Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
a 50-year - old female occupational therapist with a history of laparoscopic anterior resection 4 years previously for a t1 n0 m0 recto - sigmoid adenocarcinoma was found to have an elevated serum carcinoembryonic antigen ( cea ) of 415.0 g / l on surveillance blood testing .
a computed tomography ( ct ) scan demonstrated a large mass in the left lobe of the liver involving the left and middle hepatic veins .
core biopsies demonstrated moderately differentiated adenocarcinoma , positive for ck20 , cea , and cdx2 and negative for ck7 , ttf-1 , and wt-1 , consistent with metastatic colorectal cancer .
since the liver lesion was potentially operable , a f - fluorodeoxyglucose - positron emission tomography ( pet)/ct scan was arranged to check for occult extra - hepatic metastases . the pet / ct demonstrated a left iliac bone metastasis , retroperitoneal lymphadenopathy and a f - fluorodeoxyglucose ( fdg)-avid thyroid nodule , reported as suspicious of malignancy ( figure 1 ) .
given the presence of extra - hepatic metastases , the patient was treated with 6 months of palliative oxaliplatin and modified de gramont chemotherapy .
although the possibility of a primary thyroid cancer was considered , in the context of inoperable metastatic colorectal cancer , further investigation of the thyroid abnormality was not considered appropriate at that time .
ct performed upon completion of treatment demonstrated partial response to chemotherapy : reduction of the liver metastasis , resolution of the retroperitoneal lymphadenopathy , and sclerosis of the right iliac bone metastasis .
after 3 months , she underwent left hepatectomy and cholecystectomy , followed by radiotherapy to the left ilium 2 months later .
after 2 years of follow - up , a ct scan demonstrated progression of the thyroid nodule and serum cea had risen to 2.2
ultrasound - guided fine needle aspiration of the thyroid nodule was graded thy5 with glandular malignant cells , which were negative for ttf1 and positive for cdx2 by immunocytochemistry .
this was consistent with metastatic colorectal adenocarcinoma , and , given that other disease sites had not changed over 2 years , the patient was offered a right hemi - thyroidectomy .
the patient is under ct and cea surveillance and remains in remission 10 months later with undetectable serum cea levels .
although benign and malignant  incidentalomas  are rare in routine clinical practice,1 some clinicians have claimed that widespread use of whole - body imaging examinations has led to increased detection of thyroid
incidentalomas2 two systematic reviews ( 55,160 and 125,754 subjects ) , analyzing studies using fdg / pet for various indications and patient populations , identified an incidence of focal fdg - avid thyroid lesions of 1%1.6%.3,4 malignancy was detected in 33%34.8% of those with follow - up data available , of whom 81.3%83% had papillary thyroid cancer ( ptc ) , in keeping with the overall proportion of thyroid cancers that are ptcs .
of two studies reporting focal fdg - avid thyroid incidentalomas in patients with known or suspected nonthyroid malignancy , an incidence of 2.0%3.9% was reported , with 34.7%41.7% of these malignant lesions.5,6 in kim et al s study,6 all incidentalomas operated upon were identified as ptcs .
there has been a debate over the need to treat all ptcs . despite the threefold increase in the reported incidence of ptc over the last 3
decades,7 the death rate has remained stable.8 this is supported by the studies of active surveillance , which has not been associated with increased morbidity,9 and evidence of a significant burden of clinically occult ptc at autopsy.10 follicular , medullary , and anaplastic thyroid cancers carry worse prognoses and are considered to require intervention unless the patient has a very poor prognosis from the known nonthyroid malignancy .
a retrospective study of 47,813 thyroidectomies performed for various indications , identified thyroid metastases in 0.13% of samples.11 similar large data sets are not available for thyroidectomies performed only in patients with a known nonthyroid malignancy .
moreover , patients with thyroid metastases will typically have advanced malignancy and not proceed to thyroidectomy , so such data would underestimate the true incidence . in an autopsy series ,
the incidence was 1.9%24% in patients with known malignancy.12 cohort studies have suggested an association with renal cancer,13 although autopsy series indicate they are most commonly derived from lung , breast , and melanoma.12 this case emphasizes the importance of considering carefully whether or not to intervene when an incidental fdg - avid thyroid nodule is detected in a patient with metastatic cancer .
appropriate investigation and management depend on the disease stage , patient s performance status , prognosis , and treatment plan for the known nonthyroid cancer , and whether or not the thyroid abnormality is symptomatic . if there are symptoms , ultrasound and fine needle aspiration for tissue diagnosis is warranted , and multidisciplinary team discussion involving an endocrine surgeon prior to considering further investigation and treatment
. for asymptomatic patients , further investigation of fdg - avid thyroid lesions is only appropriate where demonstrating either metastatic disease to the thyroid or a more aggressive thyroid cancer will alter management strategy for that individual patient .
the patient in our report had inoperable metastatic disease , so the  incidentaloma  was not considered likely to affect clinical outcome . however , after the patient underwent potentially curative liver surgery and high - dose radiotherapy , and completed follow - up for 2 years , it became appropriate to further assess the thyroid lesion .
one study recruited 43 patients with metastases to the thyroid gland and reported a longer survival ( 34 vs 25 months ) for those undergoing surgery than in subjects treated nonsurgically.14 this was not replicated in another nonrandomized study of 36 patients with metastasis to the thyroid in which 21 patients received surgery versus 15 that did not.11 there was no statistical difference in overall survival despite the worse clinical situation of the nonsurgical cohort . therefore with such weak evidence available , in patients suitable for intervention for their  incidentaloma ,
 surgery is generally the treatment of choice for solitary thyroid metastasis and for known thyroid metastasis in patients where other extrathyroid metastases are resectable.13 patients must be counseled regarding the 1%6% risk of surgical complications associated with thyroidectomy , including vocal cord paralysis , hypothyroidism , and hypoparathyroidism.2 in summary , fdg - avid thyroid nodules occur relatively frequently . on finding thyroid
incidentalomas  in patients with a history of cancer , metastasis should be considered , even though the majority of these lesions will be benign or ptc .
 incidentalomas  must be seen in the context of the prognosis and treatment plan for the known malignancy .

Answer:
the routine use of 18f - fluorodeoxyglucose - positron emission tomography ( pet)/computed tomography scans for staging and assessment of treatment response for cancer has resulted in a large number of thyroid abnormalities being detected as incidental findings (  incidentalomas  ) .
 since most pet / ct scans are performed in the setting of a known nonthyroid malignancy , the need for  incidentalomas  to be further investigated and managed depends on the stage , prognosis , and current treatment plan for the known malignancy .
 we present a case describing the management of an incidental f - fluorodeoxyglucose - avid thyroid nodule detected in a patient with known metastatic colorectal cancer . on the basis of this case
 , we discuss the management of incidental pet - detected thyroid nodules in patients with metastatic cancer . thyroid
 incidentalomas  must be seen in the context of the prognosis and treatment plan for the known malignancy .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
the procedure included augmentation with transcortical wiring of an onlay - type prosthesis in twelve knees ( nine patients ) after it had been determined that conventional resurfacing was inadequate .
this technique was indicated when the thickness of the remnant patella was less than 8 mm and the cortical rim was not intact .
there were 9 patients ( 12 knees ) with a mean age of 68 years ( range , 53 to 80 years ) at the time of surgery .
the patellae were revised because of infection ( five knees ) , loosening of the patellar component ( four knees ) and polyethylene wear in the presence of a metal - backed patella ( three knees ) .
an onlay - type , all polyethylene prostheses ( universal dome patella , scorpio , stryker , nj , usa ) which are compatible with the femoral component were used .
after arthrotomy using a medial parapatellar approach , the patella is everted laterally and fixed in this posture by grasping the quadriceps tendon or patella tendon with towel clips .
cement stuck to the undersurface of the prosthesis is meticulously removed with an oscillating saw and a high - speed burr after implant removal . the new , properly sized patellar prosthesis
is then placed on the undersurface , implant location is decided and the margin of the prosthesis and the contact points for each peg are marked .
bone bed preparation is performed with a burr according to marking lines and contact points .
on fitting the patellar prosthesis , a check is made to determine whether it matches the concave portion of the undersurface and confirm the peg sites .
three points are then drilled for the pegs and bone holes are placed for wire passage .
the next steps involve connecting the wires to the pegs and passing through drill holes .
a wire is connected to one peg by winding it around the narrow part of the neck under the peg head and fixing it to the peg .
the three wires on the pegs are passed from the undersurface of the patella to the outer surface through the bone holes .
before the prosthesis is brought into contact with the patella , the space between the bone bed and the polyethylene is filled with cement ( fig .
2 ) . after approximating the patellar prosthesis to remaining bone as closely as possible ,
the prosthesis is compressed with a compressor and the cement is given time to harden .
subsequently , sufficient tension is placed on the three wires on the outer surface with wire holders and the wires are twisted together immediately above the cortex . after checking that the wires are under sufficient tension , they are cut and their ends are pressed with an impactor to prevent irritation ( fig .
after arthrotomy using a medial parapatellar approach , the patella is everted laterally and fixed in this posture by grasping the quadriceps tendon or patella tendon with towel clips .
cement stuck to the undersurface of the prosthesis is meticulously removed with an oscillating saw and a high - speed burr after implant removal . the new , properly sized patellar prosthesis
is then placed on the undersurface , implant location is decided and the margin of the prosthesis and the contact points for each peg are marked .
bone bed preparation is performed with a burr according to marking lines and contact points .
on fitting the patellar prosthesis , a check is made to determine whether it matches the concave portion of the undersurface and confirm the peg sites .
three points are then drilled for the pegs and bone holes are placed for wire passage .
the next steps involve connecting the wires to the pegs and passing through drill holes .
a wire is connected to one peg by winding it around the narrow part of the neck under the peg head and fixing it to the peg .
the three wires on the pegs are passed from the undersurface of the patella to the outer surface through the bone holes .
before the prosthesis is brought into contact with the patella , the space between the bone bed and the polyethylene is filled with cement ( fig .
2 ) . after approximating the patellar prosthesis to remaining bone as closely as possible ,
the prosthesis is compressed with a compressor and the cement is given time to harden .
subsequently , sufficient tension is placed on the three wires on the outer surface with wire holders and the wires are twisted together immediately above the cortex . after checking that the wires are under sufficient tension , they are cut and their ends are pressed with an impactor to prevent irritation ( fig .
if the patellar component can be retained during revision tka , this may offer the best option in terms of morbidity .
however , if the prosthesis is malpositioned , damaged or mechanically loose , removal is probably the advisable option .
the onlay - type all polyethylene patellar prosthesis is an efficient tool when patellar bone stock is sufficient , being over 10 to 12 mm.5 ) but it is not easy to determine an optimal procedure if bone stock is poor . according to maheshwer et al.,2 )
patellar resurfacing using an all polyethylene biconvex patellar prosthesis is successful when the remnant patellar thickness is less than 10 mm and the peripheral rim is intact .
when the bone stock is too thin or the peripheral rim has been destroyed , it is highly likely to fail when a prosthesis is only cemented to bone .
a biconvex patellar prosthesis may also not be likely to be effective . in our series ,
the remnant patellar thickness averaged 5.6 mm ( range , 3.2 to 7 mm ) and variable amounts of the peripheral patellar rim were damaged . with regard to these cases , some authors advocated alternative options including a porous tantalum component , a bone grafting and soft tissue flap procedure or a gull - wing osteotomy .
nelson et al.4 ) evaluated short - term results following patellar resurfacing with a trabecular metal patella in the setting of marked patellar bone loss .
hanssen6 ) suggested a bone grafting and soft tissue flap procedure . at final follow - up of nine patients
, it was found that the mean patellar thickness increased from 8 to19.7 mm and their functional outcomes were improved .
klein et al.7 ) performed a gull - wing osteotomy in a nonresurfacable patella and reported that there was a significant improvement in the range of motion and knee society scores .
though several shortcomings were encountered during follow - up period , the above techniques showed reasonable outcomes.3,4,6,7 ) however , further follow - up is required to assess the longer term benefits of these methods .
the deficient patella was revised using this technique when the thickness of the remnant patella was less than 8 mm and the cortical rim was not intact .
moreover , it is easily reproducible and does not need a long learning curve , in our experience . because it protects the extensor mechanism and provides the same contact during patellofemoral articulation as primary tka , painless articulation is possible and
hereby , the range of motion is improved . however , there are a few concerns about the use of this procedure in thin patellae .
it may not be indicated if the osseous cortical shell is too thin for wiring , so the use of transcortical wires place the patella at risk to fracturing .
also , the problems related with prominent hardware also may occur as is oft en seen with internal fixation of patellar fractures . at a mean 10.3 months follow - up of our series , there was one patellar fracture arising during flexion exercise one week after surgery that was treated with partial patellectomy .
our described technique includes connecting wires to the three pegs of the patellar component , passing the wires from the undersurface of the patella to the outer surface through the bone holes and , after compression of a cemented prosthesis , twisting the wires under sufficient tension .
we believe that this technique provides a good alternative option in managing the deficient patella in revision total knee arthroplasty , although any prolonged benefits will require long - term follow - up .

