It has been suggested that the phenotypes of Behçet’s disease (BD) in Japan are changing. To ask whether the evolution of BD holds true in recent-onset cases in Japan, we performed a retrospective study.We reviewed the records of 578 patients with BD who met the 1987 revised diagnostic criteria of the Behçet’s disease research committee of Japan. The patients were divided into three groups based on the date of disease onset. We compared the demography, clinical features, and treatments among them with or without adjustment for the observation period. Patients having oral ulcers, genital ulcers, regional skin involvement, and uveitis are categorized as having complete-type BD, and the associated factors were determined by univariate and multivariate logistic regression analyses.Male patients had a higher propensity for uveitis and central nervous system (CNS) involvement, whereas female patients had higher rates of genital ulcers and arthritis. We found a significant trend in reduction of complete-type, genital ulcer, HLA-B51 carriers, and increment of gastrointestinal BD over time. Multiple regression analysis identified HLA-B51 positivity, earlier date of disease onset, and younger age of onset as independently associated with complete-type BD. Although treatments had been also chronologically changed, the causative relationship between therapeutic agents and phenotypical changes was not determined from the study.The present study revealed that phenotypical evolution was characterized by decreased incidence of the complete type and increment of gastrointestinal involvement in Japanese patients with BD during the last 30 years.The online version of this article (doi:10.1186/s13075-016-1115-x) contains supplementary material, which is available to authorized users. Streptococcus sanguinis and herpes simplex have been implicated in BD pathogenesis [Behçet’s disease (BD) is an inflammatory disease of unknown cause, affecting multiple organs such as eyes, skin, mucosa, and brain . A definogenesis , 3, and ogenesis . Moreoveogenesis , 6. It iEpidemiological studies from Japan and Korea have shown that the prevalence of BD, particularly of patients with serious manifestations, is decreasing –9. We prThe patients who participated in the study met the 1987 revised diagnostic criteria of the Behçet’s disease research committee, the Ministry of Health, Labor and Welfare of Japan . These pUnder the Japanese criteria, recurrent aphthous oral ulcers, skin lesions, ocular inflammation, and genital ulcers are included in “major symptoms”, whereas arthritis, intestinal ulcers, epididymitis, vascular lesions, and neuropsychiatric disease are included under “minor symptoms”. The criteria classify clinical subtypes into complete and incomplete types. The former includes patients with all four major symptoms during the clinical course, whereas the latter includes those having three major symptoms, two major and wo minor symptoms, typical recurrent ocular inflammation and one or more major symptoms, or typical recurrent ocular inflammation and two minor symptoms. Moreover, patients with central nervous system (CNS) involvement, vascular, and gastrointestinal (GI) region involvement were categorized as having special-type BD, and were further defined as the neurologic type, vascular type, and GI type, respectively.To reduce the heterogeneity of patients with BD and to be comparable with other BD studies, we also applied International Study Group (ISG) criteria to our patients . We extrt test. Univariate and forward stepwise multivariate logistic regression analysis was performed with presence of complete-type BD as the dependent variable. Sex and age of BD onset were forced into into the model. Variables that were significant in univariate analysis were further included in the multivariate analysis. A p value less than 0.05 was considered as statistically significant.Statistical analysis was performed with GraphPad Prism 6  and SPSS version 22 . Categorical variables were analyzed using the chi-square test or Cochran–Armitage test. Continuous variables were analyzed using the Student We first carefully examined patients’ records and identified 578 patients who met the 1987 revised Japanese BD diagnostic criteria, including 412 patients reported in the previous paper [As mentioned earlier, we had divided the patients into two groups of patients diagnosed before 2000 and those diagnosed between 2000 and 2007, in the previous paper . Therefop = 0.025 compared p = 0.13 for male patients), this symptom was still more common in female than in male patients.In our previous study the clinical picture was of BD evolving even after achieving the definitive diagnosis and of patients with a longer history of BD presenting with more manifestations . Thus, wAll patients met the Japanese criteria in this study, but 61 patients (10.6 %) did not meet the ISG criteria Table .The frequency of patients with the GI type of BD have been recently increasing. We and others have shown that these patients have a lower frequency of HLA-B51 positivity, complete-type disease, and uveitis , 15, sugp = 0.062).A meta-analysis has shown that HLA-B51 is associated with male predominance and moderately higher prevalence of genital ulcers, skin involvement, ocular involvement, and decreased prevalence of GI involvement . TherefoIn the current study, patients were arbitrarily segmented into three groups based on disease onset, which may have resulted in skewed outcomes. In addition, multiple factors mutually contribute to the reduced rates of complete-type BD. To identify factors independently associated with complete-type BD, we performed univariate and multivariate logistic regression analyses, with the complete type as a dependent variable. In multivariate analysis, young age of onset, HLA-B51 positivity, and earlier date of diagnosis were independently associated with risk of developing complete-type BD Table .Table 4UChange of treatment strategies, especially use of biologic agents, during the last two decades could have profound effects on the phenotypes of BD, as azathioprine has been suggested to modify the natural clinical course . In JapaIt is also possible that earlier detection of BD may lead to early intervention, resulting in a milder disease phenotype. However, there was no difference among the groups in the age of disease onset. Moreover, we have collected data on the use of prednisolone, colchicine, azathioprine, calcineurin inhibitors, methotrexate, and non-steroidal anti-inflammatory drugs (NSAIDs) in 456 patients for whom treatment data were available. As shown in Additional file In the present study, we observed a continuous reduction in complete-type BD in our district since the previous report in 2007 . MoreoveThe reduction in HLA-B51-positive BD patients in our cohort is intriguing. This phenomenon is difficult to explain, because the pathogenic role of HLA-B51 in the development of BD is not fully understood. Rather, our data suggest that interaction between HLA-B51-restricted immune responses and external factors is involved in the disease process, and that altered environmental factors attenuate the immune responses, resulting in reduced prevalence and phenotypical changes to mild forms in HLA-B51-positive individuals. Besides detailed molecular analysis, clinical observations as in this study may also contribute to understanding the pathogenesis of BD.Several lines of evidence suggest that both genetic and environmental factors are involved in the pathogenesis of BD. An epidemiological study of immigration supports the hypothesis that BD has a primarily hereditary basis , while oStreptococcus sanguinis provoke inflammation in BD [As for environmental factors, microbial pathogens are implicated in the development of BD . Previouon in BD , 23–25. on in BD . Intereson in BD , though BD flares are often caused by bacterial infection and after dental care, also suggesting oral flora involvement in the BD process , 29. MorThe present study showed that the factor most strongly attributing to reduction in complete type BD was genital ulcers, especially in female patients. Because it is likely that the decrease in prevalence of genital ulcers is caused by environmental factors, identification of the causative factors would give us a good clue in understanding the pathogenesis of BD.The ISG criteria are one of the most commonly applied in BD studies . The ISGConsistent with previous studies, we found that the GI type was the only manifestation that increased among the serious phenotypes. The most apparent difference between the Japanese criteria and the ISG criteria lies in the presence of the GI type. Our previous paper reported that Japanese patients with GI-type BD fulfilled the ISG criteria at a lower rate compared with those with the non-GI type (with the GI type 70 % vs. 92 % without the GI type) . It is sIL23R and IL10 have been identified in GWAS of BD [It has long been recognized that the incidence of inflammatory bowel disease (IBD) such as Crohn’s disease is rising in many countries, and may be attributed to change to a high-fat diet . In JapaAS of BD , which aIncrement of GI involvement was associated with increased use of NSAIDs, suggesting that NSAIDs may be a risk factor for GI involvement in BD and in IBD. However, as significant association has been identified between GI involvement and arthritis , NSAIDs In our cohort, chronological changes in therapy could have affected the phenotypes and clinical course of disease. However, care should be taken to interpret the data because of possible bias caused by incomplete data collection, particularly in the early days. Moreover, the clinical diversity of BD makes it difficult to assess the disease-modifying effect of each therapeutic agent. It is hard to determine whether a particular symptom does not appear as a natural course or whether it has been suppressed by the preceding therapy. Moreover, because most treatments were determined by the attending physicians, the therapeutic scenario was not consistent in patients having a particular symptom, even on the same date.Although we were unable to show significant effects of biologic treatment on the evolution of the BD phenotype, it is possible that immunosuppressive treatment prevented subsequent development of the complete-type and special-type BD. In a placebo-controlled trial of azathioprine, vascular involvement developed more frequently in the placebo group . In addiThere are several limitations in the study. First, the data were retrospectively collected, therefore were subject to selection bias. Second, data on important epidemiological factors such as smoking status, changes in diet, and body mass index were not available in all the patients. Third, because treatments were principally determined by the individual attending physicians and were not necessarily consistent among the patients, it was hard to assess the influence of therapeutic regimens on disease manifestations.Our cohort study showed that a reduced rate of complete-type and increased rate of GI-type BD are continuous trends in East Asia. Because the genetic background was consistently homogeneous in our study population, it is likely that the time-dependent changes were caused by environmental factors. Identification of causative factors would give a clue in the establishment of novel strategies to modify the clinical course and suppress disease flares as prophylactic medicine.


