Globally, poisonings account for most medically-attended self-harm. Recent data on poisoning substances are lacking, but are needed to inform self-harm prevention.To assess poisoning substance patterns and trends among 10–24-year-olds across EnglandOpen cohort study of 1 736 527 young people, using linked Clinical Practice Research Datalink, Hospital Episode Statistics, and Office for National Statistics mortality data, from 1998 to 2014.Poisoning substances were identified by ICD-10 or Read Codes. Incidence rates and adjusted incidence rate ratios (aIRR) were calculated for poisoning substances by age, sex, index of multiple deprivation, and calendar year.In total, 40 333 poisoning episodes were identified, with 57.8% specifying the substances involved. The most common substances were paracetamol (39.8%), alcohol (32.7%), non-steroidal anti-inflammatory drugs (NSAIDs) (11.6%), antidepressants (10.2%), and opioids (7.6%). Poisoning rates were highest at ages 16–18 years for females and 19–24 years for males. Opioid poisonings increased fivefold from 1998–2014  = 4.08 to 6.89; males: aIRR 5.11, 95% CI = 3.37 to 7.76), antidepressant poisonings three-to fourfold , aspirin/NSAID poisonings threefold  and paracetamol poisonings threefold in females . Across all substances poisoning incidence was higher in more disadvantaged groups, with the strongest gradient for opioid poisonings among males .It is important that GPs raise awareness with families of the substances young people use to self-harm, especially the common use of over-the-counter medications. Quantities of medication prescribed to young people at risk of self-harm and their families should be limited, particularly analgesics and antidepressants. Most UK data describing poisoning substances among young people have been based on attendances at specific hospitals or emergency departments (EDs) with limited generalisability,8This study aimed to estimate population level medically-attended poisoning incidence among 10–24-year-olds in England between 1998 and 2014 according to poisoning substance by sex, age, deprivation level, and changes over time.,29This study utilised routinely collected General Practice data from the Clinical Practice Research Datalink (CPRD). In the UK, 98% of the population is registered with a GP,27Poisonings are by far the most common form of medically-attended self-harm among young people and are often avoidable, but up-to-date information on the substances young people are being poisoned by is lacking. This study shows the most common substances involved in poisonings among 10–24-year-olds in England are paracetamol, alcohol, NSAIDs, antidepressants, and opioids. Between 1998 and 2014 there was a fivefold increase in opioid poisonings among 10–24-year-olds, as well as a three- to fourfold increase in antidepressant poisonings. Poisonings show a close relationship with deprivation, with the incidence of poisoning from all substances rising with increasing socioeconomic deprivation.The study outcome was a poisoning event occurring within the study period and recorded within any one of the three linked data sources. Repeat poisoning events within the same individual were included. Time dependent algorithms that have been previously developedPoisonings, and their intent, were identified using a combination of International Classification of Diseases (ICD)-10 codes  in HES/ONS data and Read Codes in CPRD data. Poisoning substances were categorised using ICD-10 categories T35–65, excluding venomous animal and food poisonings . The comprehensive poisoning code list used has been described elsewhere.The number and percentage of poisoning events involving specific substances was identified. Incidence rates (IR) per 100 000 person-years (PY) and 95% confidence intervals (95% CI) were calculated by sex, age, socioeconomic deprivation, geographical area, and calendar year for the five most common substances, as well unspecified substance poisonings and total poisonings. For clinical relevance, poisonings involving non-steroidal anti-inflammatory drugs (NSAIDs) (T39.3) and aspirin (T39.0) were combined for calculating incidence rates, as were all antidepressants (T43.0–T43.2). Age and year were included as time-varying covariates by Lexis expansion. Time period was analysed in single years in the univariate analysis and 4-year bands in the multivariate analysis. Socioeconomic status was assessed using quintiles of the Index of Multiple Deprivation 2010 (IMD) for England. This was provided by CPRD, at a lower super output area level (approximately 650 households), based on the postcode of the individual’s GP practice.P<0.01 taken as significant. Where significant interactions were found, stratified incidence rates are presented. Data were analysed using Stata/SE (version 13).Adjusted incidence rate ratios (aIRR) were calculated for the five most common substances, total poisonings (regardless of whether an exact substance was recorded for the poisoning or not) and unspecified substance poisonings using negative binomial regression, and adjusted for each of the covariates outlined above. Potential interactions were assessed including sex and age,The cohort contained 1 736 527 young people contributing 7 209 529 person-years of follow-up: 52% were female . In totaParacetamol was the most commonly involved substance 39.8%, . The othP<0.001 for each substance). The peak poisoning incidence in females was in the 16–18-year age group for all substances other than antidepressants .Poisoning events involving alcohol among 10–14-year-old males decreased over time . There was also a reduction in unspecified substance poisonings among 16–18-year-old females from their peak in 2001–2002  to 2013–2014 After adjusting for available confounders, poisonings involving the five most common substances all increased steadily between 1998 and 2014 in both sexes. The largest increases saw opioid poisonings increase fivefold from 1998–2014 , antidepressant poisonings three- to fourfold , aspirin/NSAID poisonings threefold , and paracetamol poisonings threefold in females . Unspecified substance poisonings decreased over time in both sexes, by 12% in females  and 21% in males  .A social gradient in poisonings was demonstrated for each substance with a roughly twofold increase in poisoning incidence for the most compared to least deprived groups. Excluding unspecified poisonings, the steepest gradient was for opioid poisonings in males with a 3.5 fold increase in poisoning incidence in the most compared to least deprived group  .The most common substances involved in poisonings among 10–24-year-olds were paracetamol, alcohol, NSAIDs, antidepressants, and opioids. There were increases in poisoning incidence rates of between three- and fivefold for opioids, antidepressants, aspirin/NSAIDs and paracetamol over the study period. Sex and age variation was shown with the largest rises over time being in 16–18-year-olds among females and 19–24-year-olds among males. There was a social gradient in poisonings for each of the five most common substances, with higher poisoning incidence in the most deprived groups.,28This is the first study to use population level combined English healthcare data sources to examine the substances involved in poisoning episodes among young people. As CPRD has been shown to be broadly representative of the UK population,27Limitations of this study include underestimation of poisoning incidence for specific substances as only 57.8% of the poisonings had substances involved recorded. These results showed a reduction in unspecified or unknown substance poisonings over time, but as the absolute rate reductions among unspecified or unknown poisonings were much smaller than the absolute rate increases seen for the five most common substances, improved recording over time cannot fully explain the incidence rate increases found for these substances. It was only possible to obtain deprivation data based on the IMD score of an individual’s GP practice address, which may not always accurately represent an individual household’s deprivation level. Finally, because of the large sample size some statistically significant results that are not clinically important may have been detected.,9,13,18,8The finding that the most common substances involved in poisoning were over-the-counter (OTC) analgesics is consistent with previous studies from the UK,8The most up-to-date UK poisoning substance data comes from the Multicentre Study of Self-harm, reporting ED data from five hospitals across three English cities from 2003–2012 in people aged >15 years. This showed 46% of poisonings involved paracetamol or salicylates, 25% antidepressants, 14% benzodiazepines, and 7% major tranquilisers and/or antipsychotics.,35,2Though the authors are not aware of recent data on temporal trends in opioid poisonings in the UK, data from US national hospital discharges show almost doubling of opioid poisonings among 15–19-year-olds between 1997 and 2012.33Limiting prescribing is not the only possible approach to reducing poisonings. Educating physicians and potentially the public is key, with physician education in suicide prevention having been shown to reduce suicide rates.1et al, who demonstrated a more than doubling in antidepressant poisonings from 1996–2000.2The finding of a three- to fourfold increase in antidepressant poisonings from 1998–2014 continues the temporal trend among 12–18 year-olds shown by Hawton ,9,24In the UK, paracetamol poisonings increased during the 1990s but reduced around 1998–1999,9The threefold increase in aspirin/NSAID poisonings demonstrated updates earlier UK evidence of a more than halving in NSAID poisonings among 12–18-year-olds between 1978–1990 and 1991–2003 and static rates in <15-year-olds from 1990–2000.9The overall increase in poisonings involving alcohol is similar to previous findings from UK primary care data that reported a 20% increase in alcohol poisonings among 10–17-year-olds between 1992 and 2012.41,40,42–47The findings of a social gradient in poisonings among young people reflect similar findings of 1.5 to threefold increased risk in the most compared to least deprived groups shown across a variety of countries and settings.10Future research to examine poisoning incidence in conjunction with individual prescription data would be useful to describe the source of poisonings substances used by young people.Alongside physician education, these findings primarily suggest volumes of medication prescribed to young people should be limited. This is especially relevant for those with a history of self-harm, where similar precautions should be taken when prescribing for family members. This is important when prescribing for both psychiatric and non-psychiatric conditions, especially analgesics. Though the largest increases in poisonings were seen for opioids, adding to the increasing volume of recent evidence suggesting the need to curb opioid prescribing, this should be seen in the context of the most common poisoning substances being OTC analgesics. It is important for GPs, as well as hospital-based clinicians assessing young people after an episode of self-harm, to raise awareness of the types of substances young people use to self-harm with the families of those at risk. In particular, that these commonly include OTC medications that may be easily accessible within households or which young people may buy themselves. This is also a key message for community pharmacists, when selling over-the-counter analgesia to young people.