Answer:
the management of patellae with a severe bony deficiency during revision total knee arthroplasty is a challenging problem .
 however , using a technique of augmentation with transcortical wiring of an onlay - type prosthesis allowed the authors to revise a deficient patellae successfully . after making the decision to revise the existing patellar component ,
 the procedure was found to be technically straightforward .
 furthermore , the procedure does not require sophisticated instruments , only an onlay - type prosthesis , cement and wires .
 this technique entails fixing wires to the three pegs of the patellar component , passing the wires through drill holes in the anterior cortex and , after compression of a cemented prosthesis , augmenting the fixation by twisting the wires anteriorly .
 we believe that stable fixation and painless articulation will be obtained with the described technique for deficient patellae .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
obstructive sleep apnea ( osa ) is characterized by frequent episodes of termination of respiratory airflow caused by upper airway collapse during sleep , followed by oxyhemoglobin desaturation , persistent inspiratory attempts against the obstructed airway and arousals from sleep .
the inspiratory airflow can either decrease ( hypopnea ) or be completely absent ( apnea ) , and an apnea that lasts 10 seconds or longer , associated with ongoing ventilatory effort , characterizes a patient with osa .
the airflow limitation episodes are usually accompanied by decrease in hemoglobin level , which are usually terminated by quick micro - arousals as a result of excessive respiratory drive caused by the continuing hypoxemia [ 23 ] . to establish a definite diagnosis ,
the diagnosis of osa is confirmed when a person has an apnea / hypopnea index ( ahi : number of apneas and hypopneas per hour of sleep ) of more than five events per hour , associated with symptoms of excessive daytime sleepiness .
although known to be a benign disease , numerous studies have shown that osa is usually correlated with increased morbidity and mortality because of cvd such as systemic and/or pulmonary hypertension as its most common consequence , heart failure , myocardial infarction and stroke [ 69 ] .
oxyhemoglobin desaturation - resaturation , which is common in osa patients , results in free radical production , release of proinflammatory cytokines and prothrombotic mediators and endothelial dysfunction and leads to sympathetic nervous system activity and increased blood pressure , as well as impairment of cerebrovascular auto - regulation .
continuous positive airway pressure ( cpap ) has been shown to have cardio protective effects , decreasing mortality and morbidity among these patients [ 1214 ] .
numerous community - based studies have examined the relationship between osa and cvds [ 10 , 1821 ] .
based on these studies , age , gender , smoking status , bmi , ahi , total sleep time and day sleepiness were some of the clinically important predictors of cvd outcomes in osa patients .
we hypothesized that the ahi , currently used to determine the severity of osa , is not by itself enough to accurately predict cardiovascular outcomes in individuals with osa .
we also hypothesized that several factors such as patients demographic and clinical characteristics would have greater accuracy for predicting cvds . based on our electronic search ,
there is no published data about the prevalence of cvd among the iranian population with osa .
our study aimed to resolve conflicting evidence on the impact of severity of osa , gender , age , bmi , smoking status and socioeconomic status on the association between osa and development of cvds .
medical files of 385 patients ( from 2009 to 2011 ) with definite osa , confirmed by overnight polysomnography were selected in noor sleep clinic , tehran , iran .
participants were eligible if they only had osa ( not other types of sleep apnea such as central or mixed sleep apnea ) with ahi of equal or more than five events / hour .
demographic data were collected from patient files and included gender , age ( as reported by patients ) , smoking status and educational status ( last academic degree reported by patients ) .
three modes for smoking status were considered : never - smoker , ever - smoker and ex - smoker .
bmi ( weight in kilograms divided by the square of height in meters ) and ahi ( events per hour ) were derived from the polysomnography reports .
several questions were designed in a questionnaire to detect cvds such as presence of cvd , type of cvd and medications used .
if there was any controversy in the answers , the patients were questioned about their disease status to clarify their health / disease state .
the data were analyzed using single regression analysis followed by multiple regression analysis ( by backward method ) to identify variables that were independently associated with cvd .
the majority of patients were males ( 71.9% ) . among the studied individuals , 26.5% showed at least one sign / symptom of cvd and hypertension was the most commonly reported sign ( 74.5% ) .
demographic characteristics and polysomnographic data of patients in cvd positive and cvd negative groups ( values are presented as meansd ) of patients , 17.9% had hypertension , 2.6% had coronary artery disease , 0.5% had arrhythmia and 0.3% had stroke ; 2.3% of the patients had both hypertension and coronary artery disease , 0.3% had both hypertension and history of myocardial infarction and 0.3% had both hypertension and history of stroke ; 0.8% of patients had myocardial infarction and one of them had hypertension as well .
all variables had a significant association with cvd , except for smoking status ( p=0.77 ) .
we only selected variables with p - values less than 0.20 in simple regression analysis and entered them into the multiple logistic regression model .
multiple logistic regression analysis showed that the odds ratios for one grade increase in bmi and one year increase in age were 1.13 and 1.12 , respectively ( p<0.001 ) . in presence of these variables , severity of apnea ,
gender and level of education ( as a socioeconomic index ) had no significant correlation with cvd ( p=0.36 , p=0.83 and p=0.79 , respectively ) .
this study provided information on the association between osa and cvds . in our osa population ,
26.5% showed at least one sign / symptom of cvd , with hypertension being the most common sign ( 74.5% ) .
while ahi was found to predict cvd in simple regression analysis , no significant association was found in multiple model adjusted for potential confoundders .
multiple regression analysis showed that aging and obesity were significant predictors of the occurrence of cvd in osa patients .
lavie and lavie   in a case - control study on seventy of osa showed that severity of osa affected biochemical markers associated with cvds only in severe stage and not mild or moderate stage of osa .
shahar et al ,   in a cross sectional study also showed modest to moderate effects of sleep disordered breathing on various manifestations of cvds within a range of ahi values that were considered normal or only mildly upraised .
kendzerska et al ,   in a decade - long cohort study showed that osa - related factors other than ahi were important predictors of composite cardiovascular outcome .
our findings were in agreement with the afore - mentioned studies indicating that osa - related factors other than ahi ( bmi and aging ) are important predictors of cvds .
the mean of bmi in cvd+ group was calculated to be approximately 32 kg / m2 , which put them in obese group of bmi classification . in parallel with our study , dacal quintas
et al ,   found that the prevalence of osa in normal weight patients was lower than that in overweight and obese patients .
seetho et al ,   reported that patients with osa and severe obesity had increased arterial stiffness , which would possibly affect cardiovascular risk independently of metabolic abnormalities .
carlson et al ,   showed that age , sleep apnea and obesity represented both independent and additive risk factors for development of systemic hypertension .
similarly , lenfant   described the correlation among obesity , hypertension and osa as a triangular relationship ; osa and obesity have an interactive relation and both of them have increasing effect on incidence of hypertension .
our study showed that aging was another significant factor to explain the presence of cvd among osa patients .
pywaczewski et al ,   showed that the frequency of cardiovascular complications occurring in osa population increased with age .
evidence has been inconsistent on the effect of gender on the association between osa and cardiovascular events . in our study , women with osa were more susceptible to develop cvd than men .
drummond et al ,   and quintana - gallego et al ,   found that women with osa had hypertension more frequently than men .
faulx et al ,   found that ahi was inversely associated with flow - mediated dilation and peak blood flow in women .
in contrast , no relationship between ahi and flow - mediated dilation was found in men .
these results raise the possibility that women with sleep - disordered breathing are more vulnerable to related cvds than men .
on the other hand , mohsenin et al ,   showed that markedly obese men with osa may have a nearly two - fold greater risk for hypertension than women .
gaines et al ,   showed that although women have naturally higher levels of inflammatory and metabolic markers than men , men with sleep apnea appear to have a more severe inflammatory profile compared to women .
it is important to consider the role of bmi in this study and its conclusion : male sex is more susceptible for developing cvd only  at the highest quartile of bmi  . in a case - control study by lavie and lavie
, a comparison was made between smoker and non - smoker patients with osa and they showed a significant interaction effect between smoking and severity of apnea on ceruloplasmin and high - density lipoprotein ( hdl ) levels .
smokers with severe sleep apnea had the highest level of ceruloplasmin and the lowest level of hdl .
they concluded that smoking and sleep apnea had a synergistic effect on some of the biochemical cardiovascular risk markers .
patients with severe sleep apnea who smoked were at a greater risk for developing cvds than smokers with mild - moderate sleep apnea and patients who did not smoke .
in our study , no significant correlation was observed between smoking and cvds ( p=0.77 ) .
one probable reason may be that most ex - smokers stopped smoking before doing the sleep test according to the doctor s advice . some studies categorized ex - smokers in the non - smoker group [ 3536 ] .
based on the electronic search , the current study is the first to provide comprehensive information about the role of severity of osa as a cause of cvd and its relationship with other important risk factors in an iranian population .
we included patients with a wide range of osa severity and a relatively large number of females .
our findings are based on patients referred to a single center , which may reduce the generalizability of our findings .
our study showed that ahi was significantly associated with cvd in simple regression analysis ; however , this association was not significant after controlling for other predictors .
other osa - related predictors , such as bmi and age were significantly and independently correlated with increased risk of cvds , respectively . in presence of these variables , other phenotypic and socioeconomic factors like severity of apnea ,
thus , health care providers should implement bmi control strategies and improve the quality of care for the elderly patients .