Introduction: Zika virus could be transmitted in the state of Queensland, Australia, in parts of the state where the mosquito vectors are established.Methods: We assessed the epidemic potential of Zika in Queensland from January 2015 to August 2016, and estimate the epidemic potential from September to December 2016, by calculating the temperature-dependent relative vectorial capacity (rVc), based on empirical and estimated parameters.Results: Through 2015, we estimated a rVc of 0.119, 0.152, 0.170, and 0.175, respectively in the major cities of Brisbane, Rockhampton, Cairns, and Townsville. From January to August 2016, the epidemic potential trend was similar to 2015, however the highest epidemic potential was in Cairns. During September to November 2016, the epidemic potential is consistently the highest in Cairns, followed by Townsville, Rockhampton and Brisbane. Then, from November to December 2016, Townsville has the highest estimated epidemic potential.Discussion: We demonstrate using a vectorial capacity model that ZIKV could have been locally transmitted in Queensland, Australia during 2015 and 2016. ZIKV remains a threat to Australia for the upcoming summer, during the Brazilian Carnival season, when the abundance of vectors is relatively high. Understanding the epidemic potential of local ZIKV transmission will allow better management of threats to blood safety and assessment of public health risk. In 2015, Zika virus (ZIKV) emerged throughout the Americas and in February 2016, the World Health Organization declared ZIKV a public health emergency of international concern.Aedes aegypti and Aedes albopictus mosquitoes, vectors of dengue and chikungunya viruses. ZIKV can also be transmitted from mother to fetus, through sexual contact and via blood transfusion,ZIKV is principally transmitted from infected Ae. aegypti is present, ZIKV could be locally transmitted if imported. Between 2012 and 7 October 2016, 36 of the 76 confirmed ZIKV infections in travelers notified nationally were reported from QueenslandIn north and central Queensland, Australia, where  Study AreaAe. aegypti is well established; and, Brisbane, the state capital, where there is no evidence of Ae. aegypti since the 1950sAe. aegypti is present in regions of Queensland that are only a few hundred km north of Brisbane (e.g. township of Gin-Gin).Four cities in Queensland were selected: Cairns, Townsville and, Rockhampton, which share current potential risk of Zika transmission as Data SetMonthly minimum and maximum temperatures (°C) from January 2015 to August 2016 inclusive, were retrieved from the Australian Bureau of MeteorologyMonthly predictions of the maximum and minimum temperature medians for September to December 2016 based on historical values were used to estimate the corresponding mean temperature mediansEstimation of Zika Epidemic PotentialrVc) represents the vector’s ability to spread disease among humans relative to the vector-to-human population ratioThe relative vectorial capacity (a) the average daily vector biting rate; T) temperature;h b) the probability of vector-to-human transmission per bite; mb) the probability of human-to-vector infection per bite; µm) the vector mortality rate; n) the duration of extrinsic incubation period n, and equation 3, as a comparison, with all parameters specific to DENV.We performed three relative vectorial capacity calculations, equation 1 and 2 with a varying Equation 1: Formula 1) with the average n equal to 7, based on Chouin-Carneiro et al. (2016), Li et al. (2012), and Hall-Mendelin et al. (2016). Hereafter referred to as7 rVc.Equation 2: Formula 1) with the average n equal to 10, based on Boorman and Porterfield (1956). Hereafter referred to as 10rVc.Equation 3: Formula 1) based on the DENV-specific parameters from Liu-Helmersson et al. (2014). Hereafter named (T)denguerVc. rVc. Forecasts for future monthly epidemic potential in September-December 2016 were estimated as described above. We then compared the results from equations 1 and 2 using an analysis of variance (ANOVA), with the null hypothesis being that the mean of the relative vectorial capacity remains the same for both scenarios.Monthly epidemic potentials and range from equations 1, 2, and 3 were calculated for each city. For January 2015-August 2016, mean maximum and minimum temperatures each month were used for calculations ofThreshold Value for the Epidemic PotentialrVc^ for an epidemic to take place is defined by:The threshold value Th) for ZIKV are still ongoing, a recent study of 297 PCR-confirmed clinical cases in French Polynesia estimated Th to last for four to seven days,Th of 5.5 days, and assuming that the human-to-mosquito ratio, m, equals 1, the rVc^ must be larger than 0.18  per day for a Zika outbreak to occur. As an uncertainty analysis, we used the variability range of the infectious period  to estimate the range of the threshold value for the epidemic potential.Although analyses of the infectious period (rVc from equations 1 (rVc7), 2 (rVc10) and 3 (rVc(T)dengue) are presented in rVc(T)dengue is consistently higher than rVc7 and rVc10 throughout the study period in Townsville and Cairns  of 0.119 in Brisbane, 0.152 in Rockhampton, 0.170 in Cairns, and 0.175 in Townsville. Throughout 2015, the lowest rVc7 was estimated for Brisbane. When compared with Townsville, the estimated rVc7 in Cairns was lower from January to April and October to December 2015, but higher during the rest of the year , Brisbane would also become suitable for ZIKV transmission during the warmer months and Rockhampton, Townsville and Cairns, would have a longer potential transmission season for ZIKV. If, however, Th is equal to four days (rVc = 0.25 day-1), none of these cities would be suitable for ZIKV transmission. When the threshold value rVc varies within , the suitability for each city to transmit ZIKV might change  to allow more accurate estimates of the epidemic potential for ZIKV in Australia.While estimates are preliminary, these analyses point to the importance of further investigations of the infectious period as well as the infection and transmission rates of ZIKV and Australian mosquitoes (The Rio de Janeiro 2016 Olympics (5–21 August 2016) and the Paralympic Games (7–18 September 2016) were the two most prominent mass gathering events to take place in the Americas since the emergence of ZIKV in this region. A large number of visitors attended these events,,Our study considered only the risk posed by vector-mediated transmission and did not include consideration of the potential for sexual transmissionMore importantly, ZIKV poses a particular challenge in that 80% of cases have no symptoms, and thus would not be detected by a syndromic surveillance systemWolbachia, which is currently being released in Cairns and Townsville regions as a research field trial)Ae. aegypti from Brisbane since the 1950s, and detect any incursions from the nearby endemic regions of Queensland. ZIKV transmission through blood transfusion is possible. Therefore, this virus poses a threat directly to blood safety, and indirectly on donor attendance.Vector-borne transmission of ZIKV is expected to have a similar seasonal pattern to that of dengue and chikungunya, with lower transmission in winter. Nonetheless, the potential for vector-mediated transmission in the absence of overt cases due to asymptomatic infections will likely require a shift of focus for health authorities from emergency response currently effective for dengue case notifications toward broad-scale preventative programs, and emerging control methodologies , who are traveling to Queensland where the vector is established, should follow the precautions and recommendations issued by their national health authorities. In north and parts of central Queensland where the vectors are present, immediate reporting of clinically suspected cases of ZIKV infection to local public health units is critical.Elvina Viennet: eviennet@redcrossblood.org.auThe authors have declared that there are no competing interests.All relevant data have been made available in the figshare repository (DOI: 10.6084/m9.figshare.3993981).