Background and purpose — Most often, the goal of non-geriatric femoral neck fracture surgery is to preserve the native hip joint. However, reoperations for painful implants, osteonecrosis, and nonunion are common. We determined the reoperation rate and time-to-reoperation following internal fixation of these fractures in a large population cohort.Patients and methods — This retrospective cohort study included patients between the ages of 18 and 50 years old who underwent internal fixation for a femoral neck fracture during 1997–2013. Patients were followed until December 2013. Primary outcomes were reoperation rate and time-to-reoperation. Time-to-event analysis was performed to estimate the rate of any reoperation and for THA specifically, while testing the dependency of time-to-reoperation on secondary variables.Results — 796 young femoral neck fracture patients were treated with internal fixation during the study period . Median follow-up was 8 years (IQR 4–13). One-third underwent at least 1 reoperation at a median 16 months after the index surgery (IQR 8–31). Half of reoperations were for implant removal, followed by conversion to total hip arthroplasty. 14% of the cohort were converted to THA. The median time to conversion was 2 years (IQR 1–4). Neither female sex nor older age had a statistically significant effect on time-to-reoperation or time-to-THA conversion.Interpretation — Following internal fixation of young femoral neck fracture, 1 in 3 patients required a reoperation, and 1 in 7 were converted to THA. These data should be considered by patients and surgeons during treatment decision-making. Femoral neck fractures in non-geriatric adults are a challenge to treat successfully. They often occur from high-energy trauma and result in displaced fracture patterns  and time-to-reoperation for patients aged 18–50 after internal fixation of femoral neck fractures. Secondarily, we sought to determine the relationship between age, sex, and hospital volume on the rates of reoperation and conversion to THA in this patient population. We hypothesized that male sex, older age, and having the index procedure done at a low-volume center would be associated with an increased risk of reoperation.www.popdata.bc.ca).This was a retrospective cohort study. We used British Columbia (BC) administrative health-care data collected and linked by Population Data BC, a multi-hospital data and education resource facilitating interdisciplinary research on the determinants of human health, well-being, and development of the citizens of BC. The main data sources were Medical Services Plan (MSP) Payment Information Files that capture data on medically necessary services provided by physicians  to individuals covered by MSP, the province’s universal insurance program ; the Discharge Abstracts Database (DAD), which contains demographic, administrative, and clinical data for all patients discharged from acute-care hospitals in BC  with subsequent osteosynthesis  . Reoperation was defined as any of any of the following procedures undertaken after the index surgery: implant removal (MSP code 55415 or 55420), proximal femur osteotomy (55603), bone grafting (MSP code 55651), non-union fixation (MSP code 55633), hip hemi-arthroplasty (55662), and THA (MSP code 55663). Secondary outcomes included time-to-any-reoperation and time-to-THA.The Pearson chi-square test was used to compare patient demographic and hospital variables by outcome status. A descriptive analysis of reoperation type was also conducted. A Kaplan–Meier analysis was performed to estimate the rate of failure of the index procedure for any reoperation and for THA specifically at 1-, 2-, 5-, and 10- year intervals as well as a mean time-to-reoperation. A Cox proportional-hazards regression model was used to study the dependency of time-to-reoperation and time-to-THA on patient and hospital variables. All statistical analyses were conducted using SAS 9.4  and SPSS, Version 22 .The study was approved by the Clinical Research Ethics Board at the University of British Columbia (H14-03413). No external sources of funding were utilized. The fees for accessing the administrative databases held by Population Data BC were waived via a Student Waiver. None of the authors have any conflicts of interest. All inferences, opinions, and conclusions drawn in this study are those of the authors, and do not reflect the opinions or policies of the Data Stewards at Population Data BC.The final cohort consisted of 796 patients aged 18–50 years who underwent internal fixation for femoral neck fracture between 1997 and 2013. The number of included patients ranged between 40 and 60 cases per year. The median age of the cohort was 43 years (IQR 35–48) and 61% were male . Median There were 351 reoperations performed during the study period among 235 unique patients (30%) who required at least 1 reoperation. The most common reoperation was implant removal , followed by conversion to THA . 52 patients (7%) in the cohort required 2 or more reoperations within the study period. Among these 52 patients, the median number of reoperations was 2 (IQR 2–4) .The median time to the first reoperation was 16 months (IQR 8–31). The Kaplan–Meier survival curve  shows that the 1-, 2-, 5-, and 10-year reoperation rates were 12%, 21%, 30%, and 34% respectively. Reoperation rates were similar whether stratified by age or hospital volume . Our resData on comorbidities, socioeconomic status, and time-to-fixation were incomplete and were not included in the multivariable model. In the final model, neither age, sex, nor hospital volume was associated with a higher risk of reoperation, or with a higher risk of conversion to THA .This study used population-based health data to estimate the long-term outcomes of young femoral neck fractures. This represents the largest North American cohort of such fractures with long-term outcomes to date. A 10-year reoperation rate of 34% and a 10-year rate of conversion to THA of 14% suggests a substantial opportunity to improve the treatment of femoral neck fractures in the non-geriatric population.Our results are comparable to previous literature, which predominantly consists of single-center case series. The largest series, by Huang et al. , followeScant population-based data exist for young femoral neck fractures. Samuel et al.  performeTo our knowledge, no other study has quantified the trajectory of reoperations for young femoral neck fractures. With a median time-to-reoperation of 16 months and the initially steep Kaplan–Meier survival curve seen in In our cohort, the most common type of reoperation was implant removal (55%) followed by THA (29%), nonunion fixation (5%), and revision internal fixation (5%). Previous studies have suggested that the most common reasons for reoperation following internal fixation of young femoral neck fracture are osteonecrosis and nonunion  accounted for 32% of reoperations while hip-preserving procedures  accounted for 14%. An arthroplasty procedure typically denotes an unsalvageable joint, most likely due to advanced osteonecrosis or nonunion. With regard to nonunion, some surgeons in British Columbia may treat difficult cases with arthroplasty; however, in many cases the first option for an aseptic nonunion is a hip-preserving procedure. Revision fixation using a valgus-producing trochanteric osteotomy is a recommended treatment for nonunion in high Pauwels angle fractures (Deakin et al. Recent evidence supporting primary total arthroplasty for difficult periarticular fractures with high complication rates has emerged for certain proximal humerus, distal femur, and elbow fractures (McKee et al. Our secondary analyses were unable to support our hypothesized associations between key variables and the risk of reoperation or conversion to THA. Neither age, sex, nor hospital volume were associated with these outcomes.The most significant limitation of this large administrative database study is our inability to measure the fracture severity or fixation quality. Additionally, the socioeconomic, provider volume, and time-to-initial fixation data were incomplete and therefore had to be excluded from the multivariable analyses. Excluding patients that died or moved out of province may have slightly biased our estimates if these patients were more prone to reoperation. Furthermore, while our analyses focused on the important outcome of reoperation, we are unable to comment on the functional outcome of the cohort, which could be associated with hospital or patient variables. Regardless, these limitations are mitigated by the unique strength of using a linked, population-based database from a single-payer health system, which ensures that reoperations that occurred several years after the index fixation or at another hospital were accurately captured.In summary, our study expands the understanding of young femoral neck fracture outcomes by estimating short-, medium-, and long-term reoperation rates. 1 in 3 patients will require a reoperation, while 1 in 7 will be converted to THA. These values are useful prognostic information for both surgeons and patients, and they provide further impetus for research to determine what fracture- and patient-related characteristics should be used to discern the optimal treatment for this difficult fracture.DJS: study design, data collection, data analysis, writing of the draft paper, and revision of the paper. LMO, NNO, GPS: study design, data analysis, and revision of the paper. KAF, PJO: study design and revision of the paper. Acta thanks Hans Berg and Ville Mattila for help with peer review of this study.