Answer:
objectives : obstructive sleep apnea ( osa ) can lead to various cardiovascular disorders ( cvd ) such as hypertension .
 there is no documented data about this relationship among the iranian population .
 the aim of this study was to obtain comprehensive information about the severity of osa as a cause of cvd and its relationship with other important risk factors.materials and methods : in this cross sectional study , we studied patients with osa and apnea / hypopnea index of 5 or more .
 the data were collected from the patients polysomnography report and medical files .
 data analysis was done with spss version 18.results:the majority of patients were males ( 71.9% ) . among the studied individuals , 26.5% showed at least one sign of cvd , and hypertension was the most common condition ( 74.5% ) .
 multiple regression analysis showed that the odds ratios for one unit increase in bmi and one year increase in age were 1.13 and 1.12 , respectively ( p<0.001).conclusions : in our study , bmi and age had the strongest relationship with cvd .
 thus , public health care providers should implement weight control strategies and improve diagnostic and treatment procedures for the elderly patients .


Question:
You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.

Title:
Iodine(III) promotes cross-dehydrogenative coupling of N-hydroxyphthalimide and unactivated C(sp3)–H bonds

Paper sections:
C

ross-dehydrogenation coupling (CDC), a type of chemical bond construction by direct dehydrogenation, has emerged as an important approach in chemical synthesis because of its excellent efficiency, atomic economy, and wide substrate scope [1][2][3][4] . Catalysts based on transition metals such as copper, iron, ruthenium, and manganese are typically used in CDC reactions [5][6][7] . However, issues associated with these metallic catalysts, such as high cost, harsh reaction conditions, toxicity, and metal residues, have restricted their application in organic synthesis 8,9 . Therefore, the development of efficient, simple, environmentally friendly, and metal-free CDC reactions has become a major trend 10 .

In 1985, the Masui group first applied N-hydroxyphthalimide (NHPI) as a metal-free oxidant to the oxidation of olefins via a free radical reaction 11 . The 'non-persistent' nitrogen-oxygen radical, i.e. phthalimide nitrogen-oxygen (PINO) radical 12 , is often used to activate inert hydrocarbon bonds due to its high activity 13 . Moreover, oxygen-substituted NHPI derivatives could be converted into alkoxyamines via hydrazinolysis 14 . Alkoxyamines can be further used to synthesize new cephalosporins, oxiconazoles, glucokinase activators, and other organic compounds with antibacterial activity [15][16][17] . Disadvantages of conventional synthetic methods for accessing these compounds include poor atom economy, tedious synthetic procedures, and unsatisfactory selectivity. Recent researches on the CDC reactions involving NHPI have focused mainly on activated C(sp 3 )-H bonds. Reaction sites are typically at benzylic positions or at the α position of carbonyl moieties or ethers  . The CDC reaction between NHPI and alkanes with inert C(sp 3 )-H bonds has rarely been studied, and only few examples have been reported so far (Fig. 1) [40][41][42][43] . For example, copper nitrate trihydrate-catalyzed functionalization of C(sp 3 )-H bonds adjacent to the oxygen atoms of ethers was realized with oxygen as the co-oxidant in 2017 37 . Functionalization either αto the oxygen atom of ethers or at the benzylic position of benzyl derivatives was accomplished with tetrabutylammonium iodide and tert-butylhydroperoxide under sonication 31 . It is noteworthy that the substrates in the previous reports did not involve acyclic alkanes or nitriles, and transition metal catalysts or superstoichiometric quantities of (volatile, toxic and explosive) tert-butylhydroperoxide were often required.

Hypervalent iodine can be used as an initiator to trigger various chemical reactions, functioning like a transition metal catalyst, and this reagent has been widely applied to drug synthesis and total synthesis of natural products [44][45][46][47][48] . Considering the potential value of R-ONH 2 compounds, we herein report an approach to constructing C-O bonds in unactivated alkanes, cyanides, ethers, and thioethers via a CDC reaction with NHPI in the presence of iodobenzene diacetate as a radical initiator (Fig. 1). The current method features a number of advantages, such as mild metal-free reaction conditions, high synthetic efficiency, environmentally friendliness, and applicability to a wide range of substrates.

Results and discussion

Reaction optimization. The project was commenced with the reaction of cyclohexane with NHPI at room temperature, in which the effect of oxidants [tert-butyl hydroperoxide (TBHP), PhI(OCOCF 3 ) 2 , H 2 O 2 , and PhI(OAc) 2 ] was investigated (Table 1, entries 1-5). The NHPI derivative 3 was formed in 40% yield only when PhI(OAc) 2 was applied as the oxidant (entry 5). The solvents [chloroform, water, N,N-dimethylacetamide (DMA), 1,2dichloroethane (DCE), acetonitrile (MeCN), ethyl acetate (EA), chlorobenzene (PhCl), dichloromethane (DCM), and benzene (PhH)] were next screened (entries 6-14). When PhI(OAc) 2 was used as the oxidant, DCM (entry 13) and benzene (entry 14) gave the best results. The reaction with PhI(OCOCF 3 ) 2 as the oxidant in DCM and PhH was then investigated, and the desired product 3 was obtained in 42 and 49% yield, respectively (entries 15, 16). The influence of the temperature (0 o C and 60 o C) on the reaction was examined with DCM as the solvent and PhI(OAc) 2 as the oxidant, and no better result was obtained (entries 17, 18). Notably, when DCM was used as the solvent, compound 4 was formed (15%) along with 3; the formation of 4 was obviously due to the reaction of the solvent molecule itself with NHPI (see Fig. 2 for the structure). The bond dissociation enthalpies (BDEs) for cyclohexane (cyclohexane-H) and DCM (DCM-H) were calculated by Gaussian 16 at B3LYP/6-31 G basis set level and found to be 402.3 and 416.5 kJ mol −1 , respectively, which indicates that cyclohexane should be slightly more prone to undergo this kind of reaction.

When the reaction was performed with DCM as both the solvent and the substrate, compound 4 was obtained in 50% yield (Fig. 2). Although no additional coupling products were produced when benzene was adopted as the solvent, considering the toxicity of benzene, DCM was chosen as the solvent for most of the subsequent experiments.

Substrate scope. The substrate scope was then explored under the optimal reaction conditions obtained (see Table 1, entry 15), and the experimental results are summarized in Fig. 3. First, the reactions of the cycloalkanes with NHPI were investigated. The C-O CDC reactions of cyclopentane, cycloheptane, and amantadine with NHPI proceeded smoothly and afforded compounds (5-7) in the yields of 55-85%. It should be mentioned that no reports have been disclosed concerning this kind of C-H activation for acyclic alkanes so far. The reactions of acyclic alkanes (e.g., n-pentane and n-hexane) with NHPI were then tested and inseparable oxidation products 8a/8b (1.7/1) and 9a/9b (1/2.4) were obtained, respectively, while single products were delivered from the reaction of 2,2-dimethylbutane and 2,2,4,4-tetramethylpentane in 48% (10) and 88% (11) yields, respectively. In these cases, no activation of the primary C(sp 3 )-H bond occurred. Further studies revealed that toluene, trimethylbenzene, p-nitrotoluene, p-chlorotoluene, 2-methylfuran, and 2-methylthiophene were suitable substrates as well, and the corresponding oxidation products (12-17) were afforded in 56-94% yields. The benzyl C(sp 3 )-H bond was involved in the CDC reaction for these substrates, and the chloro substituent on the phenyl ring does not affect the desired transformation essentially.