Acute periradicular abscess is a condition characterized by the formation and propagation of pus in the periapical tissues and generally associated with debilitating pain.The aim of this study was to compare the overall analgesic effectiveness of two combinations of opioid and non-opioid analgesics for acute periradicular abscess.This study included 26 patients who sought emergency care in a Brazilian dental school. The patients were randomly divided into two groups: Co/Ac - oral prescription of codeine (30 mg) plus acetaminophen (500 mg), every 4 h, for 3 days or Tr/Ac - oral prescription of tramadol hydrochloride (37.5 mg) plus acetaminophen (500 mg) on the same schedule. Two factors were evaluated: (1) pain scores recorded by the patients in a pain diary 6, 12, 24, 48, and 72 h after treatment, using the Visual Analogue Scale; and (2) the occurrence of adverse effects.In both groups, there was a reduction in pain scores over time. For the Co/Ac group, there was a significant reduction in the scores 12, 24, 48, and 72 hours after treatment (P<0.05). In the Tr/Ac group, the scores significantly decreased over time from time point 6 h (P<0.05). Comparing the pain at each time point, the groups were not significantly different (P>0.05), i.e., both treatments were effective in controlling pain caused by APA; however, the combination of Tr/Ac caused more adverse reactions as two patients had to stop using the medication.This study suggests that, considering both analgesic efficacy and safety, the combination of codeine and acetaminophen is more effective to control moderate to severe pain from acute periradicular abscesses. Clinical signs include swelling, edema and it is generally associated with debilitating pain,,In the treatment of APA, besides the local clinical approach, which relies on surgical access and/or root canal debridement and provide pus drainage, a systemic medication oncoming that involves the use of analgesics and antibiotics is also considered. Antibiotics can be prescribed as a complementary measure especially for abscesses associated with systemic involvement, including fever, malaise and lymphadenopathy; disseminating infections resulting in cellulitis, progressive diffuse swelling, and/or trismus; and abscesses in medically compromised patients at increased risk of a secondary infection following bacteremiaCodeine/acetaminophen is the most frequently used drug combination due to its efficacy and safety for the management of moderate-to-severe acute painThis study was approved by the Ethics Committee of the Federal University of Rio Grande do Sul (12671913.1.0000.5347).This double-blind, codeine/acetaminophen-controlled parallel design clinical trial was conducted following the Consolidated Standards of Reporting Trials (CONSORT) 2010 guideline. The sample consisted of APA patients who sought emergency care at the dental school of the Federal University of Rio Grande do Sul. Diagnosis was established based on clinical and radiographic findings. Classic symptoms of APA were obtained after subjective expressions reported by the patient.per group in order to observe a significant difference among groups.Sample size was calculated based on the outcome of Mehrvarzfar, et al.Patients eligible for inclusion in the experiment included 18+ years-old adults diagnosed with APA and reporting spontaneous pain greater than 40 mm as measured in the 0-100 mm Visual Analogue Scale (VAS) (moderate to severe pain)All endodontic procedures, performed by the same investigator (M.F.S.) were standardized. Anesthesia was induced with 2% lidocaine with epinephrine 1:100,000. Pulpal chamber was accessed under rubber dam isolation. Next, septic-toxic contents were neutralized with K files #08,10 or 15  and 2.5% sodium hypochlorite (NaOCl) . Then, the coronal portions of the canals were enlarged with a LA Axxess drill  and the work length was electronically determined by the apex locator Apex DSP . The apical part of each root canal was prepared to a size 25 K-file using a crown down technique. The canals were profusely rinsed with 5 mL of 2.5% NaOCl and dried with paper points. A sterilized cotton pellet was placed in the access cavity and subsequently restored with the glass ionomer cement Vitro Fil . Finally, the occlusion was checked.After the first appointment, the patient signed a consent form outlining the procedure and its possible risks. Subsequently, patients were allocated to one of the following groups: Co/Ac, which received one fixed-dose oral tablet containing codeine/acetaminophen (30 mg/500 mg) every 4 hours for 3 days, or Tr/Ac, which received one fixed-dose oral tablet containing tramadol/acetaminophen (37.5 mg/325 mg) every 4 hours for 3 days. Instructions on how to perform the pain recordings using the VAS were given to each patient. An assistant accompanied the patients while the first dose of medication was taken.The patients received a pain diary, containing the VAS, and a sealed package with the other doses of medication. If patients experienced pain that was not controlled by the tested medications, they were instructed to take additional medication  using under an on-demand scheme.Four days after the first visit, the patient returned the pain diary. To indirectly check adherence to the treatment plan, patients were also asked to return the medication package. Numerical values obtained at each time point  for each patient were recorded.In cases that drainage was not possible or in the presence of systemic symptoms , 21 amoxicillin capsules (500 mg) were prescribed and given orally every 8 hours for 7 days.The random allocation sequence was performed using random table numbers generated at randomizer. org. A pharmacist encapsulated the drugs in identical capsules, and packaged in white bottles numbered 1 to 26. Information on drug administration was described on the label. An assistant who was blinded to the aim and the protocol of the study generated the numbers using a spreadsheet program (Microsoft Excel).The primary outcome was the pain scores. They were obtained using VAS before and after the first appointment. Secondary outcomes included frequency of additional medication use and adverse reactions reported by patients. All information was registered in the pain diary by the patient.The Number Needed to Harm (NNH), i.e., the number of patients receiving Tr/Ac treatment to cause one additional patient to be harmed, compared with patients who received Co/Ac treatment was also calculated.The analyses were performed on an intention-to-treat basis. All statistical analyses were performed using SPSS v.18.0 .th and 75th percentiles.Descriptive statistics were performed, with presentation of data as absolute and relative frequencies, median and 25Student's t-test for independent samples was used to determine differences between the mean ages for each group. The Chi-square test was used to verify differences between the groups regarding gender, tooth type, antibiotic use and frequency of adverse reactions. Mann-Whitney U test was used to identify the difference between the mean initial pain scores between groups.The two groups were compared considering a score-based evaluation in the same time interval using the Mann-Whitney U procedure. Friedman test was used to compare the results over time within the same group, followed by the multiple comparison test of Friedman when needed. Differences were considered significant at P=0.05From April 2013 to December 2014, 27 patients were evaluated as potential study participants. Twenty-six patients met the inclusion criteria and agreed to participate in the clinical trial. Out of these 26 patients, three from the Co/Ac group and one from the Tr/Ac group did not return the pain diary and were excluded from the study. Two patients from the Tr/Ac group showed worsening clinical status, sought care elsewhere and also did not return the pain diary. Two patients from the Tr/Ac group dropped out of treatment due to the occurrence of adverse reactions that impaired their daily activities and were excluded from analysis of pain scores, but not from analysis of adverse effects . The numth and 75th percentile pain scores at each time point are shown in In both groups, pain scores decreased over time. in the Co/Ac group, pain reduction was significant at 12, 24, 48 and 72 hours compared to baseline (P<0.05). The scores at 48 and 72 hours were also lower than the 6 hours scores (P<0.05). In the Tr/Ac group, pain scores decreased in all experimental time points compared to baseline (P<0.05). The median, 25Forty percent of patients in each group used the additional drug, a number that is not different between the groups (P≈0.999). An average of 1.5 and 1.6 additional tablets per patient was used in the Co/Ac and Tr/Ac groups, respectively.There was no difference between the groups regarding the frequency of adverse reactions (P≈0.999). Eight patients (80%) from each group experienced at least one adverse reaction, including dizziness, drowsiness, nausea, headache, vomiting and others . The NNH,,,The combined use of analgesics is indicated to control pain of moderate to severe intensityThe maximum daily dosage of paracetamol is 4 grams, bearing in mind that, after the administration of 1 g, the analgesic effect wears off within an average of 6 hours. This dosage must not be exceeded, even if it becomes necessary to reduce the interval between two doses to 4 hoursIn a meta-analysis that used third molar extraction as a pain model,In the present study, no difference between the analgesic combinations with respect to pain relief was observed over 72 hours (P>0.05). Both Co/Ac and Tr/Ac treatments were able to decrease the pain scores over time. Therefore, the hypothesis set was partially accepted. In a study by Smith, et al.The frequency of additional drug use was also not a discriminating factor among groups. In both groups, four patients (40%) took additional acetaminophen. Endodontic literature lacks information about the use of additional drugs in controlling pain of endodontic origin. Some studies in other fields have measured the use of additional drugs as a way to evaluate analgesic efficacy. Da Costa-Araujo, et al.In this study, both groups presented similar frequency of adverse reactions, which is in line with the findings of Smith, et al.Opioid analgesics are useful agents for treating pain of various etiologies, however, adverse effects are potential limitations to their use. In a systematic review, Moore, et al.,,,,Most clinical trials have assessed the management of endodontic pain using a single oral dose schemeDuring the phase of abscess development, the pus is aiming to reach the exterior through the bone or periodontal tissue, which explains the pain reported by the patient. Prostration and pain lead the patient to the clinic, however, this situation does not happen and then this clinical condition remains for several days regardless the use of analgesics and antibioticsP>0.05).It is also important to emphasize that the analysis was performed on an intention-to-treat basis, as referred in the methodology. Our aim was to provide external validity to the study, since in clinical practice analgesics are prescribed to patients developing abscess that use antibiotics or not. Nevertheless, frequency of antibiotics use comparison was performed in both groups, since this could cause confusion when analyzing the analgesic response . In homoTherefore, the identification of a systemic therapy that presents an overall analgesic effectiveness as measured by its analgesic efficiency and safety is an important clinical subject to improve treatment quality of acute endodonticallyabscessed patients.The present randomized clinical trial indicated that Tr/Ac and Co/Ac treatment presented similar analgesic efficacy when used to control pain caused by APA However, Tr/Ac has a worse safety profile than Co/ Ac, resulting in a greater frequency of abandoning treatment due to ineffectiveness or intolerance to adverse effects.


