutrition and infections including the exact time (date) of introduction of different food items during the first year of life. The 1-year questionnaires were completed by 10,883 families, and in addition, diaries were collected for 9849 children. All subjects with missing values were excluded from the statistical model.The current study was part of the All Babies in Southeast Sweden-project (ABIS), which aims to study causes of immune-mediated diseases by following a general population birth cohort though childhood and adolescence. All parents with children born between Oct 1st 1997 and Oct 1st 1999 in Southeast Sweden  as substrate . ANA poshttps://www.iso.org/standard/32957.html) and 2 (https://www.iso.org/standard/62962.html), and the EPA Method 200.8 (https://www.epa.gov/homeland-security-research/epa-method-2008-determination-trace-elements-waters-and-wastes). Heavy metals analysed were: Aluminium (Al), Cadmium (Cd), Mercury (Hg), Lithium (Li), Lead (Pb), Zinc (Zn), Copper (Cu), Arsenic (As), Magnesium (Mg) and Iron (Fe).The analysis of heavy metals was performed by ALS Scandinavia AB  using the ‘ultrasensitive inductively coupled plasma sector field mass spectrometry method’ (ICP-SFMS)  after acHomogeneity of variance was tested using Levene’s test and the normality for independent variables was revised both graphically and by the Shapiro–Wilk test.p < 0.1 in the univariate analyses were included in the final multivariate logistic regression model as possible confounding factors associated with fish consumption.Odds ratio (OR) with 95% confidence intervals (95% CIs) were estimated using (univariate) logistic regression. JIA and ANA positivity were used as the dependent variables. Amount of dietary fish intake and possible confounding factors (listed below) associated with incidence of JIA were analysed. Dietary fish intake was also dichotomized to either low intake (< 1 per week) or moderate-high intake (≥1 per week). At the time when ABIS was initiated, the Swedish National Institute of Public Health recommended dietary intake of fish 2–3 times a week during pregnancy and 2–3 times a week during the first year of life. Variables with P-values are two-tailed and a value below 0.05 and a 95% CI not overlapping the null value 1.00 for the OR were considered as statistically significant.Independent samples t-test and Mann-Whitney U-test, adjusted for confounding factors (listed below), was used to calculate differences in levels of heavy metals and fish consumption between the groups. All Possible confounding factors included heredity for rheumatism (JIA or RA in first- and second-degree relatives), parity, mode of delivery, preterm birth, duration of  breastfeeding, introduction of formula, parental age, education, smoking habits, and whether or not the parents were born outside Sweden.Statistics were calculated using the Statistical Package for Social Science .Forty-one cases of JIA with complete questionnaires after delivery were identified. The number and proportion of patients in each JIA category are shown in Table p < 0.001). The child’s consumption of fish more than once a week during the first year of life was also associated with an increased risk of JIA (aOR 5.1 (2.1–12.4) p < 0.001), as illustrated in Table p = 0.002).Fish consumption more than once a week during pregnancy was associated with an increased risk of JIA (aOR 4.5 1.95–10.4); .95–10.4;(aOR 5.1 .1–12.4 pFish consumption more than once a week during pregnancy as well as during the child’s first year of life was associated with an increased risk of ANA-positivity (aOR 2.2 1.4–3.6); p = 0.002 and p < 0.001, respectively). 100% of children with ANA-positivity had consumed fish more than once a week during their first year. Fish consumption at the age of 2.5 and 5 years showed no association with ANA-positivity  showed significant results for Al (p = 0.040), Cd (p = 0.008) and Li (p = 0.006). 82% of the children with ANA antibodies had concentrations of Al, Cd, or Li higher than the mean, and 64% had concentrations two standard deviations above the mean. 91% (10/11) of the ANA-positive had elevated concentrations higher than the mean of one or more of all the analysed heavy metals.Concentrations of Al, Cd and Li in cord blood were significantly higher in the ANA-group than in controls Table . Chi2-te2-test of heavy metals dichotomized below/above the detection level  showed significant results for Al (p < 0.001), Cd (p < 0.001), Hg (p < 0.001) and Li (p < 0.001). 71% of the children with JIA had concentrations of Al, Cd, Hg or Li higher than the mean, and 52% had concentrations two standard deviations above the mean. 95% (40/42) in the JIA-group had elevated concentrations higher than the mean of one or more of all the analysed heavy metals.Concentrations of Al, Cd, Hg and Li in cord blood were significantly higher in the JIA-group than in controls Table . Chi2-tep = 0.003), Li (p = 0.015) and Hg (p = 0.011) in cord blood, but not with concentrations of Al (p = 0.261) (Table p = 0.028), Li (p = 0.006) and Hg (p = 0.012). Frequency of consumption of fish from fresh water was extremely low during pregnancy, as shown in Table Frequency of  fish consumption during pregnancy correlated with concentrations of Cd , especially n-3 PUFAs and micronutrients that may have anti-inflammatory properties and may modulate immune responses –11. GestMurphy et al. have suggested that cadmium inhalation could be a plausible trigger for RA . SmokingThe main source of cadmium exposure in non-smokers is the diet . IntestiHumans do not have an effective elimination pathway for cadmium, and as a consequence the half-life of cadmium in the body is estimated to be 15–20 years . MassiveAluminium is a potent stimulator of the immune system, which is the very reason it is used as an adjuvant . In the Mercury-induced autoimmunity in mice is an established model to study the mechanisms of the development of ANA. Immunotoxic effects, including ANA-positivity, have been clearly demonstrated in murine models in response to both organic and inorganic mercury . In humaInorganic mercury contaminates waterways, can be biotransformed to methylmercury, and bioaccumulate in fish. Consumption of methylmercury-laden fish represents the most common route of exposure for humans . GeneralLithium therapy has been acknowledged to induce thyroid autoimmunity. Studies have reported a high prevalence of antithyroid antibodies in patients with affective disorders receiving lithium , 38. MorThus, it is reasonable to believe that the increased concentrations of both cadmium, aluminium, mercury and lithium may play a role in changes in the immune balance, which could contribute to the development of autoimmune rheumatic diseases.The small patient sample is a weakness due to the nature of the study, i.e. a birth cohort of a relatively rare disease. Different categories of JIA should be studied as separate groups , 43, butOur study has some notable strengths. First, the prospective study design avoids the potential recall and selection biases of retrospective studies that collect data on nutrition and lifestyle after the diagnosis. The prospective design distributes any possible measurement biases equally between the JIA cases and non-cases, and recall bias is not likely to explain our findings. The ABIS cohort has been found to be representative for the Swedish general population in aspects such as education level . Second,In conclusion, our results indicate that consumption of fish during pregnancy and first year of life may be a risk factor for development of JIA. Heavy metals could trigger autoimmunity leading to JIA, but further studies are needed to explore the possible causal link between heavy metal diet in early life (included pregnancy) and development of JIA. Our findings suggest that even moderate exposure to aluminium, cadmium, mercury and lithium during pregnancy and early childhood may cause effects on the immune system of the offspring, resulting in ANA positivity and JIA. Exposure to heavy metals during pregnancy and early childhood should be limited, and heavy metal content should be considered for inclusion in future guidelines for food and nutrition during pregnancy and infancy. More knowledge of the role of the child’s early nutrition and its association to autoimmunity is of importance, as future guidelines for food and nutrition during pregnancy and infancy may help to prevent this chronic disease.