Cyano compounds play an important role in drug synthesis 49 , and several research groups have realised direct oxidation of α-C (sp 3 )-H in alkyl nitrile with metal catalysts 50,51 . Hence, alkyl nitrile substrates were next studied under the current transition metal-free conditions. For butyronitrile, isobutyronitrile, and pentonitrile, the corresponding α-C(sp 3 )-H bond oxidation products (18-20) were generated in the yields of 45-86%. The CDC reaction of various ethers and sulfides was also investigated. Cyclic ethers (21-23), acyclic ethers (24-30), thioethers (31-34), and even haloether (27) were converted into the corresponding oxidation products smoothly. Synthetic applications. A gram-scale reaction was performed to demonstrate the application of the current synthetic method. O-(Thiophen-2-ylmethyl) hydroxylamine is a key intermediate for the synthesis of new cephalosporins. The CDC reaction was scaled up to gram-scale with 2-methylthiophene as the substrate and compound 17 was obtained in 77% yield (Fig. 4). Alkoxyamine 35 was then obtained via hydrazinolysis of 17.

Relevant mechanistic studies were next performed (Fig. 5). The reaction of toluene (as the substrate) was found to be totally inhibited upon addition of 2,2,6,6-tetramethylpiperidinooxy (TEMPO), 2,6-di-tert-butyl-4-methylphenol (BHT), 2,2-diphenyl-1-picrylhydrazyl (DPPH), or Galvinoxyl. These results indicated that the current transformation might proceed via a radical reaction pathway.

A plausible mechanism is proposed for the current reaction (Fig. 6). Oxidation of NHPI (2) with PhI(OAc) 2 affords PINO radical 35 , which reacts with the substrate to form an alkyl radical via hydrogen abstraction. Finally, the alkyl radical couples with PINO radical to deliver the final product.

In conclusion, selective C-H functionalisation of alkanes remains a great challenge. PhI(OAc) 2 has been applied to mediating radical     coupling of N-hydroxyphthalimide and unactivated C(sp 3 )-H bonds in a range of cyclic and acyclic alkanes. The present reaction was conducted at room temperature which was compatible with various solvents. A variety of cycloalkanes, acyclic alkanes, cyanides, ethers, and thioethers reacted smoothly with NHPI avoiding volatile, toxic and explosive reagents, providing a direct and simple access to O-substituted NHPI derivatives.

Methods

General Information. All experiments were conducted under air, using commercially purchased analytical reagents and solvents which do not require further purification. 1 HNMR and 13 CNMR spectra were recorded on a Bruker spectrometer (at 400 and 100 MHz, respectively). TMS was used as reference for chemical shifts. High-resolution mass spectrometry (HRMS) was recorded on an Agilent Technologies LC-TOF instrument. X-ray crystallography of compounds 4, 11, and 17 were performed on a Bruker Smart Apex CCD area detector diffractometer using graphite-monochromated Mo Kα radiation. The regards to the suitability and safety warnings of PhH: avoid contact with the skin, the eyes; wear suitable protective clothing, gloves, eye/ face protection; avoid release to the environment.

General procedure for the synthesis of R-ONH 2 compounds. PhI(OAc) 2 (2 mmol) and NHPI (1 mmol) were added to a solution of a substrate (2 mmol) in DCM (2 mL), and the reaction mixture was stirred at room temperature for 2 h and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography (petroleum ether/EtOAc, 50:1 to 20:1) to give the product.

Procedure for compound 35. Water (36 mL) and N-hydrazine hydrate (1.8 g, 54 mmol) were added to a solution of 2-(thiophen-2-ylmethoxy)isoindoline-1,3-dione (1.2 g, 4.63 mmol) in acetonitrile (50 mL). The mixture was stirred at room temperature for 4 h. The crude product was purified by flash silica gel column chromatography (petroleum ether/EtOAc, 5:1) to give the product (0.54 g, 91%) as a brown solid.

Reaction of Toluene with NHPI in the presence of radical trapping reagent. PhI(OAc) 2 (0.54 mmol), radical trapping reagent (0.54 mmol), and NHPI (0.27 mmol) were added to a solution of toluene (0.54 mmol) in DCM (2 mL), and the reaction mixture was stirred at room temperature for 2 h and detected by TLC.

Answer: Cross-dehydrogenative coupling reactions provide a method to construct new chemical bonds by direct C-H activation without any pre-functionalization. Compared to functionalization of a C-H bond αto ether oxygen, αto carbonyl, or at a benzylic position, functionalization of unactivated hydrocarbons is difficult and often requires high temperatures, a transition-metal catalyst, or a superstoichiometric quantity of volatile, toxic, and explosive tert-butylhydroperoxide. Here, a cross-dehydrogenative C-O coupling reaction of Nhydroxyphthalimide with unactivated alkanes, nitriles, ethers, and thioethers has been realized by using iodobenzene diacetate as the radical initiator. The current protocol enables efficient functionalization of unactivated hydrocarbons and nitriles through inert C(sp 3 )-H bond activation under mild reaction conditions. O-substituted NHPI derivatives are generated in good yields under metal-free conditions.


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
ureteropelvic junction obstruction ( upjo ) in children most commonly occurs due to adynamic segment of ureter .
previously , ureteral polyp causing upjo in children has been reported in as low as 0.5% of pyeloplasties in children.1 however , in recent studies the incidence reported was around 5%.2
 3
 4
 5 as li et al mentioned in their report , authors are unsure on whether it is due to more careful patient data documentation or it is about the increase of incidence.5
  fibroepithelial polyps are more common in boys than girls.1
 2
 3
 4
 5 it is predominant at the left side in up to 70% of the patients.1
 6
 7 moreover , bilateral cases were reported as well.8 even if many phenotypes of fibroepithelial polyp ( fep ) were defined , there is no consensus on etiology such as chronic irritation , infections , hormonal imbalance , allergy , or developmental defects.9
 10
  hydronephrosis with ureteral polyp requires surgical treatment , due to the risk of malignity1
 11 and obstruction .
excision of the polyp can be performed by laparoscopy , retroperitoneoscopy , transurethral ureteroscopy , or percutaneous access.12
 13
 14
 15
 16
 17 overall , kojima et al described performing endoscopy via a working port while laparoscopic exploration.4
  in this case report , we present laparoscopic technique in a patient who had ureteral polyp close to the left upj .
a-10-year old boy was admitted at our pediatric emergency department with complaints of abdominal pain and vomiting . in his medical history , he had episodes of abdominal pain without hematuria or urinary tract infection .
the abdominal pain was located on the left upper abdomen and lumbar region . although previous ultrasound reports revealed only mild hydronephrosis , the last one showed hydronephrosis related to a polyploid lesion , which was located near upj and protruding into the proximal left ureter ( fig .
1 ) . a tc diethylenetriamine pentaacetic acid ( dtpa ) renography revealed nonobstructive hydronephrosis with late drainage after diuretic injection .
umbilical 10  mm optic port ( 10  mm reusble port , karl storz gmbh & co. kg ) and two 5  mm ( disposable ) working ports , one on the epigastric region and the other on the left lower quadrant were introduced
. pneumoperitoneum was created at a pressure of 13  mm hg with the flow of 3.5 l / min .
transmesocolic laparoscopic exploration showed a protruding mass on upj and hydronephrosis ( figs . 2 and 3 ) . following the transmesocolic dissection of upj
, a stay suture passing through the abdominal wall was placed to keep the left ureter hanging .
pelvis , close to the upj , was incised and a cauliflower - shaped polyp that was about 20  mm in diameter with a wide base protruding ( fig .
excision of the mass was performed including the regions of pelvis and ureter close to the mass ( fig .
dismembered pyeloplasty was performed with interrupted 50 polydioxanone sutures and double j stent was placed .
the total operative time was 200 minutes , with an estimated operative blood loss of 20 ml .
after a follow - up of 2 years , patient did well with normal dtpa renography .

feps of the ureter are of mesoderm origin , rare benign tumors in children.18 they may arise in any location from renal pelvis to the urethra in the order of decreasing frequency.19 on the other hand , feps may have varied sizes and shapes .
they might be 1to 50  mm long or have shapes such as pedunculated with a smooth surface or with multiple finger - like projections.1
 10
 20
 21 age of the patient , structural features of polyps , and experience level of the surgeon determine treatment preferences and consequences of surgery .
however , although there are few studies , transitional cell carcinoma arising from fibroepithelial polyp and recurrence due to incomplete resection has been reported.11
 22 on the other hand , adey et al stated in 2003 that only 22% of feps were diagnosed preoperatively and li et al mentioned in 2014 that none of the feps in their study were detected before surgery.1
 5 in our case , fep was detected after a follow - up of 4 years .
so we believe the delay in diagnosis might be due to intermittent obstruction and slow growing nature of polyp .
although malignity , recurrence , and any other associated polyp is extremely low , surgeon should ensure not to leave remnant of feps during excision . in the past ,
open surgery was the only option , however , recently minimal invasive approaches have been recommended in children and adults.4
 13
 14
 15
 23 furthermore , several authors have described their successful experience in using holmium laser resection , percutaneous , and/or ureteroscopic approaches in the treatment of feps.13
 14
 15 conversely , sun et al figured out in their study that strictures might be cause of over vaporization and kiel et al mentioned the risk of recurrence due to incomplete resection of tumor.4
 15
 24 bartone et al speculated that resecting the polyp without base might cause obstruction and recurrence.25 on the other hand , adey et al underlined the importance of dismembered pyeloplasty whereas polyps might have been missed , if spiral flap or y  v pyeloplasty is performed.1 moreover , iwatsuki et al and tsuzuki et al published their successful laparoscopic treatment of fep either in child and adult patients.16
 26
  since fep was located close to upj , we preferred to perform laparoscopy .
it should be noted that , despite postoperative controversies of endoscopic resection or fulguration of a wide base polyp ; local resection , fulguration , or pyeloplasty can be performed easily during laparoscopic approach .
the overall laparoscopic exploration shows the exact location and size of the polyp , neighboring organs , and structures .
luminal mucosal evaluation with exposure of proximal and distal resection margins could be performed well with optic magnification .
there are several options for laparoscopic approach to renal pelvis and upj region on the left side .
depending on the patient and experience of the surgeon retroperitoneoscopy , transabdominal retrocolic or transmesocolic approaches can be performed.12
 13
 14
 15
 16
 17 to our knowledge , in pediatric age group , retroperitoneoscopy and endoscopy may not provide enough surgical working space .
so we suggest transabdominal transmesocolic approach and believe that exploration and surgical manipulation might be easier compared to retroperitoneoscopy or endoscopy .
pediatric surgery is a specialty that has its own characteristics owing to relevance of congenital anomalies .
time to time , it is hard to estimate the real anomaly although advanced diagnostic tools are in use , as was in our case . and to me
, a pediatric surgeon should be always alert , for concomitant pathologies , in any anomaly .
besides open access , both endoscopic or laparoscopic approaches should be in practice of surgeon , for being minimally invasive .