Diagnosis of oral complications in the dialysis patients is important to prevent potential infections. The aim of this cross-sectional study was to compare oral findings in dialysis patients with healthy individuals and determination of the correlation of these findings and laboratory tests.In this cross-sectional study, DMFT, dmft, DI , CI , OHIS , PI, GI and enamel defects were evaluated in 25 hemodialysis patients, 30 peritoneal dialysis patients and 26 healthy individuals. Then the correlation of laboratory tests  and oral findings was determined in each groups using SPSS (Version 16). Data analyzed with One-way ANOVA test, Chi-Square , Kruskal-Wallis , Tukey’s test and Fisher’s-Exact test.Findings revealed significant differences in dmft, DI, CI, OHIs, PI and GI between study groups. A positive correlation between Ca and DI was found in hemodialysis group. In peritoneal dialysis group positive significant correlations between DMFT index and Urea, Cr , ALP and K , between OHIs and K , between PI and Cr and negative correlations between Na and CI and OHIs were found.Presence of oral problems in dialysis patients, especially hemodialysis, indicate the necessity of appropriate therapeutic considerations in these patients. The correlation of blood biochemical compounds and oral status in dialysis patients may warn clinicians to control the level of the biochemical blood compounds for oral health improvement. Key words:Hemodialysis, laboratory tests, oral findings, peritoneal dialysis. Chronic renal failure (CRF) is caused by chronic progressive destruction of nephrons occurring over several years. While renal failure is usually caused by congenital nephropathy and obstructive uropathy in children under five years, after this age glomerular disease or hereditary disorders are common causes . The cauThe presence of oral infection may act as a focus of infection in other areas of the body in patients undergoing dialysis or transplantation whose immune system has been suppressed . Recent Review of available literature indicates that most studies have been done on adult patients with renal disease and there are scare studies on children with CRF. Also, to the best of our knowledge, no study has been done on the relationship between laboratory tests and oral indicators. Therefore, the purpose of this study is to investigate the relationship between oral findings and laboratory tests in children and adolescents undergoing hemodialysis and peritoneal dialysis.In this cross-sectional study, 25 patients undergoing hemodialysis (aged six to 26 years) and 30 peritoneal dialysis patients (aged eight months to 22 years) were selected from a pediatric hospital in Mashhad, Iran, with convenience sampling method. The hemodialysis group (HD) consisted of 13 girls and 12 boys and peritoneal dialysis group (PD) consisted of 13 girls and 17 boys. All patients had end-stage renal failure diagnosed by a nephrologist and were undergoing dialysis in a pediatric hospital in Mashhad, Iran. Twenty-six healthy subjects (without any other systemic disease) with an age range of one to 26 years were recruited from patients referred to Mashhad Dental School. This group, as a control group, consisted of 12 girls and 14 boys and was almost identical to both the study groups in terms of age, gender and social status. The study protocol was approved by the ethics committee of Mashhad University of Medical Sciences, Iran. After a brief explanation of the treatment process an informed consent document was taken from each patient’s parent / legal guardian.Examination was carried out by an examiner under enough light and with sterile disposable sets including an explorer and an oral mirror as well as WHO probe for periodontal examination. The hemodialysis patients were examined before dialysis and receiving heparin, as receiving heparin may cause prolonged gingival bleeding during BOP evaluation for gingival index.In each case, first the presence or absence of specific enamel defects was determined. Then caries experience index in permanent (DMFT) and primary teeth (dmft)  and oralOHI-s comprises Debris Index (DI) and Calculus Index (CI) on six selected tooth surfaces  in six specific teeth. The surface area covered by calculus or debris was determined using an explorer along each tooth surface. The debris scores as well as calculus score were totaled and divided by the number of surfaces scored to measure DI and CI respectively.Finally, all data related to oral health were recorded in the check list. Then, laboratory tests including Hg, ALP, Ca, Ph, Na, K, Cr and Urea were recorded in all subjects. All blood tests in patients undergoing hemodialysis and peritoneal dialysis were performed in the laboratory of Dr. Sheikh Hospital, Mashhad, Iran. In children aged less than three years, due to lack of cooperation, only dmft, enamel defects and PI  were studied. The children were examined only by observation with the naked eye. In the presence or absence of dental plaque score 1 and 2 were given, respectively. The numbers obtained were divided by the number of teeth examined and the result was as PI in each individual.-Statistical analysis:For all statistical analysis software SPSS (version 16 ) was used. Kolmogrov-Smirnov was used to verify normality of the data for age. One-way ANOVA was used to compare age in study groups and Chi-Square Test was used to assess distribution of gender in each groups. One-way ANOVA test and Kruskal-Wallis were used to compare the oral finding indices and laboratory tests in the study groups. For the comparison between the two groups, Tukey’s test was used. To assess the frequency of enamel defects in each study groups Fisher’s-Exact test was used. Pearson correlation coefficient was used to determine the relationship between oral findings indices and laboratory tests.P<0.001). Tukey’s test showed that the mean age of patients in the hemodialysis group was significantly higher than peritoneal dialysis (P<0.001) and control group (P = 0.024), while the mean age in the peritoneal dialysis and control group is not significantly different from each other. Chi-Square Test also showed that the relative frequency distribution of gender among the three groups was not statistically significant.One-way ANOVA test revealed that there was no significant difference in mean age between study groups (P = 0.002) and control groups (P = 0.016), but showed no significant difference between peritoneal dialysis and control groups.The One-way ANOVA showed that DMFT among the study groups was not significantly different, but the highest value was observed in the hemodialysis group and the lowest in the control group. Kruskal-Wallis Test showed that dmft was significantly higher in hemodialysis than peritoneal dialysis (P = 0.032 and P = 0. 049 respectively). Both of these variables are also lower in healthy subjects than peritoneal dialysis patients and in the peritoneal dialysis group than in the hemodialysis group, but these differences were not statistically significant. PI was also significantly higher in the hemodialysis group than in peritoneal dialysis and control groups (P<0.001). OHI-S in the control group was significantly lower than in peritoneal dialysis (P = 0.038) and hemodialysis (P = 0.001) groups. However, no significant difference between the hemodialysis and peritoneal dialysis groups was observed. Man-Whitney test revealed that CI in the control group was significantly lower than in peritoneal dialysis (P = 0.022) and hemodialysis (P = 0.001) groups. However, the difference between hemodialysis and peritoneal dialysis groups was not significant  Association between oral findings and laboratory tests in the hemodialysis groupThe results regarding the correlation between caries experience index in primary and permanent dentition and oral health indices with laboratory tests in each of the study groups, after identifying the data for normality and based on the Pearson correlation coefficient (r), are the following:a. The DMFT and dmft were not correlated significantly with any of the laboratory tests.b. The oral health indices were poorly correlated with the laboratory tests.P = 0.025)  .B) Association between oral findings and laboratory tests in the peritoneal dialysis groupa. There is no significant correlation between dmft and none of the laboratory tests.P = 0.002), Cr, (P = 0.024), ALP (P = 0.014) and K (P = 0.003).b. DMFT was significantly increased with increasing in Urea, (c. CI (P = 0.032) and OHI-S (P = 0.047) significantly decreased with increasing in Na.P = 0.043).d. OHI-S significantly increased with increasing of K(P = 0.004)  .C) Association between oral findings and laboratory tests in the control groupP=0.001)  .b. The presence of enamel defects was not significantly associated with any of the laboratory tests.In the present study, the correlation between oral findings in dialysis patients and blood components were studied. As anemia is one of the signs associated with CRF, hemoglobin was selected and other laboratory tests also revealed the function status of kidney.Findings revealed that highest value of DMFT and dmft was in the hemodialysis group and the lowest value was in the peritoneal dialysis group. However, these differences were not statistically significant and these findings were in agreement with previous studies -16. Low In peritoneal dialysis patients, in addition to high Urea and Phosphate in saliva compared to control subjects, quality of life is almost similar to healthy subjects due to less dependence on dialysis centers and it may result in lower value of DMFT and dmft indices in these patients compared with both groups .In the present study, DMFT is decreased by increasing Ca in the hemodialysis group; however, this correlation is not significant. This may be attributed to the role of Ca in enamel maturation and its preservative effect. However, Turtola  reportedP = 0.02, r = 0.53). Increase in Cr was also associated with dmft in hemodialysis and peritoneal dialysis groups in this study. One of the possible causes for a closer and more consonant effect of Cr in oral findings, in comparison to Urea and other blood elements, is the fact that Cr is solely dependent on renal function status. So, in the case of dehydration, due to increased tubular reabsorption, more Urea is reabsorbed in the kidneys, while Cr has no reabsorption in any circumstances. Also, during gastrointestinal bleeding or intake of protein-rich diet, the level of serum Urea increases due to more ammoniac production. Hence, Urea is also influenced by factors other than kidney function . However, other studies found different results (Similar to previous studies ,19,21, i results . In thes results . They alSalivary composition may not completely similar to serum composition. Also, because of probable effect of serum composition on enamel defects, further long-term research with larger sample size is suggested. Besides, evaluation of the correlation of oral findings with salivary biochemical composition in the time of tooth germ formation is recommended.As patients undergoing dialysis, especially hemodialysis, have more oral complications than control subjects, the necessity of appropriate treatment considerations and oral hygiene improvement is more predominant in these patients. The correlation of some biochemical blood constituents with oral findings in dialysis patients may help the clinicians in prescribing necessary blood laboratory tests. On the other hand, these correlations warn the physician to balance and control the level of these laboratory tests better than before in order to improve the status of oral health.