The aim of this study was to provide an updated review of dental procedures undertaken at the dental unit of the Onco-hematology service of the Instituto da Criança at the Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (ICr/HC-FMUSP).We retrospectively reviewed 565 of 1902 medical and dental records of patients diagnosed with onco-hematological diseases who were seen in a 3-year study (January 2015 to December 2017). We assessed data regarding population characteristics, onco-hematological diagnosis and dental procedures performed.Of the selected medical records, preventive dentistry was the most common procedure undertaken in this population, followed by oral maxillofacial surgeries, restorative dentistry and oral mucositis treatment. The most prevalent malignant diagnosis was acute lymphocytic leukemia, and the most prevalent nonmalignant diagnosis was sickle-cell anemia.Preventive dental procedures represent most of the dental procedures undertaken in hospitalized onco-hematological pediatric patients. The survival rate of pediatric onco-hematologic patients has increased in the past few years due to a combination of clinical approach, surgery, radiotherapy, chemotherapy and stem cell hematopoietic transplantation (HSCT) techniques. However, short- and long-term complications have been reported Oral problems resulting from cancer therapy, such as oral mucositis, which negatively affects body weight gain in children undergoing HSCT The dental unit of the Onco-hematology service of the Instituto da Criança at the Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (ICr/HC-FMUSP) was established in 2007 with the aim of offering proper dental care to pediatric patients undergoing onco-hematological therapies. In the first year of its inauguration, the most common dental procedures among the study population were restorative dentistry, preventive procedures and the removal of infectious foci The aim of this paper was to provide an updated review of dental procedures undertaken at the dental unit of the Onco-hematology service of ICr/HC-FMUSP, including population characteristics, onco-hematological diagnosis and the distribution of dental procedures performed annually.The medical and dental records of 1902 patients seen at the dental unit of the onco-hematology service of ICr/HC-FMUSP during the 3-year study were reviewed. Only 565 patients achieved the inclusion criteria: infants, children or adolescents (0 to 18 years old) who were diagnosed with onco-hematological disease between January 2015 and December 2017. A total of 1307 medical records were excluded due to erroneous information, unconfirmed onco-hematological diagnosis or death .We collected data concerning gender, age and primary cancer diagnosis and categorized dental procedures performed in the last three years as either preventive or therapeutic.All the primary caretakers gave their signed approval to provide medical records for this study. No biological material was collected, and the study was conducted in accordance with the ethical standards of the responsible committee on human subjects. Individual information remained confidential, and all patient identifiers, such as names, addresses and personal characteristics, were thoroughly preserved in this investigation.This research was approved by the Faculdade de Medicina da Universidade de São Paulo ethics committee in May 2015 (protocol number: 1.073.602).Of the 565 medical records selected for thorough review, 380 (66.73%) were diagnosed as malignant, and 185 (32.74%) were diagnosed as hematological. In total, 53% of the population was male, and 47% was female. The mean age at diagnosis was 11.5 years , and the age distribution is shown in The most prevalent malignant diagnosis was acute lymphocytic leukemia (ALL) (69.41%), followed by acute myeloblastic leukemia (AML) (12.33%), Hodgkin lymphoma (6.85%), non-Hodgkin lymphoma (6.39%) and Burkitt lymphoma (2.74%). Other malignant diagnoses comprised 2.28% altogether. Of the nonmalignant diseases, the most prevalent diagnosis was anemia (70.51%). Of these, sickle-cell anemia comprised 42.31% of the cases. Between 2015 and 2017, 1411 dental procedures were performed at the dental unit of the Onco-hematology service of the Instituto da Criança at the Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo.The distribution of dental procedures shows the proportions of both malignant and nonmalignant groups. In total, preventive dental care was the most commonly performed dental procedure n=465; 33%). Oral and maxillofacial surgeries comprised 26% of the dental procedures . Restorative dentistry comprised 14% (n=203), and topical laser application for oral mucositis comprised 11% (n=159). In total, gum treatments (periodontics) and root canal filing (endodontics) encompassed 15% of the dental procedures. 5; 33%. OThe survivorship and free-event lifetime of childhood onco-hematological malignancies have increased due to the combination of multiple therapies that includes more effective drugs for long-term clinical follow-up, less invasive and more conservative surgeries, multiple agent chemotherapy, radiotherapy and hematopoietic stem cell transplantation Age and gender distributions found in the present study were consistent with those reported in previous publications, indicating that in Brazil, leukemia is more prevalent in boys aged 1 to 4 years old (31.6%), lymphoma is dominant in males between 15 and 18 years old (35.6%), and tumors of the central nervous system have a similar male:female ratio (26%) in patients under 14 years old Preventive dental procedures, such as topical fluoride application and professional oral hygiene, were most common (32.94%). These preventive procedures reduced the frequency of restorative treatment and the prevalence of infectious foci Oral mucositis is a debilitating dose-related complication that commonly affects hospitalized patients undergoing cancer therapy and is often addressed by a dental unit team. Oral mucositis manifests as a burning sensation in the oral mucosa and can lead to the formation of edema, erythema and ulcers. Topical laser application is a well-established and noninvasive approach that effectively controls oral mucositis Another important aspect of preventive multidisciplinary care in hospitalized patients is related to the unavailability to work during chemotherapy or radiotherapy Long-term follow-up studies with information regarding the oral conditions of pediatric onco-hematological patients are needed. These studies can enhance dental care in this population and therefore improve quality of life. Additionally, further studies are necessary to establish specific dental protocols suitable for short- and long-term cancer therapies and improve not only survivorship but also quality of life.Based on the present study, it can be concluded that preventive dental procedures were performed mostly in onco-hematological pediatric patients, followed by minor oral surgeries and restorative dentistry. Longitudinal and cohort studies are needed.Frascino AV was the main author and researcher. Fava M was responsible for the data review and organization. Cominato L was responsible for the medical records review. Odone-Filho V was the research advisor.


Emerging evidence supports a prognostic role of primary tumor location in metastatic colon cancer (mCC). We conducted a retrospective analysis to evaluate the effect of tumor location on prognosis and efficacy of biological agents  added to first-line chemotherapy in patients with RAS wild-type (wt) mCC. Patients with newly diagnosed RAS wt mCC candidates to first-line chemotherapy with anti-EGFRs or Bevacizumab were selected. Clinical outcomes were assessed and stratified by tumor location and type of treatment. Overall, 351 patients met the inclusion criteria. Primary colon cancer was right-sided (RCC) in 105 (29.9%) patients and left-sided (LCC) in 246 (70.1%). Patients with LCC had a better OS compared to those with RCC . In the overall study population, OS was not significantly different for patients treated with Cetuximab or Panitumumab as compared to those receiving Bevacizumab. However, when comparing treatment outcome according to tumor sidedness, patients with LCC treated with Cetuximab or Panitumumab had a significantly longer PFS  and OS . No relevant differences were observed in patients with RCC.We found evidence in support of the impact of tumor location in RAS wt mCC treated with first-line chemotherapy in association with targeted therapy. More favorable outcomes were observed in LCC patients, but not in RCC patients, treated with anti-EGFR agents compared with those who received Bevacizumab. Further, prospective and adequately sized studies are warranted to confirm our findings. Colorectal cancer represents the fourth most common cancer and the third cause of cancer-related mortality worldwide In the last few decades, we have witnessed a progressive increase in median overall survival (OS), now exceeding 30 months for patients with metastatic colorectal cancer (mCRC) It was initially found that mutations located within codon 12 and 13 of exon 2 of the KRAS gene were associated with resistance to anti-EGFR monoclonal antibodies Since the efficacy of Bevacizumab appears to be unaffected by RAS status Differential biological features have been described for right-sided colon cancer  and left-sided one  However, very few of the available studies have specifically addressed these issues in the population of patients with RAS wt metastatic tumors, which may be characterized by a more favorable prognosis as compared to the RAS-mutated ones With notably rare exceptions Thus, the present multicenter retrospective study was conducted to verify the prognostic and predictive role of tumor site in a cohort of patients with RAS wt mCC treated with first-line chemotherapy plus Bevacizumab or anti-EGFR monoclonal antibodies in the real-word setting.All patients with newly diagnosed mCC consecutively referred to five Italian cancer centers between January 2010 and December 2016 for first-line therapy were considered for inclusion in this study. Among them, only patients with documented RAS (KRAS/NRAS exons 2-4) or KRAS (exon 2) wild type tumors whose treatment included a biological agent (anti-EGFRs or Bevacizumab) were selected. For each patient, demographics , baseline clinical-pathological features , and therapy-related variables  were collected. The study protocol was approved by the local Ethics Committees and informed consents were obtained from alive patients.Response to treatment was based on imaging documentation, mostly CT scans, available in clinical records, and coded according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Progression-free survival (PFS) was calculated from initiation of first-line therapy to disease progression or death (whichever occurred first). Overall survival (OS) was defined as the time from therapy initiation to death or last annotation on clinical records. Patients with rectal cancer were excluded from the study. The date of study cutoff was December 15, 2018.Standard descriptive statistics were used to summarize patients' characteristics. Median values and ranges were used for continuous variables, while percentages were computed for categorical variables. Proportions were compared by Pearson's chi-square test or Fisher's exact test, depending on the size and number of the groups compared. Survival analyses were performed according to the Kaplan-Meier method and differences between curves tested by log-rank. Survival curves were truncated at 60 months, since the number of patients remaining at risk was too small afterward. Univariate Cox regression analysis was used to estimate hazard ratio (HR) and 95% confidence intervals (95%CI) for