Answer:
fibroepithelial polyps are a rare underlying reason of ureteropelvic junction obstruction . in the past , open surgery was the only option . however ,
 due to development of minimal invasive technics , treatment alternatives have been changed .
 resection by laparoscopy or endoscopy , laser fulguration and/or percutaneous resection are recommended in children and adults .
 here , we present a 10-year - old boy with severe left hydronephrosis due to fibroepithelial polyp close to the ureteropelvic junction and our laparoscopic approach .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
the penn diabetes heart study ( pdhs ) is an ongoing , cross - sectional study of individuals with type 2 diabetes ( aged 3575 years ) without clinical evidence of cvd ( myocardial infarction , coronary revascularization or angiographic disease , positive stress test , clinical peripheral arterial disease or peripheral arterial revascularization , stroke , or transient ischemic attack ) .
the university of pennsylvania institutional review board approved the study protocol , and all subjects gave written informed consent ( 4 ) . the ankle - brachial index ( abi )
was calculated by dividing the average of the ankle pressures by the highest brachial pressure .
participants with an abi > 1.4 ( n = 13 ) reflecting noncompressible arteries were excluded ( 5 ) .
each subject had the estimated glomerular filtration rate ( egfr ) calculated based on the abbreviated modification of diet in renal disease study equation ( 6 ) .
plasma levels of fetuin - a ( 4.3 and 10.2% , respectively , intra - assay and inter - assay coefficient of variation ) were measured by enzyme - linked immunosorbent assay ( biovendor laboratory medicine , modrice , czech republic ) .
high - sensitivity c - reactive protein ( hscrp ) was measured by immunoturbidimetric assay ( wako , osaka , japan ) .
student 's t test was used for normal continuous variables and the kruskal - wallis for nonnormal distributed variables .
the association between a 1-sd change in fetuin - a and pad was examined using unadjusted and multivariable adjusted logistic regression models as described in table 1 .
analyses were performed on stata 10.0 software ( stata , college station , tx ) .
association between fetuin - a and pad data are odds ratios ( 95% ci ) and were obtained by logistic regression model .
model 2 : model 1 + smoking , hypertension , hypercholesterolemia , metabolic syndrome , a1c , framingham risk score ( % ) , and medications ( ace inhibitors , aspirin , statins , insulin , metformin , sulfonylureas , and thiazolidinediones ) .
the ankle - brachial index ( abi ) was calculated by dividing the average of the ankle pressures by the highest brachial pressure .
participants with an abi > 1.4 ( n = 13 ) reflecting noncompressible arteries were excluded ( 5 ) .
each subject had the estimated glomerular filtration rate ( egfr ) calculated based on the abbreviated modification of diet in renal disease study equation ( 6 ) .
plasma levels of fetuin - a ( 4.3 and 10.2% , respectively , intra - assay and inter - assay coefficient of variation ) were measured by enzyme - linked immunosorbent assay ( biovendor laboratory medicine , modrice , czech republic ) . high - sensitivity c - reactive protein ( hscrp )
student 's t test was used for normal continuous variables and the kruskal - wallis for nonnormal distributed variables .
the association between a 1-sd change in fetuin - a and pad was examined using unadjusted and multivariable adjusted logistic regression models as described in table 1 .
analyses were performed on stata 10.0 software ( stata , college station , tx ) .
association between fetuin - a and pad data are odds ratios ( 95% ci ) and were obtained by logistic regression model .
model 2 : model 1 + smoking , hypertension , hypercholesterolemia , metabolic syndrome , a1c , framingham risk score ( % ) , and medications ( ace inhibitors , aspirin , statins , insulin , metformin , sulfonylureas , and thiazolidinediones ) .
among 738 subjects in the study sample , pad prevalence was 5.1% , the mean age was 58.7  9.3 years , 37.1% were female , 63.2% were caucasians , and 32.1% were african americans .
the median fetuin - a level was 292.4 ng / ml ( interquartile range 115.5 ) . individuals with pad had a significantly lower fetuin - a level compared with individuals without pad ( 269.3 vs. 293.4 , p < 0.001 ) .
no significant differences were noted in other cardiovascular risk factors , metabolic syndrome , kidney function , inflammation , bmi , serum albumin ( the only surrogate marker of liver function collected on the pdhs ) , or medication use .
fetuin - a levels decreased consistently ( p for trend < 0.02 ) across abi clinically relevant cut points ( < 0.7 , 0.70.9 , 0.91.1 , and 1.11.4 ) ( 7 ) ( see supplemental fig . 1 in the online appendix [ available at http://care.diabetesjournals.org/cgi/content/full/dc09-1541/dc1 ] ) . the odds of pad were significantly increased for each sd decrease in fetuin - a ( odds ratio 1.6 [ 95% ci 1.12.3 ] , p = 0.001 ) and the association persisted in incremental models that adjusted fully for age , sex , race , kidney function , cardiovascular risk factors , medication use , and hscrp ( 1.6 [ 1.0582.5 ] , p = 0.03 ) ( table 1 ) .
a similar trend was noted among subjects with egfr > 80 ml  min  1.73 m ( 1.9 [ 1.03.4 ] , p = 0.05 ) , suggesting that our findings were not confounded by the presence of moderate kidney disease .
finally , in a fully adjusted subgroup analysis , participants with hscrp levels <3 mg / dl ( n = 460 ) had higher odds of pad ( 2.6 [ 1.45.0 ] , p = 0.002 ) , whereas subjects with high hscrp levels ( 3 mg / dl ; n = 234 ) did not ( 0.82 [ 0.41.6 ] , p = 0.59 ) .
low levels of fetuin - a have been linked to medial arterial calcification and flow limiting aortic stenosis in humans ( 8,9 ) . in this study , we demonstrate that lower levels of fetuin - a are associated with pad in subjects with type 2 diabetes . to our knowledge , this is the first study to report such a relationship in the absence of advanced kidney disease or prevalent cvd .
notably , in analysis stratified by the centers for disease control and prevention / american heart association  defined hscrp risk strata ( 10 ) , fetuin - a conferred increased odds of pad in subjects with hscrp <3 mg / dl and also in participants with interleukin ( il)-6 levels below the median ( data not shown ) .
this is consistent with studies reporting an increased cvd risk mortality with fetuin - a deficiency independent of hscrp and il-6 ( 11 ) and points to a unique role for this negative acute - phase protein as a biomarker of pad beyond traditional and novel cardiovascular risk factors . remarkably , animal models appear to track with our clinical observations . in mice lacking the fetuin - a gene ,
the aorta was found to be spared of calcification and fibrosis , whereas peripheral vessels in the skin and kidney showed evidence of extensive calcification ( 2 ) , and the small artery involvement preceded the renal impairment ( 3 ) . however , in the absence of direct imaging data , we are unable to define the type of vascular phenotype ( intimal calcification or medial calcification ) that account for the observed association .
an abi of < 0.9 is 95% sensitive and 99% specific for a stenotic lesion ( > 50% ) ( 12 ) .
therefore , we assume that some degree of eccentric atherosclerotic calcification contributes to the association observed while acknowledging that multiple types of vascular calcification may coexist in type 2 diabetes ( 13 ) . nonalcoholic liver disease and other phenotypes related to insulin resistance , including type 2 diabetes ( 14 ) , are associated with higher levels of fetuin - a ( 15 ) .
we controlled for most potential confounding factors and found no attenuation of the inverse association of fetuin - a with pad .
in particular , because of this inverse relationship , a significant confounding effect was not expected by any condition associated with high fetuin - a levels .
finally , our study is limited by cross - sectional design , which limits causal inferences . in summary ,
low plasma fetuin - a levels are associated with pad in type 2 diabetes independent of traditional and contemporary risk factors .
our findings suggest a unique role for fetuin - a deficiency as a biomarker of pad in the setting of type 2 diabetes .