Evaluate clinical aspects associated with the presence of nocturnal enuresis (NE) in children with a diagnosis of overactive bladder (OAB).A data base of 200 children who were evaluated by a structured questionnaire was analysed retrospectively . OAB was defined as the presence of urinary urgency (n=183 cases) and/or daytime urinary incontinence associated with holding maneuvers (n=168 cases). Inclusion criteria were a confirmed diagnosis of OAB, age 5-16 years, and no anatomical or neurological alterations of the urinary tract. Patients were divided into enuretics and non-enuretics. The two groups were compared with respect to sex, age, skin color, presence urinary infection, urgency, urge incontinence, non-urge incontinence, pollakiuria, urinary dysfunction, nocturia, holding maneuvers, number of episodes of enuresis and bowel alterations. In a univariate analysis, the chi-square test was used to compare proportions, with p-values <0.05 being considered significant. A multivariate analysis was conducted to identify independent predictive factors.Enuresis was diagnosed in 141/200 children. The two groups were similar with respect to sex, age and skin color. No difference was found in relation to urinary infection, non-urge incontinence, urinary dysfunction, nocturia, encopresis or constipation. The two groups were significantly different with regard to some symptoms related to OAB such as urgency (p=0.001), urge incontinency (p=0.001) and holding maneuvers (p=0.033). Following multivariate analysis, only holding maneuvers (p=0.022) remained as an independent predictive factor.The only independent predictive factor for resolution of enuresis in children with OAB, as detected in the multivariate analysis, was holding maneuvers. The International Children's Continence Society classifies enuresis as monosymptomatic (MSE) when bedwetting is the only symptom and non-monosymptomatic (non-MSE) when lower urinary tract symptoms (LUTS) are present . EnuresiDifferentiating between the types of enuresis (MSE and non-MSE) is relevant because the physiopathology and management may not be the same for the two conditions. Non-MSE is more commonly associated with urinary tract infections (UTI), vesicoureteral reflux, constipation and behavioral problems , 12. ParA database of 200 children who were evaluated by a structured questionnaire was analyzed retrospectively. OAB was defined as the presence of urgency (n=183 cases) and/or daytime incontinence (n=168 cases). The inclusion criteria were a confirmed diagnosis of OAB, age between 5 and 16 years and the absence of any anatomical alterations or neurogenic disorders of the lower urinary tract. Patients for whom the database information was incomplete, and those who had recorded fewer than 4 voids per day in the bladder diary were excluded from the study. The internal review board of the Escola Bahiana de Medicina e Saúde Pública approved the study protocol under reference number 12141113.0.0000.5544.A structured questionnaire was administered to all the patients to obtain the following information: demographic data , number of voids, the presence of nocturnal enuresis (and its intensity), daytime incontinence (and its intensity), nocturia, urgency, straining, holding maneuvers, constipation (in accordance with the Rome III criteria), and a history of UTI confirmed by culture. Daytime incontinence was classified as urge or non-urge incontinence. Daytime incontinence and enuresis were classified according to intensity as daily, three times a week or more, less than three times a week or occasional.Holding maneuvers were considered present when the child's parents reported typical body posturing such as squeezing the genitals, crossing the legs, going on tiptoe or squatting on the heel (Vincent's curtsy). All patients underwent uroflowmetry plus electromyography. Dysfunctional voiding was defined as an abnormal voiding pattern in the uroflow curve and activity on electromyography . Only 85 patients completed a 3-day bladder diary. The association between enuresis and the number of voids, the presence of daytime incontinence, and constipation was evaluated. Patients with and without enuresis were compared with respect to the presence of all the aforementioned clinical variables.The SPSS software program, version 20.0 was used throughout analysis. In a univariate analysis, the chi-square test was used to compare proportions, with p-values <0.05 being considered statistically significant. Multivariate analysis was conducted for identifying the independent predictor variables. The variables that were significant in the univariate analysis were consecutively added to a multivariate hierarchical model, which started with a simple predictor.Of the 200 children with a diagnosis of OAB, 84 were boys (42%) and 116 girls (58%). Age ranged from 5 to 16 years, with a mean of 8.6±2.9 years. NE was diagnosed in 141 children (70.5%). Of these children, 83 (58.9%) were female. The mean age of the children with enuresis was 8.6±2.7 years, while the mean age of those without enuresis was 8.6±3.2 years (p=0.831). In 112 patients (80.6%), NE occurred at least three times a week. NE rate of 68% (n=87) in children ≤9 years and 75% (n=54) in those 10 years of age or older.Regarding the demographic characteristics of the enuretic and non-enuretic patients with OAB , no statThe clinical characteristics of both groups are showed in Few studies have dealt with the subject of non-monosymptomatic NE. Since the principal complaint of families generally concerns nocturnal enuresis, daytime complaints are often undervalued and forgotten, hampering the implementation of appropriate treatment. In some cases, parents may even be unaware of daytime symptoms, since the frantic rhythm of modern life tends to leave parents with less time to participate in the day-to-day routine of their child's life. Nocturnal enuresis causes problems with socialization, resulting in low self-esteem and stress both of the child and the family. In addition, NE has been found to be associated with behavioral alterations such as attention-deficit/hyperactivity disorder .In the present sample, enuresis was shown to be a common symptom in patients with OAB, occurring in 70.5% of cases. Despite the extent to which NE distresses parents, little attention has been paid to factors potentially associated with NE in patients with LUTS. A better understanding of this relationship may help identify possible factors associated with more severe conditions. Consequently, physicians will be able to act more effectively by implementing more individualized treatments. When performing the clinical assessment of NE, physicians have frequently neglected daytime symptoms. To the best of our knowledge, this study is innovative in that an inverse analysis was used, i.e. the presence of enuresis was investigated in patients with symptoms of OAB.In this series of patients, both the daytime urinary symptoms and enuresis were more common in girls. This finding in children with overactive bladder differs from cases of monosymptomatic NE, which tend to be more common in boys. In a study conducted with a group of 51 patients, Naseri et al. confirmed an association between enuresis and daytime incontinence, and reported twice as many girls being affected as boys . In the The frequency of monosymptomatic enuresis tends to decrease progressively with age until reaching a rate of 0.5 to 1% in adults. In cases of nonmonosymptomatic enuresis, however, some studies have shown that this does not occur, with the frequency of enuresis tending to remain the same in older children, possibly as a consequence of the mechanisms involved in overactive bladder , 12, 15.Children and adolescents with symptoms of overactive bladder should be investigated for nocturnal enuresis, principally in the presence of holding maneuvers. The present results suggest that one of the principal mechanisms involved in non-MSE is nocturnal overactive bladder, given that the abovementioned symptoms are characteristic of this condition. The hypothesis that these children may have more difficulty waking up than non-enuretic children has to be investigated, since the involvement of assorted physio-pathological mechanisms cannot be discarded. Furthermore, the psychological impact of NE in children with OAB, and the influence of NE in rendering prognosis poorer in these patients are factors that remain to be evaluated. It is important to note that it has been found a higher rate of psychiatric disorders in children who postpone voidind with holding maneuvers . FurtherConstipation and bowel problems are often associated with urinary tract abnormalities and 90 (46.4%) of the patients in this series had at least one complaint. Nevertheless, the groups of enuretic and non-enuretic patients were not significantly different with respect to these symptoms. None of the other clinical characteristics of the patients with lower urinary tract dysfunction were found to be associated with NE. Factors such as the presence of urinary tract infection, irrespective of the number of episodes, and nocturia were not found to be significantly associated with enuresis.This study has some limitations. For example, the subjective nature of the symptoms may have led to interpretation errors. Moreover, the severity of enuresis was assessed based on the responses provided by parents and children rather than by analyzing the number of dry nights recorded on a chart. However, to the best of our knowledge, although the association of OAB in patients with NE has been studied extensively, the association of NE in patients with OAB has not. The results of the present study may shed more light on the actual rate of enuresis in children with OAB and on the profile of patients who are more prone to enuresis, thus opening perspectives for new studies. The impact of enuresis on both the patients with OAB and their caregivers remains to be evaluated. Nevertheless, understanding this impact is relevant since more than half of the patients present with this symptom. Furthermore, those patients with OAB who would benefit from a simultaneous treatment for enuresis should be clearly identified.NE and OAB are commonly associated, with NE being present in 70.5% of children with OAB. In this study on children with overactive bladder, daytime urinary symptoms and non-monosymptomatic enuresis were both more common in girls. No reduction in enuresis was found with increasing age. Therefore, as long as overactive bladder and, consequently, daytime symptoms remain untreated, there will be no improvement in nocturnal symptoms. Of the OAB symptoms, only holding maneuvers were found to be associated with enuresis as an independent predictive factor. This suggests that when these daytime symptoms are present, OAB and NE probably share the same genesis.


