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:
knowledge of the anatomy of root canal systems is an essential prerequisite for endodontic treatment .
many of the problems encountered during and after root canal treatment occur because of inadequate understanding of the pulp space anatomy .
studies on the internal and external anatomy of teeth have shown that anatomic variations can occur in all groups of teeth and can be extremely complex .
this applies to mandibular incisor teeth as well , as many dentists fail to recognize the presence of a second canal .
current knowledge of pulp space anatomy is based on research findings and individual case reports .
there is a lack of consistency in the reported prevalence of second canals in mandibular incisors.[15 ] the differences may be related to study design ( in vivo versus ex vivo ) , technique of canal identification ( radiographic examination , sectioning and clearing ) or to racial divergence .
it is important to be familiar with variations in tooth anatomy and characteristic features in various racial groups , since such knowledge can aid location and negotiation of canals , as well as their subsequent management .
additionally , a number of studies have shown different trends in shape and number of roots and canals amongst the different races.[1368 ] these variations appear to be genetically determined and are important in tracing the racial origins of populations .
descriptions of the frequently occurring root canal systems of permanent teeth are based largely on studies conducted in europe and north america , and relate to teeth of mainly caucasian origin .
these descriptions may not be fully applicable to teeth of non- caucasian origin . there are no published reports on the root canal anatomy of mandibular incisors in north east indian population .
however , some studies have examined an indian population . the north - eastern population in india is mostly comprised of indo - aryans ( caucasoid ) mongoloids ( tibeto - burman and paleo - mangoloid sub race ) and dravidian sub populations .
the population of north - east india is nearly 38 million , out of which tribal mongoloid population accounts for almost 42 - 45% of the total population .
a total of five hundred and thirty six extracted mandibular incisors were randomly collected from general dental clinics within north - eastern india.out of the collected teeth , fifty six teeth were excluded because of immature or resorbed apices and four hundred and eighty teeth were selected for the present study . the gender and age of patients was not known , and no attempt was made to differentiate between central and lateral incisors .
the samples were stored in 5.25% sodium hypochlorite ( organo bio tech laboratories pvt ltd new delhi , india ) for 30 minutes for the removal of organic debris , and then in 10% formaldehyde until use .
the teeth were cleaned under running water , access cavities were prepared and the coronal pulp tissue extirpated in the canal orifices .
the samples were stored in 5% nitric acid solution ( aries laboratories , india ) for 5 days .
demineralization was assessed by the insertion of a paper pin in the crown and with the help of radiographs .
the samples were then rinsed under running water for 4 hours and placed in 70 , 80 and 95% ethyl alcohol successively , for 1 day . at the end of this period ,
the clearing procedure was completed by placing the samples in methyl salicylate ( regent chemicals , mumbai ) ) . at the end of the third day , complete transparency was achieved .
india ink ( united ink and varnishes pvt ltd , mumbai , india ) was injected into the root canals of the transparent teeth using syringes with 27 gauge needle ( shree uniya surgical , india ) . after the ink had dried , root canal morphology was examined by a magnifying glass of 5x magnification [ figure 1 ] , and the following observations were made : transparent specimen showing canal bifurcation
 number and type of root canals , presence and location of lateral canals and intercanal communications , location of apical foramina , andbifurcation of canals.canals were categorized into the first five types of vertucci 's classification as follows :
 type i : a single canal is present from the pulp chamber to the apex.type ii : two separate canals leave the pulp chamber , but join to form one canal to the site of exiting.type iii : one canal leaves the pulp chamber , divides into two within the root , and then merges to exit in one canal.type iv : two separate and distinct canals are present from the pulp chamber to the apex.type v : single canal leaving the pulp chamber but dividing into two separate canals with two separate apical foramina .

  number and type of root canals , presence and location of lateral canals and intercanal communications , location of apical foramina , and bifurcation of canals .
canals were categorized into the first five types of vertucci 's classification as follows :
 type i : a single canal is present from the pulp chamber to the apex.type ii : two separate canals leave the pulp chamber , but join to form one canal to the site of exiting.type iii : one canal leaves the pulp chamber , divides into two within the root , and then merges to exit in one canal.type iv : two separate and distinct canals are present from the pulp chamber to the apex.type v : single canal leaving the pulp chamber but dividing into two separate canals with two separate apical foramina .