PFS and OS. A p value ≤ 0.05 was retained as the limit of statistical significance. The SPSS version 15.0 statistical software was used to perform all the analyses.Six hundred and thirty-three consecutive patients with newly diagnosed mCC were treated with first-line therapy at the participating Institutions. Thirty-six patients with undetermined KRAS or RAS status and treated only with chemotherapy were excluded from the study, as were 246 patients with mutations in exons 2-4 of KRAS or NRAS. Overall, 351 patients met the inclusion criteria  were previously treated with fluoropyrimidine-based adjuvant therapy, which included oxaliplatin in most cases (65.7%). At diagnosis, 168 (49.7%) patients presented with multiple site metastases, mostly localized in liver and lungs. Two-hundred and forty-five (69.8%) patients received an anti-EGFR agent (Cetuximab in 154 and Panitumumab in 91 cases), and 106 (30.2%) were treated with Bevacizumab. Fluorouracil, folinic acid, and irinotecan (FOLFIRI) was the most widely used chemotherapy backbone (41.3%), especially in association with Cetuximab (88.5% of the cases).Main patients' characteristics according to the location of primary tumor are summarized in Table One hundred and forty (57.1%) patients among those treated with Cetuximab or Panitumumab, and 74 (69.8%) among those treated with Bevacizumab received at least one additional line of treatment after disease progression. Second-line therapy included Bevacizumab in 80% of the patients treated with anti-EGFRs in first-line, while a similar percentage (79.8%) of patients receiving Bevacizumab in first-line was treated with an anti-EGFR agent at progression. Notably, the biological agent used in first-line was maintained beyond progression in 14.3% of patients in the anti-EGFR group, and in 20.3% of those treated with Bevacizumab.In the whole cohort of patients, analysis of best response revealed 30 (8.5%) complete responses, 152 (43.3%) partial responses and 97 (27.1%) stable diseases. Overall response rate was significantly higher in the group of patients with LCC as compared to the RCC group , as was DCR .When the type of biologic agent was considered, neither ORR (54.3% vs 46.2%) nor DCR (77.1% vs 75.5%) were significantly different between patients treated with anti-EGFRs or Bevacizumab. Similarly, no difference in ORR and DCR was observed between treatment groups in LCC or RCC. Overall, 95 patients underwent surgical removal of metastatic lesions, mostly after first-line therapy. More frequently, although not significantly, they had left-sided tumors (28.9% vs 22.8%).At the date of study cutoff, 193 (55%) patients were dead. Median follow-up of surviving patients was 26.9 months (interquartile range 18.1 to 38.1 months). Overall survival was significantly, although marginally, affected by primary tumor location. Median OS was 33.6 months for patients with LCC and 23.5 months for those with a RCC . A trend toward superior PFS was also observed for patients with LCC, but the difference was not statistically significant  , while median PFS was 10.7 vs 8.7 months .When the efficacy of anti-EGFR agents versus Bevacizumab was analyzed according to tumor location, patients with LCC treated with Cetuximab or Panitumumab had a significantly longer median OS  and PFS  , DCR (81.3% vs 65.7%), median OS (33.6 vs 23.5 months) and median PFS (11.6 vs 8.7 months) appear to be in line with those reported in previous studies. For example, post-hoc analyses of the CALGB/SWOG 80405 phase III trial of first-line FOLFIRI plus Cetuximab or Bevacizumab in patients with RAS wt mCRC, found that RCC is associated with a substantially reduced median OS (19.4 vs 34.2 months) as compared to LCC, which translate in about 40% increase in risk of death Similar findings were reported in a pooled analysis of five randomized trials of first-line treatment and one randomized trial of second-line treatment Another real-life retrospective study focusing on RAS wt mCRC has also found a superior OS for LCC as compared to RCC 42 vs 37 months), but this difference was not statistically significant likely due to the small number of patients, as acknowledged by the Authors  months, In our series, PFS and OS, the latter only numerically, were higher in patients treated with anti-EGFRs as compared to those receiving Bevacizumab, while no significant difference in response was observed. Although not significantly different from a statistical viewpoint, median OS values for left- versus right-sided tumors (34.6 vs 28.1 months) appear to be very similar to those reported for patients treated with FOLFIRI plus Cetuximab or Bevacizumab in the post-hoc analyses of the FIRE-3 trial restricted to the RAS wt subgroup of patients, in which, however, no difference in PFS was seen Superior median OS 41.3 vs 28.9 months) for patients treated with Fluorouracil, folinic acid, and Oxaliplatin (FOLFOX) plus Panitumumab as compared to those receiving FOLFOX plus Bevacizumab, have been reported also in the subgroup of RAS wt patients enrolled in the PEAK randomized phase II trial .9 monthsAmong RAS wt patients treated with anti-EGFR agents, we observed a significantly superior OS for those with primary tumor located on the lift side, with a trend toward superiority for PFS. Similarly, in the retrospective analyses of the CRYSTAL and FIRE-3 The fact that, differently from what we observed for anti-EGFR antibodies, the efficacy of Bevacizumab was not influenced by primary tumor location, may possibly indicate a predictive effect of primary tumor location. Indeed, when efficacy of anti-EGFR agents was compared to that of Bevacizumab after stratification by site of primary tumor, we found that the former were associated with a significant advantage in median OS (40.7 vs 28.6 months) and PFS (12.4 vs 10.7) in the group of patients with LCC, while no difference was observed in those with RCC.A comparison of the two biological types of RAS wt tumors according to sidedness has been reported in retrospective analyses of FIRE-3 Reasons for the discrepancies among these studies are largely speculative. However, it has been suggested that the more frequent use of Bevacizumab beyond progression in the CALGB trial as compared to FIRE-3 may give a survival advantage to patients treated with this monoclonal antibody in first-line, thus explaining their higher survival observed in the former study It is believed that the prognostic and predictive effect associated with the site of the primary tumor descend from distinctive biological characteristics, rather than simply from the different embryological origin of the right and left side of the colon. From a molecular view point, mutations in the APC, SMAD4, TP53, and KRAS genes are more frequently described for LCC For its retrospective nature, our study has some limitations. In a small group of patients (8%), testing of RAS status was limited to KRAS exon 2. Therefore, it cannot be excluded that some RAS mutant cases have been misclassified as wild-type. In addition, all cases with a tumor in the transverse colon were included in the right-sided group, since from the clinical records it was not possible to distinguish those originating in the distal third of transverse colon that should have been included in the left-side-group. It should also be noted that the study did not account for the possible different policy adopted for the timing of response assessment at the participating institutions, which may have affected estimation of PFS. Moreover, it was not possible to analyze the cancer-specific survival because the cause of death was not always found in the clinical records. Assessment of BRAF status is not usually performed in routine clinical practice, and its unavailability surely represents one of the main limitations of our study. Given that BRAF mutation prevents response to anti-EGFR monoclonal antibodies Nevertheless, our study is one of the few real-life studies that have specifically addressed the prognostic and predictive role of tumor sidedness in RAS wt mCRC patients treated in first-line with a combination of chemotherapy plus anti-EGFR agents or Bevacizumab.Our findings support the notion that in this population of patients from the real-world setting response to anti-EGFR agents and prognosis are significantly influenced by tumor sidedness. In particular, we observed significantly more favorable outcomes following administration of Cetuximab or Panitumumab compared with Bevacizumab in combination with chemotherapy for the treatment of LCC. Conversely, no significant differences emerged in patients' outcomes by category of biological agents for RCC.


Warfarin is the standard of care and NOAC  are a group of newer drugs for such purposes. NOAC has a generally better profile . However, its efficacy on valvular atrial fibrillation remains unclear.2 Test. The bias of studies was first tested by examining the symmetry of Funnel Plot. Cochrane’s Collaboration Tool was also used to report any presented bias.We researched literature articles from Embase, Cochrane and PubMed. Then we meta-analysed these six articles to assess pooled estimate of relative risk (RR) and 95% confidence intervals (Cl) using random-effects model for stroke, systemic embolic event, major bleeding and all-cause mortality. Heterogeneity across study was tested with Cochran’s Q Test and IWe collected 496 articles in total and finally we included six articles in our meta-analysis. For SSEE , the pooled relative risk showed a significantly better clinical outcome of NOAC . However, there is no significant difference in major bleeding  and all-cause mortality .Compared to Warfarin, NOAC is significantly more protective against the embolic event, but no significant difference in lowering risk of major bleeding, all-cause mortality or all aspects of post-TAVI .The online version of this article (10.1186/s12872-019-1089-0) contains supplementary material, which is available to authorized users. Valvular heart disease (VHD) can increase the risk of stroke, atrial fibrillation (AF) and systemic embolic events (SSEE) , therefoHowever, recent studies implied that NOAC can also reduce the risk of SSEE in patients with valvular heart diseases. The RE-LY  trial with dabigatran , the ROCTherefore, we would like to assess the outcome differences between NOACs and VKA in VHD patients with larger sample sizes by joint analysis of several different types of trials. We planned to focus on the VHD patients that have undergone valvular replacement surgery to evaluate the efficacy and safety outcomes. For this reason, we performed this meta-analysis of available comparative trials of NOACs versus VKA to compare the clinical outcomes of NOACs with VKA on management of valvular heart diseases.This meta-analysis was planned and conducted under the statements for study design, data analysis and reporting of meta-analyses of RCT that are currently available and widely adopted. We adopted the protocol for systematic reviews and meta-analyses developed by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) in order to improve the quality of the study .For the type of studies, we included data from all published Controlled Intervention Studies that available for public access. We excluded all non-english studies, unfinished studies (before Phase III) and certain types of literature . For the types of participants, we included patients with significant valvular heart disease (SVD). Significant valvular heart diseases are defined by follow characteristics  includinWe included specific efficacy outcome measures, namely Stroke, Systemic Embolic Event and all-cause mortality , and ISTWe searched for all published Controlled Intervention Studies with results available for public access from the Cochrane, Embase and PubMed