Female genital mutilation/cutting (FGM/C) is a common harmful traditional practice in many communities in Africa and to a lesser extent in Middle East and other regions in the world. In order to better understand publishing on this topic, we conducted a bibliometric study on FGM/C. Bibliometric analyses can be used as an indicator of the extent of interaction of researchers, health authorities, and communities with a particular health issue.Scopus database was used to retrieve data on FGM/C. Keywords used were “female genital mutilation”, “female genital circumcision”, “female genital cutting” and “female circumcision”. Specifically, the number of publications, top productive countries and institutions, highly cited articles, citation analysis, co-authorships, international collaboration, role of African countries, top active authors, and journals involved in publishing articles on FGM/C were reviewed and analyzed. We indirectly assessed the impact of publications using total number of citations received, average number of citations per article, Hirsch-index, percentage of highly cited articles, and journal’s impact factor.One thousand and thirty-five publications on FGM/C were retrieved. The h-index of retrieved articles was 37. A steep rise in number of publications was noticed in mid-1990s and again in 2012. More than half of retrieved articles were published from 2006 – 2015. A total of 65 countries contributed. The top ten productive countries included ones from Northern America, Europe and Africa. Nigeria and Egypt were the most active African countries in FGM/C publications. At least nine African academic institutions were actively involved on FGM/C publications. Articles on FGM/C that received the highest number of citations were those that focused on negative physical and psychosexual consequences of FGM/C. Journal topic areas were obstetrics/gynecology, public health, and psychological sociology. Collaboration between African and European countries on FGM/C research was evident.Bibliometric analysis reveals that research publications on FGM/C have been increasing since the l970s, with collaboration between African and Western countries, and articles are being published in higher impact journals, not only obstetrics, but also public health and social sciences. FGM/C research can be helpful to international health agencies and governments not only to document negative outcomes, but also to identify best practices, and to note gaps in implementation and practice. Female genital mutilation/cutting (FGM/C) is a common practice in many African and some Middle Eastern countries, as well as among some migrant groups in the United States of America (USA), Canada, Europe, and Australia. In addition to its potential serious acute and/or chronic health consequences, FGM/C is considered a violation of human rights. This study was carried out to assess worldwide research productivity on FGM/C, which can be used as an indicator of the extent of interaction of researchers, health authorities, and communities with a particular health issue. Our results showed that research productivity on FGM/C has increased markedly in the last two decades. African countries and institutions, particularly those in Nigeria and Egypt, had a noticeable number of publications. Many African countries contributed to FGM/C publications through international collaboration. Articles on FGM/C with the highest number of citations were those that focused on negative physical and mental health consequences of girls and women who were subjected to FGM/C. Many articles on FGM/C were published in gynecology/obstetrics journals, but also in public health and social sciences. Publications on FGM/C appeared in highly influential and prestigious journals emphasizing the international dimension and importance of this topic as a global public health issue.Female genital mutilation/cutting (FGM/C) is a traditional practice that involves intentional removal of some or all of the external female genitalia for non-therapeutic purposes and with no health benefits for females . There aBibliometric analysis is a statistical tool used to assess the quantity and quality of publications, as well as the extent of success and achievements accomplished on a certain topic , 11. BibA literature search using Google Scholar, Pubmed, and Scopus for the period 1980 – 2016 found no bibliometric analysis or assessment of research output on FGM/C. The number of articles published on FGM/C from any particular country may be an indicator of how common this practice is in that country. On the other hand, the absence of publications on FGM/C from any particular country might suggest the absence of this practice. Therefore, bibliometric analysis of the source of research on FGM/C could be a tool for geographically mapping this traditional practice. We carried out this bibliometric study to assess the growth of publications, active countries and institutions, highly cited articles, citation analysis, co-authorships, international collaboration, role of African countries, top active authors, and journals involved in publishing articles on FGM/C to determine if it is indeed recognized as a growing public health problem.The methodology used in this study has been previously described in published bibliometric studies , 17. DifKeywords used to retrieve data included all terms used in literature to describe female genital mutilation. Such terms include “female genital cutting”, “female genital circumcision”, “female circumcision” and “female genital mutilation”. Search of these terms was confined to title search. Quotation marks were used to increase accuracy of search query. The time limit of the study was set from 1900 – 2015. Retrieved documents were limited to journal articles. Books, book chapters, and errata documents were all excluded. Retrieved data were analyzed for types of published documents, language, annual research productivity, top ten productive countries, institutions, citation analysis, collaboration analysis, top active authors and highly cited articles. Growth of publications was presented graphically using Statistical Package for Social Sciences software (SPSS). Indicators used to assess the scientific impact of retrieved data were the number of citation per article and the impact factor of the journal.Scopus can be used to provide country analysis on any certain topic. An article in which all authors are from the same country is counted once for that country. However, for example, if a certain article has two authors from two different countries, then the article will be counted twice. Scopus allows researchers to count the number of articles produced by authors affiliated with the same country and articles produced by authors with different country affiliation. Single country publications (SCP) are articles in which all authors have the same country affiliation and such publications represent intra-country collaboration. Multiple country publications (MCP) are articles in which authors have different country affiliation and such publications represent inter-country collaboration. The standard competition ranking (SCR) was used to rank top ten productive countries, institutions, and authors. Whenever necessary, data pertaining to SCP and MCP were also presented.Quality of publications is difficult to measure or assess directly. However, the impact of publications could be assessed indirectly using indicators such as total number of citations received, average number of citations per article, Hirsch-index (h-index), percentage of highly cited articles, and impact factor (IF) of journals publishing the documents of interest. H-index has been developed to assess productivity and citation impact of individual researchers . HoweverEthical approval of this study was not required by IRB since no human subjects or data were involved. All data analysis was carried out on July 22nd, 2016 to avoid the dynamics of citations from one day to another.Lancet, 1931 [A total of 1035 journal articles were retrieved. Of this number, 688 (66.47 %) were research articles. The remaining types of documents were review articles , notes , letters , editorials , short surveys , conference papers , and articles in press . Retrieved articles were published in 15 different languages. English  was the primary language, followed by French  and German . Retrieved articles had 7998 citations with an average of 7.73 citations per article. The h-index of retrieved articles was 37. The oldest publications on FGM/C were three letters appearing in et, 1931 –25.Figure A total of 65 countries contributed to the advancement of FGM/C research. Table Top ten productive countries on FGM/C were shown in Table The share of specific African countries to FGM/C publications was investigated. Table Karolinska Institutet in Sweden. Publications of the University of Washington, USA had the highest average number of citations per article (22.56) and the highest percentage of publications that were highly cited (33.33 %). King Saud University (KSA), Kingdom of Saudi Arabia was among the top ten productive institutions. Other institutions in the top ten productive list included those in the UK and the USA. The WHO was also among the top ten productive institutions/organizations.Institutions and organizations with at least five publications on FGM/C are shown in Table BMJ , Lancet and International Journal of Gynecology and Obstetrics. Table Journals that had published at least 5 articles on FGM/C were shown in Table Female genital mutilation and obstetric outcome: WHO collaborative prospective study in six African countries” published in 2006 in Lancet. The article received a total of 221 citations. Seven of the top 10 cited articles were original articles and three were review articles. Most articles in the top cited list discussed reproductive and psychological/emotional/sexual consequences of FGM/C on girls and women. One article was on epidemiology, one was about public health aspect of FGM/C and one was about medicalization of FGM/C.Top 10 cited articles on FGM/C were shown in Table Universite de Geneve Faculte de Medecine, Faculty of Medicine, Geneve, Switzerland was the most productive author with 13 publications and 31 co-authorships. Table At least 1726 authors participated in publication of retrieved articles. Therefore, the minimum average number of authors per article was 1.7. Of course it would be impossible to list all authors of retrieved articles in this study. However, we used the VOSviewer to present authors with highest number of links with other authors, i.e., have high number of co-authorships. VOSviewer, might not show authors with low or no links, even if they have large number of published documents and therefore one should be cautious when interpreting VOSviewer maps. A total of 500 authors with the highest number of links were selected and analyzed by VOSviewer. Of those 500, the largest set of 125 authors were shown in a network visualization map. The map consisted of 11 clusters. In the map, authors with the highest number of links were shown with larger font size and larger circle size Fig. . ProfessThe aim of this study was to give a bibliometric overview of publications on FGM/C and how research on FGM/C had evolved in the past decades. Publication activity on FGM/C could be found starting in 1931 –25. HoweStarting from 2003, the United Nations began sponsoring an “International Day of Zero Tolerance to Female Genital Mutilation,” which is held every 6 February . SeveralInternational efforts and active campaigns against FGM/C led to a decline in the prevalence of FGM/C in Africa and other parts of the world , 36. HowThe continuing practice of FGM/C among certain immigrant communities in Western countries has been reported –44. The As expected, analysis of highly cited articles showed that the majority were about the health consequences, both physical and mental, on girls and women with FGM/C. However, authors also published on different social, religious, and anthropological aspects of FGM/C –48. The International collaboration on FGM/C publication was shown in VOSviewer maps, which indicated the presence of strong collaboration between African and Western countries. Such international collaboration may aid African countries to recruit international agencies and funded programs to help eliminate the practice. Most countries with high prevalence of FGM/C are lower-resourced and international collaboration in creating public awareness about FGM/C is needed.To the best of the author’s knowledge, this is the first bibliometric study on FGM/C. However, the author acknowledges the presence of some limitations in this study. The fact that one fourth of retrieved articles had no country affiliation made analysis pertaining to country profile relatively inaccurate and might under-estimate the actual number of publication for each country. Lack of country affiliation in some retrieved articles might be due to a delay in Scopus updating the system or due to publications authored by international organizations such the World Health Organization (WHO) or UNICEF. There are local and regional journals in Africa and Middle East that are not indexed in Scopus. Self-citation is common in publications and needs to be taken into consideration when interpreting results of citation analysis for countries and institutions. Finally, results pertaining to active authors might not be 100 % accurate because some authors use different name spelling, middle initials, etc. and therefore results will be affected.Assessing research productivity and scientific impact of FGM/C publications can be considered a new addition to FGM/C literature. This study shows that literature on FGM/C is increasing, and being published in some high impact journals, indicating recognition of FGM/C as a global public health concern. International collaboration had a positive impact on research productivity from lower resourced African countries, where the majority of FGM/C occurs. Further research from different countries, cultures, organizations, and individuals focusing on knowledge, awareness, legalization, opinions of lay and religious people, particularly including women rights activists, and women with FGM/C, are needed to widen and enrich the literature on FGM/C. This bibliometric analysis may be a first step to tracking the growth and quality of FGM/C research and literature.