type i : a single canal is present from the pulp chamber to the apex .
type ii : two separate canals leave the pulp chamber , but join to form one canal to the site of exiting .
type iii : one canal leaves the pulp chamber , divides into two within the root , and then merges to exit in one canal .
type iv : two separate and distinct canals are present from the pulp chamber to the apex .
type v : single canal leaving the pulp chamber but dividing into two separate canals with two separate apical foramina .
results of this investigation indicate that one third of the teeth exhibit two canal system ( 36% ) . of the teeth with two canals ,
type iii configuration was most common followed by type ii and type v [ figure 2 ] .
although two canals were found in 36% of teeth , only 6.25% of canals exited in two separate foramina ( type v ) [ table 1 ] . out of all the canals showing two canal configuration , around 83% joined and exited in single foramen ( type ii and iii ) and remaining 17% exited in two separate foramina ( type v ) [ table 1].the apical foramen was found to coincide with the apical root tip in 47.2% of teeth [ table 2 ] . in the present study
, lateral canals were observed in around 13% of the cases [ figure 3 ] [ table 3 ] .
anastomosis were found only in type iii canals which accounts for 2.5% of all the teeth [ table 4 ] .
apical ramifications were seen in around 7.42% of the teeth , out of which 75.7% were with two rami , 24.3%with three rami , and none with four rami [ table 4 ] [ figure 4 ] . in teeth with two canals ,
bifurcations were seen maximum in middle third ( 64% ) followed by in cervical third 23.3% and in apical third 1.25 % [ table 5 ] .
intercanal communications were observed in 28.4% of all teeth and in 70.2% of teeth with two canals [ table 6 ] .
canal configuration ( from left to right ) types i , ii , iii and v number and percentage of canal system types in mandibular incisors ( n=480 ) in the study distribution of apical foramen in mandibular incisors ( n=480 ) in the study curvatures in type i canal configurations- straight , s shaped and j shaped distribution of lateral canals in mandibular incisors in the study distribution of apical ramification in mandibular incisors in the study type i variations- apical ramification , reticular structure and lateral canals distribution of position of canal bifurcation in mandibular incisors in the study distribution of intercanal communications in mandibular incisors in the study
various methods have been used to study root canal morphology including radiographic examination , root sectioning , staining and clearing techniques , direct observation with microscope , sectioning and macroscopic observation , stereo microscope , spiral computed tomography , and cone beam computed tomography .
vertucci used the clearing technique to study the root canal morphology of extracted mandibular anterior teeth .
it has been reported that fine details of the root canal system can be visualized by staining and clearing[figure 1 ] .
this technique also makes canal negotiation with instruments unnecessary , thereby maintaining the original form and relation of canals , and provides a three - dimensional view of root canal .
the process of changing the tooth into a transparent object involves many physical and chemical changes .
the inorganic constituents of the tooth are first dissolved by decalcification , and further water , air , and lipid components are removed by dehydration and by subsequent immersion in the clearing agents , th and this method was used in the present study as well .
the literature on mandibular incisors reveals that 1168% of mandibular incisors possess two canals , although in many of these cases , the canals merge into one in the apical 13 mm of the root .
vertucci examined the root canal morphology of 300 mandibular anterior teeth and reported a second canal in 27.5% of mandibular incisors .
miyashita et al . , reported that 12.4% of mandibular incisors contained two canals ; however , only 3% had two foramina .
sert et al . , noted that two canals were present in 68% of mandibular central incisors .
mauger et al . , evaluated the canal morphology at different root levels in one hundred mandibular incisors , and reported that 98100% of the teeth had one canal in the area 13 mm from the apex .
the differences between these morphology studies may be related to variations of examination methods , classification systems , sample sizes and ethnic background of tooth sources . in a study in jordanian population , it was found that 73.8% of the mandibular incisors possessed a single root canal , and 26.2% of teeth were with two canals .
the results of the present study indicate that one third of the teeth exhibit two canal system ( 36% ) [ table 2 ] [ figure 2 ] .
it was found that 63.75% of mandibular incisors possessed a single root canal ( type i ) with straight , j and s shaped curvatures [ figure 3 ] as well as frequent apical ramifications , lateral canals and reticular structures [ figure 4 ] .