Answer:
objectivefetuin - a is an inhibitor of vascular calcification and a mediator of insulin resistance .
 this study evaluated the association of plasma fetuin - a and peripheral arterial disease ( pad).research design and methodsa total of 738 individuals with type 2 diabetes ( mean age 58.7 years , 37.1% female ) without known cardiovascular or kidney disease were included in this cross - sectional analysis.resultssubjects with pad had a significantly lower fetuin - a ( 264.3 vs. 293.4 ng / dl , p < 0.001 ) . in multivariable analysis , a 1-sd decrease in fetuin - a increased the odds of pad ( odds ratio 1.6 , p = 0.02 ) .
 subgroup analysis revealed an increased odds even in subjects with glomerular filtration rate > 80 ( odds ratio 1.9 , p = 0.05 ) or high - sensitivity c - reactive protein <3 mg / dl ( odds ratio 2.7 , p = 0.002).conclusionslower circulating fetuin - a is associated with pad in type 2 diabetes beyond traditional and novel cardiovascular risk factors .
 our findings suggest a potentially unique role for fetuin - a deficiency as a biomarker of pad in patients with type 2 diabetes .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
neurofibromatosis affects 1:3,000 individuals , and characterized by largely benign but often debilitating tumors that grow in the nervous system .
its course is unpredictable : it can cause a variety of benign nerve tumors including plexiform , dermal , and optic glioma tumors ; in some cases malignant peripheral nerve sheath tumors can develop in the plexiform tumours .
down 's syndrome is one of the most common and easily recognized genetic conditions in humans .
the estimated prevalence in the united states is approximately 15 per 10,000 live births ( ie , 1 out of every 700 )
most often , it is the result of nondisjunction on chromosome 21 during maternal meiotic division .
we herein present the case of a 17-year - old boy with complaints of skin lesions over the back associated with mild itching since 3 months .
he was a known case of down 's syndrome with a history of seizures in childhood [ figure 1 ] .
the lesions gradually increased in size and number , and similar lesions started developing over his forehead since 23 weeks . on examination , multiple skin colored papules of varying size were present over the entire back and the forehead .
velvety thickening of the skin and hyperpigmentation of the axillae suggestive of acanthosis nigricans was present .
the characteristic features of down 's syndrome , including simian crease , mongoloid facies , and mental retardation were present .
canities and a solitary keloid over the chest were also seen apart from the clinical features of down 's syndrome . on oral examination , scrotal tongue , abnormal dentition , and
other investigations such as ct scan brain , 2d echo , and ecg were normal .
histopathology of the nodule from the back revealed focally thinned out epidermis with intact basal layer ; the papillary dermis showed a mild perivascular infiltrate .
deeper dermis showed a benign spindle cell proliferation suggestive of neurofibromatosis [ figure 3 ] .
physical appearance of down 's syndrome ( a ) neurofibromas ( b ) sebaceous cyst ( c ) acanthosis nigricans , and axillary freckling ( d ) scrotal tongue focally thinned out epidermis with intact basal layer with the papillary dermis showing a mild perivascular infiltrate .
the presentation of a patient with two unrelated genetic disorders is uncommon , although not statistically impossible .
however , in two of these reports , a third medical condition was also present . in one report , breast cancer was reported . in the other ,
our patient had down 's syndrome , neurofibromatosis , dental anomalies , and ocular defects and keloids . in the large majority of cases , trisomy 21
there is no current evidence to support the idea that this is anything other than a chance occurrence .
the two conditions are not related , and the likelihood of a person being born with these two conditions is approximately 1 in 2,700,000 births .
they however overlap in their manifestations . both are associated with intellectual impairment to differing degrees .
macroglossia occurs in both conditions , as may facial , dental , and occlusal abnormalities .
hearing and speech are affected in both conditions , as may the ability to maintain an acceptable level of oral hygiene .
mutations in the gene results in abnormal control of cell growth , differentiation , and aberrant myelination . our patient with of neurofibrmatosis type 1 with down 's syndrome is the first such to have a keloid and sebaceous cyst apart from myopia and dental anomalies . the unpredictable nature and course of the two genetic disorders along with multiple acquired conditions in this patient make it difficult for patients , teachers , care givers , and medical / dental providers to create and maintain long - term care plans . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .
the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .

Answer:
we report a patient with down 's syndrome and neurofibromatosis who presented with a keloid , sebaceous cyst and acanthosis nigricans , along with dental and ophthalmological defects .
 the coexistence of neurofibromatosis type 1 and down 's syndrome which are two unrelated genetic conditions is itself a rarity .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
we describe a case of pseudotumor cerebri in a young man developing 4 years post - traumatic brain injury ( tbi ) .
this is a rare clinical scenario and delayed presentation following tbi with chronic headaches should raise this possibility .
detailed clinical history and examination with appropriate investigations must be performed to diagnose this condition .
a 29-year - old male was admitted to our unit with head injury following a road traffic accident .
his glasgow coma score was 15/15 at admission and had no neurological deficits on examination .
ct brain showed small right frontal extradural hematoma with associated pneumocranium , right orbital roof , and cribriform plate fracture .
a repeat ct brain scan revealed an increase in the size of the extradural hematoma following which he underwent a frontoparietal craniotomy and evacuation of the extradural hematoma .
he recovered well postoperatively and was discharged home . since discharge , he experienced intermittent frontotemporal headache and worsening of short - term memory .
five months later , he developed a right - sided facial swelling and erythema , with frontal headache , fever , and episodes of vomiting .
removal of infected bone flap was performed , and staphylococcus aureus was isolated from the bone flap .
his headache persisted following treatment , and he had no signs suggestive of raised intracranial pressure .
he remained well for the next 12 months apart from episodes of headaches on and off .
a lumbar puncture was performed after imaging and was noted to have an elevated csf pressure of 20 mmhg and a diagnosis of pseudotumor cerebri was made .
he underwent a lumbar - peritoneal ( lp ) shunt and postoperatively his symptoms improved transiently over the next few weeks .
he had gained 9 kg of weight over the course of 4 years .two months subsequent to lp shunt insertion , he presented with worsening headaches and a new lumbar puncture showed an opening pressure of 25 mmhg , and closing pressure of 8 mmhg with no evidence of csf infection .
ct brain revealed no evidence of increase intracranial pressure , and a right ventriculo peritoneal ( vp ) shunt was inserted .
his headache persisted following vp shunt insertion and subsequent to this he underwent bitemporal decompression ( craniectomy ) in 3 weeks time with the removal of lp shunt [ figure 1 ] .
he had two further vp shunt blockages and he developed a slit ventricle syndrome despite the shunt malfunction [ figure 2 ] .
a ct venogram was performed 1 year later , which demonstrated a stenosis of the left transverse sinus and sigmoid sinus with hypoplastic right transverse and sigmoid sinuses .
the cerebral venous pressure was measured with significant left transverse sinus stenosis , and pressure gradient of 2612 mmhg , > 50% gradient .
this was managed nonoperatively , and it was found not to contribute to his on - going symptoms . he was also commenced on acetazolamide for the management of pseudotumor cerebri .
ct brain demonstrating bitemporal decompressive craniectomy ct brain with vp shunt in situ and slit - ventricle with an underlying shunt malfunction
pseudotumor cerebri is more commonly seen in young obese women than men . in a study by durcan et al .
determining the incidence of pesuedotumor cerebri in iowa and louisiana , it was noted that obesity increased the incidence in both males and females with a overall female - to - male ratio of 8:1 .
pseudotumor cerebri is a relatively common neurologic illness and may be an important preventable cause of blindness in obese young women .
pseudotumor cerebri usually presents in adults with transient visual obscuration and blurred vision in contrast to development of diplopia in the pediatric age group .
various clinical conditions and factors are associated with development of pseudotumor cerebri . in our case
we focus on the possible etiology following tbi and have attempted to outline the possible causes for the development of pseudotumor cerebri .
the question then arises as to why all the patients with tbi do not develop pseudotumor cerebri .
the mechanism of csf flow dynamics alteration following central nervous system infection and cerebral blood flow alteration is usually seen during the period of insult to the brain and transient alteration in the physiology is a reversible phenomenon depending on the severity of head injury .
the pathological process reverts to normal and very rarely , as in this case , may lead to the development of pseudotumor cerebri .
possible etiologies contributing to pseudotumor cerebri mastoiditis and subsequent venous thrombosis is a known to cause pseudotumor cerebri , and there was no evidence of sinus thrombosis on imaging in our case .
the bone flap infection may have altered the cerebral venous drainage and subsequently caused changes in the csf slow dynamics .
the patient had gained weight following the head injury , and weight gain and obesity are important etiological factors in the development of pseudotumor cerebri .
the management was aimed at preventing the possibility of optic nerve damage and blindness in benign intracranial hypertension ( bih ) , vp shunt , and lp shunt are the surgical options available for pseudotumor cerebri and our patients visual symptoms got better following csf diversion procedures .
we experienced the difficulty in managing the patient in the later stage due to shunt dysfunctions with associated slit - ventricle syndrome .
this procedure was resorted to , as a last option for controlling headaches and it is known to be effective in symptomatic control in the some group of patients described in the literature . the prognosis for vision in most patients with pseudotumor cerebri is excellent ; however , visual loss , which is the only serious complication , may occur either early or late in the course of the disease .
when a post - head injury patient presents with history of chronic headache with visual disturbance , pseudotumor cerebri should be considered a strong possibility .
neuroimaging in the form of brain ct , mri , and mr venogram must be considered to rule out vascular pathology and a diagnostic lumbar puncture is recommended .
csf flow diversion techniques must be adopted to treat this condition , and these may require long - term follow - up .

Answer:
we describe a case of pseudotumor cerebri in a young man developing 4 years post - traumatic brain injury ( tbi ) . a 29-year - old man was admitted after sustaining a fall with headache , and no clinical deficits
 were noted on examination .
 ct brain demonstrated an extradural hematoma .
 this was successfully evacuated after his symptomatic worsening . following this , he developed bone flap infection and had the infected bone flap removed .
 he developed chronic mild - to - moderate headache following these procedures , which failed to respond to medical treatment .
 pseudotumor cerebri was diagnosed .
 a lumboperitoneal ( lp ) shunt , ventriculo - peritoneal ( vp ) shunt , and bitemporal craniectomy were performed as a part of management at different stages .
 post - tbi patients may present with chronic headache and in such circumstances , a possibility of pseudotumor cerebri must be considered .
 investigations should include neuroimaging in the form of mri / mrv and fundoscopy to look for papilledema .
 management in the form of csf flow diversion techniques ( vp and lp shunt ) with medical management results in good clinical outcomes


Question:
You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.

Title:
Mechanistic Insight Leads to a Ligand That Facilitates the Pd-Catalyzed Formation of 2-(Hetero)Arylaminooxazoles and 4-(Hetero)Arylaminothiazoles

Paper sections:

Palladium catalyzed C–N bond-forming reactions have impacted the synthesis of nitrogen-containing molecules in a range of scientific disciplines1, including materials science2, chemical biology3 and medicinal/process chemistry4. Insights into the mechanism of the reaction have informed the development of better ligands and reaction conditions, resulting in C–N cross-coupling protocols of substantial utility and generality.5 Nevertheless, important limitations to the scope of the reaction remain, especially with respect to the coupling of highly functionalized or heterocyclic substrates, which are of particular relevance to the synthesis of biologically active compounds.6 Indeed, medicinal chemists at Merck recently disclosed that 55% of the metal-catalyzed C–N cross-coupling reactions performed at their facilities failed to deliver any desired product in late stage synthesis of drug leads, highlighting some of the persistent barriers to overcome in the development of this transformation.7

The cross-coupling of five-membered heteroarylamines with aryl halides remains challenging in many cases despite their frequent occurrence as substructures of natural products8, pharmaceuticals and other biologically active molecules.9 For example, researchers at AstraZeneca recently reported their difficulties in developing conditions for the palladium-catalyzed cross-coupling of 2-aminooxazoles.10 The authors reported that only trace amounts of coupling product could be obtained in the case of the parent 2-aminooxazole (1), although a handful of 4- and 5-substituted derivatives could be coupled in low to moderate yield. To prepare the coupling product of 1, a multistep procedure involving the saponification and decarboxylation of the 4-ethylester derivative was required. In general, improvements in the cross-coupling of five-membered heteroarylamines, such as 2-aminooxazole 1, would be a useful advance for the field of transition metal-catalyzed cross coupling.