until 9 December 2018 under the following searching strategy listed in the Additional file Four authors independently participated and completed the initial title and abstract screening. We then retrieved full texts for the studies that were eligible. We resolved disagreements by meeting with all authors. The selection process is documented in a PRISMA  flow diagram in Fig. Four authors independently extracted data from all the eligible studies included. When data from a trial had been published more than once, it will be only extracted once. Disagreements between review authors were resolved by consensus after formal meetings.Data item for extraction of study characteristics were classified into two categories. First, regarding baseline characteristics which include first author, year of publication, study design, age, number of included individuals and disease status of participants in each group. Secondly, for outcome analysis, the characteristics include the followings: (1) Number of patients with and without SSEE in both groups, (2) Patient with and without major bleeding in both groups, (3) Deceased and survived patient in both groups respectively.2 tests for heterogeneity among all studies [2 > 50% for the presence of heterogeneity, and I2 > 70% high heterogeneity. Subgroup and sensitivity analyses were conducted.These articles were analysed for statistical heterogeneity. We used Cochran’s Q test, I studies . We used2 > 50%), BDL random-effects model has better performance on small meta-analysis [2 test to test for the heterogeneity.Meta-analysis for a particular factor is performed using STATA version 14.0 MP. The principal summary measures are computed based on Relative Risk (RR) and 95% Confidence Interval (95% CI). Individual data were pooled using the Bootstrapped DerSimonian-Laird (BDL) random-effects model with 1000 repetition. The reason for using a BDL model is because of the data having significant heterogeneity  . If asymWe retrieved 347 citations from EmBase, 115 citations from Cochrane, 32 citations from PubMed and included two citations from manual search. We exported those retrieved citations to EndNote X8 for further analysis. The software automatically identified 484 non-duplicated articles. According to the pre-specified selection criteria, we were able to exclude 467 articles based on the title and abstract of those studies. We performed a full-text screening on remained articles, which excluded ten more articles according to the selection criteria. Then, we extracted data from eight eligible articles. At the data extraction process, we excluded one more article as the article did not provide the desired data. Finally, we included six articles. Figure The detail study characteristics are shown in Tables The meta-analysis aimed at comparing efficacy outcomes and safety outcomes of NOACs and Warfarin by conducting subgroup analysis, stratified by Valvular Heart Disease (VHD) and Transcatheter Aortic Valve Implantation (TAVI). The efficacy outcomes of interest for this meta-analysis were Stroke and Systemic Embolic Event, and all-cause death. Due to the data in ROCKET-AF RCT were not wholly documented in one article, data from the two articles were pooled for analysis.2, around an “overall” true effect therefore a random-effect model was used to address for this issue [The primary meta-analysis included 2438 patients received apixaban 5 mg twice a day and 2370 patients received warfarin titrated to INR 2.0 to 3.0 who were enrolled in ARISTOTLE trial; 1869 patients received edoxaban 60 mg once a day, and 955 patients received warfarin titrated to INR 2.0 to 3.0 who were enrolled in ENGAGE AF-TIMI 48 trial; 2646 patients received dabigatran 110 mg and 150 mg once a day, and 652 patients received warfarin titrated to INR 2.0 to 3.0 who were enrolled in RE-LY trial; 939 patients received rivaroxaban 20 mg once a day, and 1001 patients received warfarin titrated to INR 2.0 to 3.0 who were enrolled in ROCKET-AF trial; 141 patients received apixaban, and 131 patients received phenprocoumon who were enrolled in a trial conducted by Seeger et al. in 2017; 154 patients received NOAC, and 172 patients received warfarin titrated to INR 2.0 to 3.0 who were enrolled in a trial conducted by Geis et al. in 2018, the details of number of patient in each group is listed in Table Visual inspection of the funnel plot Fig.  for each2 > 50%, Cochran’s Q test P-value < 0.05), the value for each test are listed in Tables The result showed that there was a statistically significant heterogeneity across all three focused outcomes (I2 = 62.70%). For ISTH Major Bleeding, only ENGAGE AF-TIMI 48 and RE-LY trials showed the protective effect of NOACs are more significant than that in warfarin, and the ENGAGE AF-TIMI 48 trial showed higher RR than that in RE-LY . In contrast, other four trials showed no significant difference in effect of NOACs compared with the warfarin group. The overall result in Major Bleeding showed there was no significant effect favouring NOACs or VKA . The heterogeneity I2 test was performed and showed that heterogeneity across studies have a great chance of affect the pooled RR (I2 = 87.89%). For All-Cause-Mortality, only RE-LY trial showed the more significant protective effect of NOACs compared with warfarin , while other five trials showed no significant difference of the protective effect of NOACs compared with warfarin. In essence, the overall results of All-Cause-Mortality showed there was no significant difference in effect of NOACs compared with warfarin . The detailed data and corresponding forest plot is showed in Tables The main characteristics of patients in the included articles were shown in Tables Moreover, we also performed subgroup analysis of VHD-only group and post-TAVI group, to analysis more details about the effect of NOACs and warfarin under different patient characteristics. For subgroup of VHD, ARISTOTLE trial  and RE-LY trial  showed positive protective effect of NOACs than warfarin while ENGAGE AF-TIMI  and ROCKET-AF  showed negative results in event of SSEE. Also, the overall results  showed that there was a protective effect of NOACs compared with warfarin in SSEE event. For ISTH Major Bleeding in subgroup analysis of VHD, ENGAGE AF-TIMI 48 trial  and RE-LY trial  indicated NOAC was more protective than warfarin, whereas the overall results  showed negative protective results of NOACs and warfarin. For All-Cause-Mortality in the subgroup analysis of VHD, RE-LY trial indicated that there was a positive protective effect of NOACs compared with warfarin . However, the overall results of four trials included in subgroup analysis demonstrated no extra protective effect of NOAC . In the subgroup analysis of TAVI, Seeger trial indicated a stronger protective effect of NOACs than that in warfarin  but no effective protection in overall results . When it comes to ISTH Major Bleeding in subgroup TAVI, no statistical significance were portrayed between two trials . For All-Cause-Mortality in the subgroup of TAVI, both trials showed statistical insignificance between NOACs and warfarin .The subgroup analysis of VHD showed the same result as overall analysis with respective RR 0.652 and 0.665, 95% CI: 0.457, 0.930 vs 95% CI: 0.468, 0.945, which the value of each dataset were similar and indicated almost the same result between overall and subgroup analysis. However, there are several factors can influence the consequence: the change of population of each trial, different methodology, and different baseline characteristics of patients can lead to the variation of the analysis result.From our analysis, the superiority of NOACs over warfarin in reducing the rate of stroke and systemic embolic events is consistent with previous studies , 19, 20.According to our analysis of various trials, RE-LY Trial demonstrated the trend that NOAC exhibited the most significant benefit when compared with other selected trials. At the same time, the RE-LY trial showed NOAC superiority in reducing SSEE, major bleeding and all-cause mortality. The explanation was unknown, but several reasons may be responsible. Focusing on the study design, the main characteristic of the RE-LY Trial was the selection of dabigatran. Not similar to other NOAC, dabigatran acts as a direct thrombin inhibitor. However, whether this mechanism exerts an additional protective effect on VHD required further investigations. However, some patients co-administered with amiodarone may enhance the effect of dabigatran . The druOn the contrary, an indirect comparison of dabigatran and other NOAC was performed in this study. Besides, RE-LY Trial is an open-label trial, which may exert some influence in the intervention group. Nonetheless, more studies were required to confirm the superiority of dabigatran.Since NOAC has been introduced to anti-coagulating therapy, its role in valvular surgery has been investigated. RE-ALIGN trial has explored the efficacy of dabigatran in patients with mechanical valves. However, major bleeding, as well as embolic events, were significantly higher than the control group , and henAlthough NOAC has been proven to be harmful on mechanical valve, its effect on bioprosthetic valve has been questioned. Among the selected trials, ENGAGE AF-TIMI 48 and ARISTOTLE included bioprosthetic valve replacement as eligible candidates, but analysis of NOAC effect on valve surgery has not been clearly stated . Thus, aThe exact mechanism of corresponding findings was unknown, but some researchers , 26 repoWith the results from this meta-analysis, NOAC was shown to be more beneficial in lowering the chance of stroke and systemic embolic event in VHD except for post-TAVI patients. Till now, warfarin remained to be the main anti-coagulant for VHD and valve surgery , 24. WarNo universal consensus has been made regarding the definition of valvular heart diseases until now, though 2014 AHA/ACC/HRS guideline stated the definition of non-valvular diseases as the absence of rheumatic mitral stenosis, mechanical/Bioprosthetic heart valve or mitral valve repair . As statOn the other hand, the choice of valve materials of patients undergoing valve surgery  with anticoagulation may have a variable effect on the prognosis. VHD is a broad category of different cardiac conditions that may have entirely different aetiologies, pathogenesis, treatments and prognosis. There is insufficient literature focusing on the sub-groups analysis .On top of that, limited classification or access of VHD sub-groups in both intervention and control group is one of the possible barriers of further data analysis , 10. DueSeveral studies investigating NOAC and Warfarin on AF with VHD were selected to perform a meta-analysis. NOAC was shown to be superior to warfarin in reducing stroke and systemic embolic event in VHD but not major bleeding and all-cause mortality. Surgical sub-group regarding bioprosthetic TAVI were analysed among those studies revealed NOAC had no advantages over the warfarin group. Further trials about the VHD sub-groups and TAVI were necessary.The available evidences were not enough to provide a recommended agent of choice. We advise physicians choose the agent based on a case to case, individualized analysis of the valvular pathology, functional status of the patient and the socioeconomic status to provide a management plan that is most suitable to the patient.Additional file 1:Searching query. Searching query of Cochrane, EmBase and PubMed (DOCX 15 kb)