Vandetanib is the most largely used tyrosine kinase inhibitor (TKI) in patients with locally advanced and/or metastatic medullary thyroid cancer (MTC). Here, we conducted a systematic review on its efficacy and attempted to perform a meta-analysis adopting standardized RECIST criteria as end-points.ClinicalTrials.gov, and CENTRAL. Only original studies reporting the use of Vandetanib as single agent in MTC were included. The last search was performed on October 31, 2017 and registered in PROSPERO on December 12, 2017 (n = CRD42017081537).The terms “medullary thyroid” and “protein kinase inhibitor”  were searched in PubMed, The search revealed 487 articles, and, after removing duplicates, reading title and abstract, and screening the eligible papers, 10 studied were finally included. Two papers were randomized controlled trials and eight were observational longitudinal studies. No data were available for overall survival. No heterogeneity nor publication bias were recorded in the pooled rate of complete response (0.7%) and stable disease (47%). Mild to moderate heterogeneity were recorded in the pooled rate of other endpoints. Data of the studies did not allow to perform a meta-analysis of time-to-event outcomes.Vandetanib should be considered as a promising treatment in advanced MTC. However, data based on RECIST endpoints do not currently provide high-level evidence on its efficacy. Medullary thyroid carcinoma (MTC) is a thyroid tumor which can occur as hereditary (20% of cases), due to an activating germline mutation of the REarranged during Transfection (RET) protooncogene, or sporadic (80%), with a somatic RET mutation . While tCytotoxic chemotherapy and external beam radiation therapy are poorly effective for metastatic MTC. For this reason, current guidelines support the use of tyrosine kinase inhibitors (TKIs) as first-line therapy in patients with significant tumor burden and symptomatic or progressive metastatic disease according to RECIST criteria . The patHere, we have conducted a systematic review on the efficacy of Vandetanib in the treatment of locally advanced and/or metastatic MTC, attempting to perform a meta-analysis with the adoption of standardized RECIST criteria as endpoints , 10.The study design included studies investigating the efficacy of Vandetanib in MTC patients in terms of RECIST criteria. The present systematic review was registered on December 12, 2017 in PROSPERO (n = CRD42017081537) and performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The PRISMA checklist can be found in Table S1 in Supplementary Material.Participants were MTC patients treated with Vandetanib due to advanced disease. There was no comparator.ClinicalTrials.gov, and CENTRAL. Third, according to our aim, original studies reporting on the use of Vandetanib as a single agent in patients with locally advanced or metastatic MTC were included for the present analysis. Fourth, references of included studies were searched for additional papers on the same topic. The last search was performed on October 31, 2017. No language restrictions were adopted. Articles with unclear data, case reports, and series with overlapping results were excluded. Two investigators (Marco Castellana and Pierpaolo Trimboli) independently searched papers, screened titles, and abstracts of the retrieved articles, reviewed the full-texts, and selected articles for their final inclusion.To retrieve the best of published literature on the efficacy of Vandetanib in MTC, a four-step search strategy was planned. First, we identified keywords and MeSH terms in PubMed. Second, the terms “medullary thyroid” and “protein kinase inhibitor”  were searched in PubMed, The same two investigators (Marco Castellana and Pierpaolo Trimboli) extracted data independently and in duplicate and in a piloted form. The following data were reported: 1. general information on the study ; 2. endpoints according to RECIST, including complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), OS, time to response (TTR), duration of response (DOR), and PD as reason for discontinuation. Discrepancies were solved by a mutual consensus among all authors.I2 index was used to quantify the heterogeneity among the studies, a significant heterogeneity being defined as an I2 value >50%. Egger’s test was also carried out to evaluate the presence of significant publication bias, and a p value <0.05 identified the presence of bias. Statistical analyses were performed using the StatsDirect statistical software version .For CR, PR, SD, PD, ORR, DCR, and PD as reason for discontinuation, a proportion meta-analysis was performed; the number of patients with a specific endpoint was extracted from the paper or calculated from the frequency reported in the text. In addition, data on SD at 6, 12, 24, and 36 months, respectively, were searched. For time-to-event outcomes , a log-rank analysis was attempted. For statistical pooling of the data, the fixed method was used. Pooled data are presented with 95% confidence intervals (95% CI) and displayed using a Forest plot, when possible. The search revealed 487 potentially relevant articles. After duplicates removal, 478 were initially selected, and by reading their title and abstract 450 studies were excluded. The full-text of the remaining 28 papers was obtained and evaluated; 18 articles were excluded because of several reasons . Finally, 10 studies were included in the present systematic review –20  identified by our search strategy focused on the side-effects, rather than on the efficacy of TKI, and only two RCTs and eight OLSs were eligible for inclusion in our analysis. As a major result, no analysis could be performed for OS because this finding was not reported in any of these 10 articles. The pooled CR and SD were the most statistically relevant results; less than 1 in 100 MTC patients had a CR to Vandetanib and about a half (47%) showed a SD at the end of the study. The other dichotomous endpoints presented statistical limitations , while time-to-event outcomes could not be meta-analyzed due to the design of the studies.As mentioned above, OS of MTC patients is significantly reduced in the presence of metastases . BesidesA meta-analysis on TKIs for advanced metastatic thyroid cancer, including several cancer types, has been recently published. Six RCTs were included, one of which herein included also . Higher Some potential limitations of our meta-analysis should be addressed. According to our search strategy, we could find both RCTs and OLSs. The study design of these papers was obviously highly different  and the series included different patient types . Also, some studies adopted RECIST 1.0  to evaluThis study demonstrates that a negligible rate of patients with advanced MTC treated by Vandetanib has a CR at the end of the study and less than a half has SD. Vandetanib, the most largely used therapy in advanced MTC, should be considered as a promising treatment in these patients. However, data on RECIST endpoints to be analyzed are limited, and the overall evidence on the efficacy of Vandetanib in advanced MTC should thus be considered as low at present. Furthermore, RCTs are needed to obtain more robust information, especially in terms of OS.This article does not contain any studies with human participants or animals performed by any of the authors.This systematic review was registered in PROSPERO (n = CRD42017081537).PT, MC, and LG conceived and designed the study. PT, MC, and CV performed the literature search; PT analyzed the data; FG and LG critically reviewed the results. All the authors contributed to write 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.


Health system delays in diagnosis of cancer contribute to the glaring disparities in cancer mortality between high-income countries and low- and middle-income countries. In Botswana, approximately 70% of cancers are diagnosed at late stage and median time from first health facility visit for cancer-related symptoms to specialty cancer care was 160 days (IQR 59–653). We describe the implementation and early outcomes of training targeting primary care providers, which is a part of a multi-component implementation study in Kweneng-East district aiming to enhance timely diagnosis of cancers.Health-care providers from all public facilities within the district were invited to participate in an 8-h intensive short-course program developed by a multidisciplinary team and adapted to the Botswana health system context. Participants’ performance was assessed using a 25-multiple choice question tool, with pre- and post-assessments paired by anonymous identifier. Statistical analysis with Wilcoxon signed-rank test to compare performance at the two time points across eight sub-domains . Linear regression and negative binomial modeling were used to determine change in performance. Participants’ satisfaction with the program was measured on a separate survey using a 5-point Likert scale.176 participants attended the training over 5 days in April 2016. Pooled linear regression controlling for test version showed an overall performance increase of 16.8% after participation (95% CI 15.2–18.4). Statistically significant improvement was observed for seven out of eight subdomains on test A and all eight subdomains on test B. Overall, 71 (40.3%) trainees achieved a score greater than 70% on the pretest, and 161 (91.5%) did so on the posttest. Participants reported a high degree of satisfaction with the training program’s content and its relevance to their daily work.We describe a successfully implemented primary health care provider-focused training component of an innovative intervention aiming to reduce health systems delays in cancer diagnosis in sub-Saharan Africa. The training achieved district-wide participation, and improvement in the knowledge of primary health-care providers in this setting.www.ClinicalTrials.gov, identifier NCT02752061. Cancer is more deadly in resource-rich than resource-limited regions of the world. The mortality-to-incidence ratio of cancers in the United States and the European Union are 0.36 and 0.48, respectively, while they range between 0.66 and 0.70 in World Health Organization’ Western Pacific, Southeast Asia, and Africa regions , 2. As aPatient, provider, and health system factors contribute to late diagnosis of cancer . Fears, In Botswana, a middle-income country of two million people, approximately 70% of cancers are diagnosed at late stage  despite efforts to increase cancer screening and provision of treatment of major cancers to citizens free of charge. We previously found that median time from symptom onset to first presentation at a health facility was 29 days (IQR 0–185), while median time from first health facility visit to specialty cancer care was 160 days (IQR 59–653) . TherefoThe Potlako initiative is an implementation study in Kweneng-East district in Botswana that aims to enhance timely diagnosis of cancer through a package of (a) training primary care clinicians to identify, manage, triage, and refer patients with cancer-related symptoms, (b) developing a standardized referral algorithm, (c) introducing a nurse coordinator role to support patients and clinicians across facility levels to navigate the health system, and (d) providing transport assistance for vulnerable patients . To the Botswana has a relatively well-resourced health-care system, with primary health-care services available for free to all citizens and over 95% of residents residing within 8 km of a health facility . There aPatients with cancer are referred for treatment at Princess Marina Hospital, a 500-bed facility that is one of the two national referral hospitals providing oncology specialty services. Cancer pathology-based diagnosis and treatment  are available at public facilities for free to citizens; radiotherapy at a private hospital is also available for free for patients referred through the public facility system.Potlako initiative is based in Kweneng-East District, one of Botswana’s 27 health districts located approximately 50 km west of Botswana’s capital city Gaborone. The health district serves 150,131 residents , sexual and reproductive health clinic, and general medical and surgical outpatient clinics (OPD). For the two district hospitals, providers from the inpatient medical, surgical, and gynecologic wards were also invited. Overall 170 health-care providers were invited to the training, with a goal of training at least 40% of those working in primary clinics and at least 