We previously reported BrettPhos11 (Figure 1b/2a, L1) as an effective supporting ligand for selective monoarylation of primary amines catalyzed by palladium.4b,12 The methoxy substituentat the C3-position (Figure 1b) has been found to play an important role in the selectivity and reactivity of catalysts supported by this ligand.11a, 13 Reductive elimination studies have demonstrated that BrettPhos-supported palladium(II) complexes will reside as the O- and C-bound isomers (Figure 1b), and the O-bound isomer is less competent for reductive elimination. We thus hypothesized that the O-bound complexes may be "off-cycle" palladium intermediates that must be eventually converted to the product-producing C-bound complex (IV). We felt that the development of a ligand that favored C-bound isomers might enable a catalyst system with improved reaction rates and efficiencies for challenging substrate classes.

With this hypothesis in mind, we synthesized an array of L1 analogues that we believed could decrease the percentage of the O-bound isomer. This study (detailed in the supporting information) led to the identification of EPhos (L3) as an effective ligand for the cross-coupling of 1 with an array of hindered and/or functionalized aryl chlorides and bromides, as well as commercial pharmaceuticals. In addition, the catalytic system was used to prepare several functionalized 4-(hetero)arylaminothiazoles. Studies that employed reaction calorimetry and NMR implied that reactions with palladium catalysts based on L3 show improved reaction rates and the resting state of the catalystis solely as the C-bound isomer.

The results in Figure 3 show the improved reactivity observed with L3-based palladium catalysts. The cross coupling of 2-aminooxazole 1 with 3-chloropyridine (2a) and 2,6-dimethylchlorobenzene (2b) was examined with a range of ligands and reaction conditions. A series of precatalysts14 based on BrettPhos (P1), tBuBrettPhos (P2), EPhos (P3), and XPhos (P4) as the supporting ligands were evaluated in the presence of either NaOPh (Conditions A) or K2CO3 (Conditions B), and it was determined that the use of P3 provided the highest yields for either pair of starting materials (see the supporting information for the full set of details for this study). P1–P3 each afforded product with 3-chloropyridine (2a), while no product was obtained using P4, highlighting the importance of the 3-alkoxy substituent in the ligand structure. In the case of 2,6-dimethylchlorobenzene (2b), P2 was found to be ineffective, presumably due to the combined steric hindrance from the ligand and the aryl chloride.

With two sets of conditions (Conditions A and B) employing P3 as the precatalyst, the scope of the cross coupling of aminooxazole 1 was explored with a wide variety of aryl chlorides and bromides. When relatively simple and unhindered aryl halides were employed, precatalysts based on BrettPhos (P1) and EPhos (P3) performed comparably. However, when the cross coupling of more complex or sterically hindered substrates was attempted, significantly better yields were obtained with the EPhos-supported Pd catalyst P3 (4h–4m). A variety of functional groups could be tolerated, including a ketone (4a), a nitro group (4e), an unprotected alcohol (4i), an acetal (4l), and secondary and tertiary amines (4m, 4o, 4p, 4q). A collection of heterocycles also proved to be efficiently transformed under these conditions. Importantly, ortho-substituted substrates (4k–4n) reacted efficiently when P3 was employed and several densely functionalized pharmaceuticals also underwent coupling in high yields (4o–4q).

3-Chlorobenzonitrile did not undergo cross coupling with 1 when either BrettPhos (P1) or EPhos (P3) was employed, although a nitrile group was tolerated when a different heteroarylamine was used (4d). When using an aryl chloride bearing a methyl ester group in the ortho position, condensation took place, resulting in the formation of the tricyclic heterocycle 4j. An appreciable yield could be obtained with P3 in the presence of NaOPh (Conditions A). The unsubstituted 5H-oxazolo[2,3-b]quinazolin-5-one is previously unknown, although the thio-analog has been prepared using a copper catalyzed reaction.15

As 4-bromothiazole is also sensitive to strong base, a mild homogeneous base was similarly expected to improve reaction outcomes with this coupling partner. P3
(A) afforded 5a and 5d in significantly higher yields with lower catalyst loadings than what has previously been reported (Scheme 1).10b Furthermore, products 5b and 5c could be obtained in excellent yields with 2.0 mol% catalyst loading at 80 °C. Although the aryl bromide was used in excess for the case of 5c, no diarylation product was observed, highlighting the high selectivity for the monoarylation product using this catalyst system. Notably, excellent yields were also obtained when aminopyrazine (5e) and aminopyrimidine (5f) were employed.

Although NaOPh is a relatively uncommon base for palladium catalyzed C–N cross-coupling reactions, several previous reports have documented its use.16 Hartwig reported that KOPh was optimal for the palladium-catalyzed arylation of fluoroalkylamines, and the resting state of the catalytic reaction was determined to be a LPd(Ar)OPh complex.16a We queried whether analogous phenoxo complexes based on L1 or L3 might be observable under catalytic conditions. Subjecting a solution of L1Pd(Ar)Cl (Ar=2-MeC6H4) (OA1b) or L3Pd(Ar)Cl (Ar=2-MeC6H4) (OA3c) in THF to NaOPh at room temperature gave rise to new signals in the31P NMR spectrum 4–5 ppm downfield of the signals for OA1b and OA3c (see the Supporting information). The cross-coupling of aniline and 2-chlorotoluene using NaOPh as the base, and OA1b (5.0 mol%) as the catalyst was monitored by31P NMR at 60 °C in THF-d8. During the course of the reaction, these two phosphorus-containing species were predominant and were identified as the isomers of the phenoxo complex in which palladium is bound to either the 1'-aryl carbon (C-bound) or the 3-alkoxy group (O-bound) (Figure 1b).11a Interestingly, the O-bound isomer seemed to accumulate over the duration of the reaction. When the same experiment was conducted with OA3c, only the peak corresponding to the C-bound isomer was observed, suggesting that the bulky isopropoxy group disfavors the O-bound isomers.

While studying palladium-catalyzed amination reactions at room temperature, we observed a complex but reproducible kinetic profile for the cross-coupling of 3-bromoanisole and n-propylamine when using the L1-based complex LPd(II)ArBr (OA1, 0.7 mol%) as the palladium source and NaOtBu as base(Figure 4).17 In contrast, when the L3-based complex OA3 was used, a rapid reaction with a simple kinetic profile was observed. Although the complex kinetics observed with OA1 precluded a quantitative comparison of rates, the calorimetric data indicatedthat L3 was much more efficient with full consumption of starting material in less than 20 minutes (Figure 4, inset) compared to 250 minutes for L1.

In conclusion, a new ligand (L3, EPhos) for the palladium catalyzed C–N cross-couplings has been developed, which was applied to the formation of 2-(hetero)arylaminooxazoles and 4-(hetero)arylaminothiazoles. Furthermore, experiments have demonstrated that the respective palladium(II) phenoxo complex is the resting state for this reaction when NaOPh is applied as the base. The O-bound isomer was not observed if L3 was used as the supporting ligand (Figure 3). Although this phenomenon does represent a significant difference in behavior between L1 and L3, ongoing studies will elucidate whether this equilibrium accounts for the difference in efficiency observed between these ligands.

Answer: Using mechanistic insight, a new ligand (EPhos) for the Pd-catalyzed C\xe2\x80\x93N cross-coupling between primary amines and aryl halides has been developed. Employing an isopropoxy group at the C3-position favors the C-bound isomer of ligand-supported Pd(II) complexes and leads to significantly improved reactivity. The use of a catalyst system based on EPhos with NaOPh as a mild homogeneous base proved to be very effective in the formation of 4-arylaminothiazoles and highly functionalized 2-arylaminooxazoles. Previously, these were not readily accessible using Pd-catalyzed methodology.