only 6.25% of canals exited in two separate foramina ( type v ) . of the teeth with two canals ,
type iii configuration was most common followed by type ii and type v. therefore , the frequency of two canals in the present study was within the range of previous reports .
this is due to failure of the dentist to recognize the presence of the second canal , and the need for access cavities to have appropriate inciso - gingival extension to facilitate the location of lingual canals .
none of the teeth were seen with type iv canal system , which may be due to smaller number of samples examined in the present study and any conclusion drawn needs to be based on study of a larger population .
the apical foramen was found to coincide with the apical root tip in 47.2% of teeth [ table 2 ] .
this is higher than reported in previous studies that demonstrated that the apical foramen coincided with the anatomical apex in 1746% of cases . in the present study , total apical foramen count stands at 510 ( n=480 ) , which is because of type v canal configuration and apical ramifications
this finding may be of significance in working length determination which often depends on the average position of the apical constriction relative to root apex . in the present study , lateral canals were observed in around 13% of teeth and were found most frequently in the middle of the canal [ table 3 ] [ figure 4 ] .
lateral canals in the apical third account for 2.94%.this is consistent with the findings of miyashita et al . ; however , much lower than that reported by vertucci .
anastomoses were found only in type iii canals which accounts for 2.5% of all the teeth .
apical ramifications were seen in around 7.42% of the teeth out of which 75.7% were with two rami , and 24.3% with three rami , and none with four rami [ table 4 ] . in teeth with two canals ,
bifurcations were seen maximum in middle third ( 64% ) followed by the cervical third 23.3% ; and , the apical third 1.25% [ table 5].this requires an individualized procedure for preparation and filling in each of these conditions to obtain the most desirable results .
pulp space anatomy of mandibular incisors in an indian population show high incidence of complexity which includes variations in canal configuration , number of canals and presence of isthmus .
intercanal communications were observed in 28.4% of all teeth , and in 70.2% of teeth with two canals [ table 6 ] .
the high percentage of intercanal communications in teeth with two canals may be of clinical significance , because it may be difficult to debride and fill these communications adequately .
within the limitations of the present study , it can be concluded that overall , 36% of mandibular incisors in this north - east indian population had two canals . in the teeth with two canals ,
the type iii canal system was the most prevalent followed by type ii.type v was the least prevalent .

Answer:
aim : to aim of this study is to investigate the root canal characteristics of mandibular incisors in a north east indian population using a canal staining and tooth - clearing technique.materials and methods : four hundred and eighty extracted mandibular incisors , collected from dental clinics within north east india were selected for this study . following pulp tissue removal ,
 the teeth were decalcified with 5% nitric acid , dehydrated with ascending concentrations of alcohol and rendered clear by immersion in methyl salicylate . after staining of the canal systems with india ink , cleared teeth
 were examined under 5x magnification and the following features were evaluated : ( i ) number and type of root canals ; ( ii ) presence and location of lateral canals and intercanal communications ; ( iii ) location of apical foramina ; and , ( iv ) bifurcation of canals.results:the majority of mandibular incisors had a single canal ( 63.75% of teeth possessed a type i canal system ) .
 although 36.25% of the roots possessed two canals , only 6.25% had two separate apical foramina.conclusions:the prevalence of two canals in this group ( of north east indians ) of mandibular incisors was 36.25% and is within the range of previous studies performed on populations of different racial origin .


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:
lactic acid was first found and described in sour milk by the swedish chemist karl wilhelm scheele ( 17421786 ) in 1780  .
the swedish chemist jns jakob berzelius ( 17791848 ) found lactic acid in fluid extracted from meat in 1808  [ 2 , 3 ] , and the german chemist justus von liebig ( 18031873 ) , who established the world 's first school of chemistry at giessen , proved that lactic acid was always present in muscular tissue of dead organisms  . in 1859 , emil heinrich du bois - reymond ( 18181896 ) published several articles on the influence of lactic acid on muscle contraction  [ 59 ] .
araki and zillessen found that if they interrupted oxygen supply to muscles in mammals and birds , lactic acid was formed and increased  [ 1014 ] .
this was the first demonstration of the relationship between tissue hypoxia and the formation of lactate .
the occurrence of increased lactic acid in blood ( hyperlactataemia ) nowadays reflects severe illness , in which the increased blood lactate levels may result from both anaerobic and aerobic production or from a  decreased clearance .