25% of those at relevant outpatient clinics and wards in the hospital.A dedicated process of stakeholder engagement and participation in planning was followed. A series of meetings were held, first involving the head of district management team and facility managers to identify facility-based focal points at each facility. Then focal points worked with managers to identify individuals suitable for training given specified criteria such as working in the relevant units and size of facilities. Training dates were also set according to preferences expressed by facility and district leadership. Letters of invitation were emailed and faxed, and subsequently followed up by phone-call confirmation of names of those who would be attending.The overall objective was to empower primary health-care providers with increased knowledge on how to identify, provide primary care, and promptly and appropriately refer patients who may have cancer Boxes  and 2. WBox 1Box 2The curriculum was developed by a multidisciplinary team with experience working in Botswana . Consultation and inputs from the team of experts were obtained through workshops, individual discussions, and email communication, to reach consensus regarding (a) competencies of health-care providers relevant to cancer early detection within study context and relevant learning outcomes, (b) general teaching and learning strategies, (c) training material being developed, and (d) training evaluation tool (described below). Curriculum content was adapted to the Botswana context using training material that had been used for similar purposes in Rwanda’s national baseline cancer training program jointly developed by Rwanda Ministry of Health, Partners in Health and Dana Farber/Brigham and Women’s Cancer Center , 29. AdaThe curriculum was delivered as a 1-day program and was administered five times in April 2016. Most of the trainers facilitating the lectures and activities  identified the need to refine some of the questions to put less emphasis on the epidemiology, and more emphasis on practical information on evaluation, treatment and counseling as well as follow-up. The format of some of the questions was also revised from stand-alone questions to clinical vignettes containing a series of questions. This resulted in change in content of 14 questions. Given this change, analysis for pre/posttest scoring were performed and presented separately as test version A (first and second trainings), and version B .Pre/posttests were administered on paper, with trainees asked to generate an anonymous ID code to allow for matching of answers across pre/posttest time points. The posttest was identical to the pretest administered on any given training day. Following completion of posttest, questions were reviewed with open discussion of correct answers and questions that were particularly challenging. Trainees were also asked to complete an anonymous satisfaction form in order to provide feedback on the quality of execution of the training including relevance to day-to-day work, clarity of content, and general training logistics. On a daily basis, research assistants transcribed the pre- and posttests from paper into excel spreadsheet that had pre-programmed data quality checks and scoring. 10% of tests were audited by NT and MP.Correct responses were summed and overall scores were calculated as the total percentage of correct responses. Domain and sub-domain scores were also calculated. A score of 70% or greater was considered passing. Descriptive statistics were used to characterize counts of correct responses, overall score percent, and change. We used the Wilcoxon signed-rank test to compare differences between test versions and scores. Because of the changes across test versions and significant differences in scores between versions, data for each version of the exam are presented separately. We used a panel design and ran both linear regression  and negative binomial (on correct count) models clustered on the individual and controlling for the test version to determine the change in performance. Analyses were performed using Stata .Project was reviewed and approved by the institutional review boards of the Botswana Ministry of Health and Wellness and the Harvard T.H. Chan School of Public Health. Additional approvals were obtained from the participating health facilities. Requirement for written informed consent was waived given the minimal risk of the study, and to reduce risk of reputational harm based on test performance.At the beginning of the study period, Kweneng-East had 134 nurses and 7 rotating general practitioner doctors staffing the primary clinics; the two hospitals had 26 doctors and 327 nurses on their rosters. We invited 170 providers to the program, with a goal of training at least 40% of those working in primary clinics to ensure availability of trained personnel even with routine staffing turn-over. A total of 176 trainees attended with 100% of all Kweneng-East public facilities represented and 60% of general nurses, midwives, and family nurse practitioners working at the primary clinics attending the training. 111 (63%) of trainees were nurses, 36 (21%) were midwives, 7 (4%) were family nurse practitioners, and 19 (11%) were general practitioner doctors. 87 of the trainees (49.4%) were from primary clinics, while 22 (12%) were from outpatient clinics at the primary and district hospitals, 52 (30%) from the inpatient wards at those hospitals and 12 (7%) were from unspecified units at the hospitals.p < 0.001].All attendees completed pre/posttests. There were significant differences between the scores on different test versions Table . Among tWe used an arbitrary cut-off score of 70% as the threshold for passing. Prior to the training, less than half of the trainees passed the assessment test . Following the training, nearly all participants passed . Overall, about half of the sample improved from below the threshold on the pre-test to above the passing score  after the training. However, 13 (7%) did not improve their scores above passing. All but two participants with passing scores on the pre-test also passed the posttest.p = 0.04), pathophysiology (p = 0.019), social context (p < 0.0001), symptoms (p < 0.0001), evaluation (p < 0.0001), documentation (p < 0.0001), and follow-up (p = 0.0029). There was no difference in the treatment subdomain. Participants completing test version B demonstrated improvement in all subdomains: epidemiology (p < 0.0001), pathophysiology (p < 0.0001), social context (p < 0.0001), symptoms (p < 0.0001), evaluation (p < 0.0001), documentation (p < 0.0001), treatment (p < 0.0001), and follow-up (p = 0.0003).We analyzed improvement within two domains and saw significant improvements in both the knowledge and management domains on both test versions Table . ParticiNinety-six percent (169) participants completed the satisfaction survey. Overall, participants reported a high degree of satisfaction with the training program. On a 5-point scale, participants rated the format in which the training was delivered, including the balance between lectures and interactive sessions with a mean score of 4.5 (range 1–5). They rated the content of the training, including key learning points and topics covered, with a mean score of 4.5 (range 3–5). Participants rated the usefulness of the training to their job, including how they would be able to utilize the lessons from it in their day-to-day work, with a mean score of 4.7 (range 3–5). Of 169 respondents, 166 (98.2%) stated that they would be interested in attending a follow-up training.A set of training material including didactic power-point slides, case studies/scenarios, trainer’s notes, and pre/posttest has been developed. These have been placed in repository that is accessible for future trainings and adaptation for other related trainings.We successfully implemented the health-care provider training component of an innovative intervention aiming to reduce health systems delays in cancer diagnosis, had high district-wide attendance, and demonstrated gains in knowledge among participants. Knowledge gaps identified and addressed included in the areas (sub-domains) of understanding better a patient’s social context, cancer-associated symptoms, and primary-care based patient evaluation, and follow-up.Development of the curriculum of this training leveraged South–South collaboration and use of material and experience developed in the region including in Rwanda , 25 and There have been many more studies on training to improve early detection of disease focusing non-communicable diseases (NCDs) other than cancer, and those involving cancer have been specific to a type of cancer such as oral cancer in Asia and cervical cancer in Africa –36. The The positive response to training invitations reflects an interest in learning opportunities about cancers and a knowledge gap identified by facility managers. The high rate of participation was likely the result of active stakeholder engagement in the planning process.We found a statistically significant improvement in overall and across several sub-domains including in cancer-associated symptoms, appropriate evaluation, referral, and follow-up. These are notable as medical training institutions in Botswana, as with those in many LMICs , have trThis analysis is not without its limitations. First, given the revision of pre/posttest administered on the last 3 days of the training, we were not able to meaningfully analyze data across all 5 days of the training period. We thus present test scores during the first 2 days of training and the last 3 days of training separately. We were unable to collect information on demographics and other characteristics of trainees and, therefore, could not investigate differences across sub-groups of trainees. We found a statistically significant 16.8% absolute difference between pre- and posttesting scores, this was not as large an improvement as observed in other studies , 39. ThiWhile our training intervention was effective with respect to immediate learning outcomes, we recognize that this is not sufficient to translate to improved practices as has been described in many studies –42. OtheThis description of the development, implementation, and preliminary knowledge gains from a health-care provider training demonstrate an avenue by which primary care health-care providers can be engaged in efforts to diagnose cancer earlier. This report is particularly timely given increasing global discourse on leveraging the primary care platform in strengthening health systems, and in more efficiently using limited health resources in low- and middle-income countries. Further studies are needed to assess and address the other key determinants of health-care provider performance related to early diagnosis, such as provider’s motivation, attitudes and perceptions regarding responsibilities, and work environment. Our description of approach and findings thus far are a first step in this inquiry, which may inform Botswana’s cancer early detection approaches facilitated by implementation of Primary Health-care guidelines. Findings may also be relevant to other settings seeking to improve cancer early detection and quality of service delivery through training of primary care providers.The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.Project was reviewed and approved by the institutional review boards of the Botswana Ministry of Health and Wellness and the Harvard T.H. Chan School of Public Health. Additional approvals were obtained from the participating health facilities. Requirement for written informed consent was waived given the minimal risk of the study, and to reduce risk of reputational harm based on test performance.NT conducted literature review, contributed to study conception and design, supported cleaning, analysis and interpretation, and led writing and critical review of the manuscript. MP conducted literature review, performed data analysis, and contributed to writing and critical review of manuscript. REK supported data analysis and contributed to critical review and editing of manuscript. SD-P and SL contributed to the conception, analysis interpretation, and critical review of the manuscript. KB, KG, and IN contributed to data collection and data cleaning, and critical review of manuscript. IIS, MN, MM, SG, TB, and LS contributed to interpretation of findings, organization and critical review of 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.