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
a child is brought into a pediatric emergency unit with an unprovoked , afebrile first seizure .
we conduct a clinical assessment of the child and rule out any acute metabolic , traumatic or infectious causes and consequently , make the diagnosis of an epileptic seizure .
the international league against epilepsy suggests that following such a diagnosis , the next step should be the appropriate classification of the seizure type , after which an appropriate syndrome diagnosis should be made .
should an electroencephalogram ( eeg ) be arranged for this child and if so , should it be arranged within 24 h or within the next week ?
if we decide not to arrange an eeg this time and to do so if any further seizures occur , are we practicing evidence based medicine ? a recent guideline published by the royal college of pediatrics and child health ( rcpch ) asserted :  there is no need for an eeg following a first simple afebrile seizure .
 this is a very bold and clear statement however , what evidence and what quality of evidence is this statement based upon ? this review analyses and discusses prominent literature regarding this widely - discussed topic .
whilst literature on this controversial subject matter is very diverse , a large proportion of the debate surrounds the utility of the eeg for the counselling of parents / family following a first seizure ; particularly as to whether it is a viable tool to predict seizure recurrence .
one study conducted by stroink et al . aimed to assess the accuracy of the diagnosis of a first unprovoked seizure in childhood , the recurrence rate within 2 years , the risk factors for recurrence and the long - term outcome 2 years after recurrence .
a panel of three neurologists confirmed the diagnosis of seizure in children based on pre - described diagnostic criteria .
all the children deemed as having a seizure had a standard eeg , if it did not disclose an epileptiform abnormality , a second eeg was performed after partial sleep deprivation , or during daytime sleep .
one of the most interesting results was the recurrence rate of 71% in children who had an epileptiform eegs in standard eeg .
they concluded by stating that an eeg with epileptiform abnormalities proved to be the main risk factor for recurrence .
however , we must consider whether having this information after the first seizure would change our practice ; it must be noted that a significant proportion ( 29% ) of children with epileptiform eegs did not have a recurrence .
the authors , in their prospective cohort study on 347 children with a first , unprovoked afebrile seizure showed that children with an idiopathic first seizure who had an abnormal eeg were at an increased risk of seizure recurrence .
54% of those with epileptiform eegs experienced a second seizure , in contrast to 25% recurrences in those who exhibited a normal eeg .
they concluded that an abnormal eeg , particularly an epileptiform abnormality , is associated with a higher risk of seizure recurrence in children with an idiopathic first seizure . whilst shinnar et al .
, have clearly demonstrated the higher risk of seizure recurrence in children with interictal eeg abnormalities , it is essential that we remember that a significant proportion of children with an abnormal eeg had no seizure recurrence . although , an abnormal eeg would increase the risk of recurrence by nearly two folds , whether this has to be included in counseling patients and families is debatable , as an abnormal eeg is not an absolute predictor of seizure recurrence , and a normal eeg may be falsely reassuring . a review of literature conducted by pohlmann - eden et al . on the use of the eeg and neuro - imaging following an epileptic seizure also focused on the potential interpretations and limitations of the eeg following a first seizure .
they reviewed literature ( children and adults ) on seizure recurrence , timing of eeg , yield of abnormalities on eeg , yield and timing of sleep deprived eeg and focal epileptiform activity in relation to recurrence .
they concluded that an early abnormal eeg especially , when showing focal epileptiform activity seems to be an excellent predictor for seizure recurrence .
would a physician be able to effectively counsel children and carers based on the percentages identified in the studies appraised above and more importantly , is having a recurrence rate for any type of seizure contributory to the management or counselling of patients ?
another argument put forward by advocates of the use of eeg - after first seizure is its application as a prognostic marker . dr panayiotopolous , from the department of clinical neurophysiology and epilepsy at st .
thomass hospital , recommended that a revision of the current practice in pediatrics of not requesting an eeg after the first afebrile seizure may be needed .
he argued that the current practice of treating after two seizures is not in keeping with the best - available evidence .
he commented that an abnormal eeg , particularly generalized spike wave discharges have been reported as a consistent predictor of recurrence in nearly all studies .
he discussed the benefits of having an eeg after first seizure ; these include diagnosis of a specific epileptic syndrome , making a diagnosis of benign childhood partial seizures ( as these children may not have more than a single episode ) and also assessing the diagnostic and management applications of minor seizures ( such as absences and myoclonic jerks ) .
he clearly defined the advantages of an eeg after the first seizure , stating that the child and the family are entitled to a diagnosis , prognosis and management that is specific and precise , even though this may only be possible in a select - proportion of patients after the first seizure .
in his recommendations , panayiotopoulos also commented that the eeg was a harmless investigation ; this point brought disagreement from pediatric neurologist , richard appleton .
he emphasized that although the eeg was harmless with regards to its invasiveness , it could be potentially harmful in terms of its interpretation . due to the variability in the quality of eeg reports and interpretation
, there may be a significant number of inaccurate diagnoses , which could consequently lead to serious medical , psychological and social consequences .
he also added that irrespective of the eeg changes , many children would not be treated after a first seizure owing to the high non - recurrence rates after first seizures .
he has also pointed towards the fact that most children are managed outside tertiary epilepsy centers and may not have access to medical personnel who should be undertaking and reporting eegs .
the author has clearly highlighted very important issues that would be of immense practical importance and would also initiate thinking in these under - emphasized areas of this contentious topic .
some of the pitfalls of pediatric eeg interpretations were also discussed by tan et al .
; their article was written in response to the clinical guidelines published by the national institute of clinical excellence ( nice ) in 2004 .
they stated that the eeg has rarely been able to function as a  black or white  or  yes or no
diagnostic test for epilepsy , whilst also commenting that the normal eeg evolves and matures with time , reaching the normal adult pattern by approximately 12 years of age .
they proceeded to describe eeg reading as an  inexact science ,  which is learnt through experience and stated that the accuracy of eeg interpretation relies heavily on the clinical history provided by the physician , which on many occasions is insufficient .
they discuss the fact that in the united kingdom , eegs are reported by different medical practitioners including neurophysiologists , neurologists ( both pediatric and adult ) , psychiatrists and even general practitioners with a special interest in the eeg .
many of these practitioners will have had very little exposure to children and pediatric epilepsy , thus , it is difficult to monitor the quality of eeg reporting .
the authors have clearly highlighted the varied quality of eeg reports in various settings and therefore , this has to be considered when using the eeg to guide management of an individual case , especially , if the eeg has been acquired after a first unprovoked seizure . another argument that has been put forward against the routine use of the eeg following the first seizure is whether or not it will contribute to diagnosis or management .
conducted a medline search from 1980 to 1998 to quantify and analyze the value of expected information from an eeg after first unprovoked seizure in childhood .
they employed an evidence - based analytical approach to published literature to select studies providing reasonable estimates of the value of eeg in the general population of children with first unprovoked seizure .
next , the information from these studies was quantified using linear information theory and their results showed that the likelihood of making a clinically useful diagnosis by performing an eeg in every child after first seizure was low .
in addition to this , they commented that as a result of the low sensitivity and specificity of the eeg , many false predictions could occur , thus , resulting in unnecessary patient distress or reassurance .
the quality of expected information from the eeg is too low to affect treatment recommendations in most patients , thus , they concluded by stating , eeg should be ordered selectively , not routinely , after first unprovoked seizure in childhood .
their conclusion was countered by berg et al . who stated that gilbert et al .
focused on the impact of eeg on  treatment decisions  and neglected much of the additional value of an eeg .
he argued that an eeg following the first seizure may provide valuable diagnostic and prognostic information despite epilepsy being a clinical diagnosis .
furthermore , an abnormal eeg in an appropriate clinical context may help support the diagnosis of a seizure disorder , whilst also helping to distinguish between partial , and generalized seizures . in their study , gilbert and
on the utility of eeg for diagnosis following first seizure , which stated that differentiating partial from generalized seizures was non - specific ; berg et al . argued that this  non - specific  distinction has fundamental treatment implications if recurrent seizure occur , as the first line anti - epileptic drugs are different for partial and generalized epilepsy.[911 ] however , it is important to note that although differentiating partial and generalized epilepsy may have treatment implications ( it is not common practice to treat after first seizures ) these are not specific syndromic diagnoses and thus , having this information may not contribute to the first counseling the child or carers receive .
both nice and scottish intercollegiate guidelines network in their guidelines acknowledged that epilepsy is primarily a clinical diagnosis and that , in isolation , the eeg should not be used to make a diagnosis of epilepsy . at present , the majority of pediatricians do not request an eeg after a first seizure and this practice has been emphasized at a recent rcpch guideline appraisal .
eeg carried out at this point has a low sensitivity and specificity for recurrence rates , which may lead to false predictions .
therefore , the information on recurrence may not be helpful in counseling ; however , an abnormal eeg would increase the risk of recurrence by nearly two folds .
there are also a significant proportion of children with first unprovoked seizure and abnormal eeg who may not have any further seizures .
therefore , including the information in counseling may lead to unnecessary psychological stress for both children and carers as the finding of an abnormal eeg does not imply that the child will invariably have a further seizure .
most parents would opt against giving their children anti - epileptic medications after a first seizure , provided they are given the right information that it is possible that there may be no recurrence . the other aspect to consider
is the quality of eeg interpretation that a physician receives to base his judgment on and as mentioned above , quality control of the eeg is very difficult to regulate . on the other hand , there are several clinical situations in which conducting an eeg after a single seizure can lead to the diagnosis of specific epileptic syndrome .
secondly , minor seizures such as absences and myoclonic jerks could be picked up , both for which prognostic and treatment implications could be deduced . children and their carers are entitled to a specific diagnosis , a prognosis , and a precise management plan .
diagnosis of a seizure , epilepsy type and an epileptic syndrome should be primarily based on clinical grounds .
if it is requested , then it should be to answer a specific question , which in turn would help to aid the diagnosis of epilepsy .
the quality of the eeg report and its interpretation has to be considered , and if in doubt , further specialized advice should be sought . as there is limited literature on eegs after first seizure in varying age groups , conducting a prospective study to evaluate the eeg after first seizure is needed .
in particular , to assess the influence of the eeg results on treatment decisions , social and emotional implications and seizure recurrence .
diagnosis of a seizure , epilepsy type and an epileptic syndrome should be primarily based on clinical grounds .
if it is requested , then it should be to answer a specific question , which in turn would help to aid the diagnosis of epilepsy .
the quality of the eeg report and its interpretation has to be considered , and if in doubt , further specialized advice should be sought .
as there is limited literature on eegs after first seizure in varying age groups , conducting a prospective study to evaluate the eeg after first seizure is needed . in particular , to assess the influence of the eeg results on treatment decisions , social and emotional implications and seizure recurrence .

Answer:
a child is brought into a paediatric emergency unit with an unprovoked , afebrile first seizure .
 we conduct a clinical assessment of the child and rule out any acute metabolic , traumatic or infectious causes and consequently , make the diagnosis of an epileptic seizure .
 the international league against epilepsy ( ilae ) suggests that following such a diagnosis , the next step should be the appropriate classification of the seizure type , after which an appropriate syndrome diagnosis should be made .
 ( 1 ) should an eeg be arranged for this child and if so , should it be arranged within 24 hours or within the next week ? if we decide not to arrange an eeg this time and to do so if any further seizures occur , are we practicing evidence based medicine ? a recent guideline published by the royal college of paediatrics and
 child health ( rcpch ) asserted :  there is no need for an eeg following a first simple afebrile seizure  .
 ( 2 ) this is a very bold and clear statement but what evidence and what quality of evidence is this statement based upon ?
 this review analyses and discusses prominent literature regarding this widely - discussed topic .