Background: Graves' disease is one of the most common autoimmune conditions, but treatment remains imperfect. This study explores the first-in-human use of antigen-specific immunotherapy with a combination of two thyrotropin receptor (TSHR) peptides (termed ATX-GD-59) in Graves' hyperthyroidism.Methods: Twelve participants  with previously untreated mild to moderate Graves' hyperthyroidism were enrolled in a Phase I open label trial to receive 10 doses of ATX-GD-59 administered intradermally over an 18-week period. Adverse events, tolerability, changes in serum free thyroid hormones, and TSHR autoantibodies were measured.Results: Ten subjects received all 10 doses of ATX-GD-59, five (50%) of whom had free triiodothyronine within the reference interval by the 18-week visit. Two further subjects had improved free thyroid hormones by the end of the study (7/10 responders), whereas three subjects showed worsening thyrotoxicosis during the study. Serum TSHR autoantibody concentrations reduced during the study and correlated with changes in free thyroid hormones . Mild injection-site swelling and pain were the most common adverse events.Conclusions: These preliminary data suggest that ATX-GD-59 is a safe and well-tolerated treatment. The improvement in free thyroid hormones in 70% of subjects receiving the medication suggests potential efficacy as a novel treatment for Graves' hyperthyroidism. Graves' disease (GD) is the most common cause of hyperthyroidism, and results from the production of autoantibodies that stimulate the cell-surface thyrotropin receptor (TSHR) . It affeThere have been no new treatment options for hyperthyroid patients with GD for >60 years . At presAntigen-specific immunotherapy, administering small amounts of antigens over time, often reinstates immune tolerance in allergy , but in ATX-GD-59 is an admixture of two soluble, synthetic peptides based on the sequence of the human TSHR that have been shown to function as apitopes in HLA-DR3 transgenic mice immunized with human TSHR . One pepHere, the results from an open-label Phase I study to assess the safety and biological activity of ATX-GD-59 in adult subjects with Graves' hyperthyroidism not currently treated with antithyroid therapy are reported for the first time.clinicaltrials.gov (NCT02973802) and approved by the East of England (Essex), Research Ethics Service (16/EE/0133). The full study protocol is available at www.daviad.euThis was an open-label study conducted at eight National Health Service endocrinology centers in the United Kingdom. The primary objective was to assess the safety and tolerability of intradermal (i.d.) administration of ATX-GD-59 in subjects with GD not currently treated with ATDs. Secondary outcomes were to explore biological activity, including changes in hormonal, immunological, and TSHR antibody levels, with treatment. The study was designed in full compliance with the ethical requirements set out in the Declaration of Helsinki  and the Eligible subjects were between 18 and 65 years of age with mild to moderately severe GD diagnosed by a physician from clinical and laboratory findings, and none had received prior treatment with ATD. Subjects had to carry at least one major histocompatibility complex (MHC) class II HLA-DRB1*15, HLA DRB1*03, or HLA DRB1*04 allele, and have quantifiable levels of TSHR antibodies, elevated levels of free triiodothyronine (fT3) and/or free thyroxine , and undetectable levels of thyrotropin (TSH) at screening. These MHC allelotypes have been demonstrated to bind the administered peptides . Men whoThis was an open-label study in which all participants received ATX-GD-59. The time course, titration schedule, and visits are shown in The first four subjects were recruited sequentially with a minimum of 48 hours between the first dose of each subject. Individual subject safety data were reviewed by the investigator and the medical monitor after the first dose of ATX-GD-59. Dosing of the remaining subjects only commenced once the first subject has received the second dose without safety concerns identified.During an eight-week period, the dose was titrated biweekly up to a final dose of 800 μg. Subjects were then maintained on the full dose for 10 weeks, followed by a 12-week safety and evaluation period off treatment.in vitro stimulation of a Chinese hamster ovary cell line expressing the TSHR , as described , serious AE including treatment-emergent serious adverse events (TESAE), and laboratory abnormalities assessed on an ongoing basis up to week 22. Secondary outcomes measures were serum fT3, fT4, and TSH concentrations assayed at a central site . Patients whose circulating thyroid hormone concentrations (fT4 or fT3) reduced during the dosing period compared to baseline measurements were designated as responders. Changes in TSHR antibody levels measured by both a TSHR antibody binding-inhibition assay  and by escribed , were alescribed .All AEs were recorded at each clinic visit and characterized by severity and relationship to the study drug according to Medical Dictionary for Regulatory Activities (MedDRA 19.1) terminology. The indication for the concomitant medications was recorded along with the dose and the period of therapy. During the dosing phase, subjects were observed in the clinic for at least two hours after administration of the study drug with regular monitoring of vital signs. Laboratory hematology, clinical chemistry, and urinalysis safety measurements were performed at all visits.Data are presented descriptively. Baseline, safety, and efficacy data are presented for the primary intention to treat (ITT) population, comprising all subjects who received one or more doses of study drug. Means ± standard deviation and medians (min–max) are presented as appropriate; changes from baseline are given as percentages. Correlations between change in thyroid function tests and TRAb levels were analyzed using the parametric Pearson's test. Outcome data were analyzed for all participants who received the full 10 doses of ATX-GD-59. For this Phase I study, no formal sample size calculation was performed.Out of the 28 subjects screened, 12 were enrolled in the study and received treatment. Due to enrolment time constraints, the estimated protocol target of 15 subjects was not achieved. The flow of participants is shown in A total of 11 subjects reported 311 TEAEs during the study, of which 180 were considered treatment related. A summary is provided in A single subject experienced three TESAEs on different occasions: nausea , vomiting , and atrial fibrillation . For each of these AEs, the categorization as serious was based on new or prolonged hospitalization for observation. Another subject developed first-degree heart block at week 4, which improved when concomitant propranolol was discontinued. One subject tested positive for antidrug antibodies at week 14 and remained positive at week 22. There were no accompanying clinical sequelae.The absolute levels of serum fT3 and fT4 for each subject are shown in p = 0.002 and p = 0.02, respectively; see p = 0.03), with a similar trend toward association with TSAb concentration (p = 0.11).Overall, there were reductions in both TBII and TSAb concentrations across the participant cohort over the study period, but they remained elevated in most subjects . There wHyperthyroidism in GD presents as a consequence of the direct effects of stimulating TSHR autoantibodies on thyroid function, rather than because of prolonged tissue damage or inflammation. Thus, unlike type 1 diabetes or Addison's disease, where it is estimated that 80–90% of the relevant functional endocrine tissue has already been destroyed before symptoms of hormonal deficiency occur ,25, GD mThe extracellular domain (ECD) of the TSHR is very well characterized as the target of both the humoral and cell-mediated autoimmune responses in GD , and preet al. reported spontaneous remission of Graves' hyperthyroidism in 2/21 patients treated with propranolol over a six-month period  and who might have few symptoms and a low risk of complications from thyrotoxicosis during the study. While this was a successful strategy, in that no patient needed ATD rescue therapy for symptomatic thyrotoxicosis before the final dose of ATX-GD-59, it does mean that these results should be considered as most relevant to GD patients with mild to moderate thyrotoxicosis at the moment. Another key issue is the potential for spontaneous remission of GD. McLarty h period . Subsequh period ,30. ThusGD is one of the commonest autoimmune disorders, and none of the current treatment options are ideal. In particular, ATDs are effective in producing long-term remission in only 50% of patients, and both thyroidectomy and radioiodine therapy lead to long-term medication dependence. Additionally, Graves' orbitopathy affects up to 40% of patients, and current management is unsatisfactory, with a significant minority being left with residual visual impairment, diplopia, or disfiguring changes to the appearance of their eyes. Emerging antigen-specific immunotherapies such as ATX-GD-59 hold several theoretical attractions for treatment of autoimmune, inflammatory, and allergic diseases ,31. As t


Previous studies have shown that the endoplasmic reticulum (ER)-anchored protein VAP is strictly required by human papillomavirus type 16 (HPV-16) for successful infectious entry. Entry appeared to be mediated in part through the induction of endosomal tubulation and subsequent transport of the virion to the trans-Golgi network (TGN). In this study, we were interested in investigating whether this mechanism of infectious entry is conserved across multiple Papillomavirus types. To do this, we analyzed the role of VAP and endosomal tubulation following infection with Pseudovirions (PsVs) derived from the alpha, beta, delta, kappa, and pi papillomavirus genera, reflecting viruses that are important human and animal pathogens. We demonstrate that VAP is essential for infection with all PV types analyzed. Furthermore, we find that VAP and EGFR-dependent endosomal tubulation is also induced by all these different Papillomaviruses. These results indicate an evolutionarily conserved requirement for VAP-induced endocytic tubulation during Papillomavirus infectious entry. The Papillomavirus family comprises over 200 different virus types, certain of which are responsible for the development of epithelial tumors and cancer  HeLa cells [generated using TALEN-based gene editing to abolish the expression of VAP-A and VAP-B; kindly provided by Pietro de Camilli , rabbit anti-α-actinin (Santa Cruz), mouse anti-VAP-B (Abcam) and mouse anti-pERK1/2 antibody  were used for immunofluorescence or western blotting. The EGFR-specific inhibitor PD168393 was purchased from Sigma-Aldrich.HPV-16, HPV-18, HPV-31, HPV-2, HPV-5, BPV-1, SfPV-1, and MmuPV-1 PsVs with a packaged luciferase reporter gene (pGL3 luci) were generated in HEK293TT cells as described previously  HeLa and VAP DKO cells were infected with diverse PsVs for 48 h at a multiplicity of infection (m.o.i.) of ~50 vge/cell. Infectivity was monitored by measuring the firefly luciferase activity using a luciferase assay system kit (Promega).To check the role of EGFR signaling in infection, HeLa cells were treated with 300 nM of the EGFR-specific inhibitor PD168393 for 30 min, or with DMSO as a control, prior to infection with 50 vge/cell. The inhibitor was maintained during the 48 h of infection and cell viability was >90%. The luciferase activity was monitored as a measure of infectivity 48 h post-infection, as described above.Twenty four hours after inhibitor application, cells were treated with 10 ng/ml of EGF for 15 min to confirm that the EGFR signaling is perturbed in response to the inhibitor. Cell lysates were then analyzed by western blot for levels of pERK1/2 expression.5 per well) were seeded in 6-well plates. Cells were infected with PsVs at 150 vge/cell, together with EdU-labeled reporter DNA, and agitated at 4°C for 1 h to allow virus attachment to the cells. Cells were then washed with phosphate-buffered saline (PBS), supplemented with DMEM, and incubated at 37°C for 2, 8, and 24 h post-infection. Cells were fixed with 3.7% paraformaldehyde for 15 min at room temperature. Immunofluorescence for MICAL-L1 was performed as described before  when VAP expression is knocked down, indicating that the VAP requirement for infectious entry of Papillomaviruses is evolutionarily highly conserved.In order to investigate the requirement of VAP for infectious entry with different Papillomavirus types, we performed a series of infection experiments using representative PsVs derived from genus alpha , genus beta (HPV-5), genus delta (BPV-1), genus kappa (SfPV-1), and genus pi (MmuPV-1), all of which carried a luciferase reporter construct and are enlisted in 3A, all the Papillomavirus types analyzed induced endosomal tubulation as early as 2 h post-infection in WT HeLa cells. This increased at 8 h post-infection and was reduced by 24 h post-infection, a pattern of endosomal tubulation very similar to that seen with HPV-16 PsVs. In contrast, when the same assays were performed in VAP DKO HeLa cells this tubulation was largely absent, confirming that the requirement for VAP in the induction of endosomal tubulation is conserved across multiple Papillomavirus types. The endosomal tubulation for each PsV in WT HeLa cells are quantified from three independent experiments and plotted in a bar graph  across the range of PsVs. In order to show that loss of tubulation in VAP DKO HeLa cells is not due to differences in the uptake of viruses, EdU was counted in WT and VAP DKO HeLa cells from three independent experiments at 2 h post-infection and shown in After establishing that VAP is required for the efficient infectious entry of these diverse Papillomavirus types, we were interested to know whether VAP also has a role in inducing endosomal tubulation, as was observed previously for HPV-16 infection .Previous studies have shown that loss of MICAL-L1 perturbs EGFR recycling back to the plasma membrane (Abou-Zeid et al., This suggests that EGFR signaling is required in the early stages of virus infection, most likely promoting virus endocytosis, which is in turn required for endosomal tubulation. However, once the virions have been endocytosed, the subsequent abrogation of EGFR signaling does not affect the endosomal tubulation process.Endocytic trafficking plays an essential role in the successful infectious entry of HPV-16, as it allows the transport of viral cargo from endosome to TGN, from whence it subsequently enters the nucleus. We had previously shown the induction of endosomal tubulation in response to HPV-16 PsVs infection, as indicated by MICAL-L1 imaging (Siddiqa et al., VAP provides the contact point between the ER and endosome. One aspect of these contact points is that they facilitate endosomal fission: when cargo-containing endosomal tubules or vesicles come into contact with the ER, they are marked by the retromer-associated protein FAM-21, which defines the time and position of endosomal fission (Rowland et al., MICAL-L1 is frequently used as a marker of endosomal tubulation (Sharma et al., Taken together, these results demonstrate a highly conserved role for endosomal-ER contact in infection with multiple Papillomavirus types, and suggest a highly conserved pathway of endosomal trafficking, via ER-associated vesicular processing, to ensure viral entry into the TGN.AS, LB, DP, and PM designed the experiments and analyzed the data. AS performed the experiments. AS and LB wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Clinical reasoning (CR) is a key learning domain for physical therapy educators and a core skill for entry-level practitioners. Integrated clinical experience (ICE) and problem-based learning (PBL) have each been reported to improve interpersonal and social domains, while promoting knowledge acquisition and CR. Unfortunately, studies monitoring CR during ICE with concurrent PBL in physical therapy education are sparse. We hypothesized that ICE with concurrent PBL would be associated with improved self-reported CR in third-year student physical therapists (PTs) in the United States. The Self-Assessment of Clinical Reflection and Reasoning (SACRR) survey was administered to 42 student PTs at the beginning and end of their third and final year of didactic training. Between the pretest and posttest analyses, the participants completed faculty-led ICE and PBL coursework for 16 weeks. The overall SACRR score and 26 individual item scores were examined. The Wilcoxon rank-sum test and paired t-test were used, with statistical significance accepted at P< 0.05. Significant improvements were observed in the overall SACRR score (P< 0.001), including 6 of the 26 survey items centered around decision-making based on experience and evidence, as well as self-reflection and reasoning. ICE with PBL was associated with improved self-assessed CR and reflection in third-year student PTs in the United States. Monitoring the impact of curricular design on CR may improve educators’ ability to enhance cognitive and psychomotor skills, which underscores the importance of increasing the explicit use of theoretical frameworks and teaching techniques for coping with uncertainty as a way of enhancing entry-level training. The aim to develop clinical reasoning (CR) in medicine and allied health trainees is resounding, particularly as health care becomes increasingly multifaceted across dynamic clinical practice settings ,2. SpeciAlthough integrated clinical experience (ICE) promoting CR has been part of medical training since the 1970s , the impA quasi-experimental nonrandomized pretest-posttest design was used with a convenience sample of 42 participating student PTs during their third and final year of didactic coursework in the Midwest of the United States. All participants completed informed consent following ethical approval granted by the university’s Institutional Review Board Ref# 238218). Students participated in two 8-week PBL courses, with concurrent ICE throughout. The ICE stemmed from a departmental-sponsored and faculty-supervised SRFC that provided pro bono physical therapy services 2 afternoons per week to underserved individuals within the community. Clients across the lifespan were treated, including those with neurologic and orthopedic diagnoses. Third-year students were paired with an underclassman and faculty supervisor for all clinical care. Simultaneously, the students completed two 8-week PBL courses with small-group case-based sessions totaling 6 hours per week for 16 weeks. Topics included the content areas of pediatrics, geriatrics, community-based practice, and mental health. The groups were small (limited to 6 students), with a local physical therapist or faculty member as a PBL tutor. After reaching conclusions regarding each case, students completed a clinical presentation using the International Classification of Functioning, Disability, and Health framework to disseminate their findings [8218. StuThe Self-Assessment of Clinical Reflection and Reasoning (SACRR) survey, with 26 items rated on a 5-point Likert scale, ranging from 5 (strongly agree) to 1 (strongly disagree), is a reliable and valid tool for examining students’ self-reported perceptions of CR development across multiple curricular designs in allied health training, including physical therapy ,9. The SUpon examining the SACRR pretest-posttest analysis for overall scores and individual items from third-year student PTs completing ICE with concurrent PBL coursework, the following results were found. The overall scores were normally distributed, demonstrating a statistically significant increase from 105.43± 7.18 to 109.40± 7.14 (P< 0.001). However, all 26 SACRR individual items demonstrated a non-normal distribution, so the Wilcoxon rank-sum test was used to analyze them. Of the 26 SACRR items, 6 demonstrated statistically significant improvements . These iThis study found that self-reported CR improved in third-year student PTs after completing ICE with concurrent PBL coursework, as shown by an increased overall SACRR score and improvements on 6 individual items . The iteFurthermore, in contrast to investigations that only demonstrated improved SACRR performance during full-time clinical rotations , this stAlthough ICE and PBL have benefits, several limitations have been noted . Recent Even though the overall SACRR scores improved, as well as those of 6 of the 26 items regarding decision-making based on experience and evidence and the promotion of self-reflection and reasoning, items associated with dealing with uncertainty and the incorporation of theory into practice showed non-significant improvements. This reinforces previous calls ,3 for phThe limitations of this study include the fact that SACRR scores were self-reported, without objective measures of CR within the classroom or clinical setting. Additionally, the small sample size limits generalizability, and geographical and institutional differences in educational practice must be considered when transferring findings beyond student PTs in the Midwest of the United States. Furthermore, a more robust experimental design with randomized student assignment using a proper control group would enhance the value of this study, as the current design was quasi-experimental in nature.This investigation measured changes in the self-reported CR of 42 student PTs completing an ICE and concurrent PBL program during their third and final year of didactic training. Improvements in the overall SACRR score, as well as the item-level analyses, are consistent with previous investigations ,6,8,9, a


Globally, hypertension affects one billion people and disproportionately burdens low-and middle-income countries. Despite the high disease burden in sub-Saharan Africa, optimal care models for diagnosing and treating hypertension have not been established. Emergency departments (EDs) are frequently the first biomedical healthcare contact for many people in the region. ED encounters may offer a unique opportunity for identifying high risk patients and linking them to care.Between July 2017 and March 2018, we conducted a prospective cohort study among patients presenting to a tertiary care ED in northern Tanzania. We recruited adult patients with a triage blood pressure ≥ 140/90 mmHg in order to screen for hypertension. We explored knowledge, attitudes and practices for hypertension using a questionnaire, and assessed factors associated with successful follow-up. Hypertension was defined as a single blood pressure measurement ≥ 160/100 mmHg or a three-time average of ≥ 140/90 mmHg. Uncontrolled hypertension was defined as a three-time average measurement of ≥ 160/100 mmHg. Successful follow-up was defined as seeing an outpatient provider within one month of the ED visit.We enrolled 598 adults (mean age 59.6 years), of whom 539 (90.1%) completed the study. The majority (78.6%) of participants were aware of having hypertension. Many  had uncontrolled hypertension. Overall, only 236 (43.8%) of participants successfully followed-up within one month. Successful follow-up was associated with a greater understanding that hypertension requires lifelong treatment  and inversely associated with greater anxiety about the future .In a northern Tanzanian tertiary care ED, the burden of hypertension is high, with few patients receiving optimal outpatient care follow-up. Multi-disciplinary strategies are needed to improve linkage to care for high-risk patients from ED settings. Cardiovascular disease is the leading cause of global morbidity and mortality , 2. Sub-Over the past few decades, in an effort to build a sustainable health financing structure for non-communicable diseases such as hypertension, many SSA countries have made crucial changes to expand health insurance coverage and promote outpatient care . SpecifiIn locations like Tanzania, where the existing primary care system is poorly-equipped to manage the expanding hypertensive population, patients may ultimately end up seeking care in emergency departments (EDs) and inpatient settings. Several studies in high-income countries have established that the emergency department (ED) is an important venue to screen for hypertension, in part because a sustained elevated blood pressure in the ED is highly sensitive for hypertension –17. HoweTherefore, we conducted a study to determine the burden of elevated blood pressure in the ED and to explore the pathways of care in a high-risk population in Moshi, Tanzania.The study protocol was approved by Duke University Institutional Review Board (#Pro00081220), the Kilimanjaro Christian Medical College (KCMC) Ethics Committee (EC#502), and the National Institute for Medical Research in Tanzania. Written informed consent was obtained from all participants, and all participants with abnormal findings received information about their results and were instructed to follow up with an outpatient provider within two weeks to one month which is the current standard of care.The study was conducted between July 2017 and March 2018 in the ED of KCMC, which is located in Moshi, a town in the Kilimanjaro region  of northern Tanzania . The larKCMC is the referral hospital for northern Tanzania with over 630 beds and a regional training center . It servAll patients presenting to the ED are initially evaluated by a triage nurse and have their vital signs measured and recorded. Per the current head of emergency medicine at KCMC, all patients with elevated blood pressure who are discharged from the ED or the hospitial are instructed to follow-up in two weeks–one month with an outpatient provider.We recruited participants using trained research nurses who were bilingual Tanzanian natives. Inclusion criteria were: adults (age ≥ 18 years old) with a measured initial triage systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mmHg. All adults presenting to the ED during the morning or evening shifts (8AM to 11PM) were recruited. Pregnant females (measured by urine human chorionic gonadotropin) and adults unable to be surveyed due to the severity of their illness or injury were excluded.The primary study outcome was defined as self-reported attendance at an outpatient provider within one month following discharge from initial ED visit. We estimated that a sample size of 600 would detect a 10% difference in proportions (assuming 95% power and precision of 0.05) between the follow-up and non-follow-up cohorts. We anticipated a 40% loss to follow-up rate based on previous studies in this setting .Initially, we included a pilot week of night shifts with a plan to stop if overall patient volume was low. Due to very low total patient volume at night (one patient recruited over one week), and study budget restraints, the night shifts were discontinued.After informed consent, study participants were verbally administered a demographic and medical history questionnaire. The questionnaire was initially written in English and translated for administration in the local language of Swahili. A bilingual trained research nurse performed back translation of the questionnaire to verify content and review of the qualitative responses. Information gathered included age, gender, level of education, traditional medicine use, alcohol use, and tobacco use. If participants were receiving anti-hypertensive therapy, then specific drug information was collected. Women additionally gave information regarding pregnancy and menstruation history. Participants also completed a quantitative knowledge, attitudes, and practices (KAP) survey on hypertension. All instruments were adapted using previously validated surveys which were developed in Moshi, Tanzania, for chronic disease , 28.The research nurses measured blood pressure using an automated Omron HEM-712 sphygmomanometer , which has an adjustable cuff size. The machine was calibrated monthly during data collection. All participants were seated in an erect position with feet flat on the floor for a minimum of five minutes before measurements were obtained, per World Health Organization (WHO) protocol . Two bloHypertension was defined as a single systolic blood pressure measurement ≥ 160 mmHg, diastolic measurement ≥ 100 mmHg, or a three-time average measurement of ≥ 140 mmHg systolic or ≥ 90 mmHg diastolic, irrespective of treatment status. Uncontrolled hypertension was defined as a three-time average measurement of systolic ≥ 160 or diastolic ≥ 100 mmHg, irrespective of treatment status. Blood pressure definitions were chosen based on Tanzanian and Joint National Commision guidelines . HyperteA measure of end-organ damage was performed using a point of care urine dipstick to assess for proteinuria . A mid-sTo assess the primary outcome (self-reported attendance at an outpatient provider within 1 month following ED discharge), we made a 1-month post-ED follow-up phone call. At that time, patients were also asked to report any other forms of healthcare  and all current anti-hypertensive medications. We did not specifically ask what type of provider  was seen. A return visit to the ED did not qualify as an outpatient follow-up visit. To reduce non-response rates, we attempted a minimum of five additional phone calls during off-hours (evenings and weekends). When possible, data were triangulated with medical records to ensure accuracy.Data were collected on paper forms and entered into Redcap by a trained data entry technician . ApproxiThe mean and standard deviation (SD) were reported for continuous variables. Alternatively, when distributions were skewed, medians and inter-quartile ranges (IQRs) were used. Differences in likelihood of follow-up for hypertension were compared using chi-square or Fisher’s exact test for categorical variables with cell counts with fewer than 5 expected observations. Prevalence was estimated by dividing the total number of hypertensive patients by the total number of ED patients.a priori assumptions about potential upstream causal association with lifestyle-related risk factors.To explore associations between hypertension risk factors and predictors of follow-up after ED visit, crude and adjusted risk ratios (RR) were estimated using generalized linear models with a log link. Separate regression models to make adjusted bivariate comparisons were fitted to follow-up status for each lifestyle-related variable, including alcohol use, tobacco use, traditional medicine use, and current antihypertensive use. Separate regression models were also fitted with responses to all KAP questions regarding patient knowledge, attitudes, and practices. All models were adjusted for confounding factors potentially associated with hypertension, including age, gender, and ethnicity. We did not include education or occupation in our models due to From July 2017 to January 2018, 7442 total patients (adults and children) were triaged in the ED during recruitment shifts (8AM -11PM) . Of the Of the 539 participants who completed the study, the median age was 61 years (IQR 52–70) . The majOf the 539 participants who completed the study, mean systolic blood pressure was 168.8 mmHg (SD 20.8 mmHg) and mean diastolic blood pressure was 100.4 mmHg (SD 12.0 mmHg). All enrolled patients met the study definition of hypertension, and most participants  were aware of having a previous diagnosis of hypertension. Most  were also currently being treated with anti-hypertensive medication. Nonetheless, 200 patients (37.1%) had uncontrolled hypertension, and 235 (43.6%) participants had evidence of proteinuria, suggestive of microvascular end-organ damage. Among all ED patients (n = 7442), 2423 (32.6%) presented to the ED solely to obtain prescription refills for anti-hypertensive medications.Of those without a pre-existing diagnosis of hypertension (n = 147), the most common chief complaint was headache , followed by abdominal pain . In total, 13 patients from this group were admitted to the hospital and the most common admission diagnosis was hypertensive emergency . Of those without a pre-existing diagnosis of hypertension (147 patients), the majority  reported they were given a diagnosis of hypertension by their outpatient provider at the follow-up visit.Only 44% of patients reported follow up with an outpatient medical provider within the month following their ED visit. When comparing individuals who did and did not complete follow-up, no statistically significant (p>0.05) differences in sociodemographic characteristics were observed, including gender, age, ethnicity, or family size . AdditioParticipants reported cost  as a major barrier to follow-up care for their hypertension . ParticiIn an ED-setting in northern Tanzania, we observed a high burden of elevated blood pressure, with substantial proportions of both uncontrolled hypertension and proteinuria. Additionally, we observed a large proportion of individuals seeking routine prescription refills for anti-hypertensive medications in the ED setting. Despite the high burden, follow-up rates from the ED were low, and anxiety about a future with hypertension was associated with lack of follow-up care.To our knowledge, this is the first study in SSA to quantify the burden of elevated blood pressure in an ED setting, and it is among the first to explore follow-up care pathways. The alarmingly high proportion (37%) of patients with uncontrolled hypertension is consistent with other studies in Tanzania demonstrating as many as half of all patients diagnosed with hypertension have uncontrolled blood pressure , 31–33. Recent studies have demonstrated that a single hypertensive event in the ED is an independent risk factor for major adverse cardiovascular events . CriticaThe large proportion of individuals using the ED for routine blood pressure treatment was also alarming and higher than utilization rates observed in high-income countries such as the United States (24–29%) and the United Kingdom (18%) , 41, 42.Given the high ED burden of hypertension and the proven benefit of follow-up care, ED settings must take a proactive role in ensuring successful outpatient follow-up. Based on the results of our study, we have identified two potential targets: patient education and reduction of access barriers. Patient education that includes both disease-specific information and general medical literacy may alleviate fears and misconceptions surrounding hypertension , 44, whiIn contrast, sustainable and affordable outpatient care is a more complex goal that will likely necessitate the involvement of stakeholders, including government and industry sponsors . Given tOur study had several limitations. Importantly, the time interval for follow-up was brief (one month), and it is unclear if patients continued to be adherent to treatment and care after this period. However, our goal was to determine if providers and patients adhered to international and Tanzanian guidelines for initial follow-up interval (two weeks–one month) , 12. SecIn an ED-based sample of adults in northern Tanzania, we observed a high burden of elevated blood pressure, with high rates of uncontrolled disease and end-organ damage. The majority of patients with hypertension did not present for outpatient follow-up care, and both cost and fears about the diagnosis appeared to be major barriers to follow-up care. Novel patient-centered interventions are needed to develop pathways to care to curb the substantial burden of poorly controlled hypertension in the region.S1 File(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table*Adjusted for age, gender, and ethnicity.(DOCX)Click here for additional data file.