it was the german physician  chemist johann joseph scherer who first demonstrated the occurrence of lactic acid in human blood under pathological conditions after death in 1843 and 1851  [ 15 , 17 ] , and carl folwarczny in 1858 who first demonstrated lactic acid in blood of a  living patient . in this article
we wish to honour scherer 's forgotten observations and describe the influence of his finding on further research on lactic acid at the end of the 19th century .
born on 18 march 1814 in aschaffenburg , germany , scherer studied medicine , chemistry , geology and mineralogy at the university of wrzburg between 1833 and 1836 .
he obtained his phd in medicine and surgery in 1838 with a  thesis entitled  versuche ber die wirkung einiger gifte auf verscheidene thierclassen
he practised medicine in wipfeld , but inspired by the chemist ernst von bibra ( 18061878 ) he completed his studies in chemistry at the university of munich between 18381840  . in 1840
he was employed at the laboratory of justus liebig at giessen , and became professor at the medical faculty in 1842 , professor of organic chemistry in 1847 , and later professor of general , anorganic and pharmaceutical chemistry .
his work especially concerned quantitative research on blood and urine in pathological conditions . in 1843
he published his book  chemische und mikroskopische untersuchungen zur pathologie angestellt an den kliniken des julius - hospitales zu wrzburg ( chemical and microscopic investigations of pathology carried out at the julius clinic at wrzburg )   ( fig .  1 )
, in which he described 72 case reports , giving details on clinical course , diagnosis , and results obtained during autopsy and analysis of body fluids .
in one chapter in his 1843 book entitled ' untersuchungen von krankhaften stoffen bei der i m winter 18421843 in wrzburg und der umgegend herrschenden puerperal - fieber - epidemie ' ( investigations of pathological substances obtained during the epidemic of puerperal fever which occurred in the winter of 18421843 in and around wrzburg ) scherer described the cases of seven young women who all died peripartum .
one of the women , the 23-year - old primipara eva rumpel , gave birth to a  healthy child on 9 january 1843 .
the same night she developed a  painfully swollen abdomen and became ill , feverish , and sweaty , with rapid pulse and severe thirst .
the next evening she deteriorated , became delirious , with anxious breathing , a  tense abdomen , cold extremities and rapid pulse , finally losing consciousness .
a.m. , 36  h after the onset of the first symptoms , she died . during autopsy
, severe purulent endometritis , vaginal pus , pulmonary oedema , and shock liver and shock spleen were found .
the blood that was obtained directly from the heart was chemically analysed , in which lactic acid was found .
most likely this unfortunate woman had died from a  fulminant septic shock caused by group a  haemolytic streptococci ( streptococcus pyogenes ) .
another patient , the 28-year - old , 7 months pregnant ( second pregnancy ) margaretha glck , was , after being icteric , nauseous , vomiting and complaining about epigastric pain for 8 days , admitted to the lying - in birth clinic on 6 february 1843 .
four days later she was transferred to the hospital with severe nosebleeds and generalised exanthema or purpura . in the evening she suffered from severe gastric bleeding and epistaxis , showing rapid pulse , cold extremities and dizziness . the next morning
, she was transferred back to the birth clinic , where she gave birth to a  premature child ( 30 weeks ) and suffered from a  severe post - partum fluxus .
she was again transferred to the hospital with the following symptoms : cold clammy skin , tachycardia , severe lochia and persistent exanthema or purpura , but without signs of an acute abdomen . during the night of february 11
autopsy revealed a  small intracerebral haematoma , normal lungs without pulmonary oedema , ascites and an anaemic , foul smelling uterus filled with purulent and decayed tissue and pus .
blood was also obtained directly from the heart during autopsy and lactic acid was found . in this case
we could think of a  haemorrhagic shock and cerebral haemorrhage due to clotting disorders possibly resulting from either acute fatty liver of pregnancy / hellp syndrome , idiopathic thrombocytopenic purpura , thrombotic microangiopathy ( ttp / hus ) or dic .
in the conclusions of his 1843 book , scherer attached high importance to the fact that he found lactic acid in cases of puerperal fever , which he had not found before in healthy persons .
he held the opinion that lactic acid was formed in blood during bodily deterioration in severe diseases like puerperal fever .
lactic acid was thus described for the first time in human blood and was demonstrated for the first time as a  symptom of septic and haemorrhagic shock . in the same period a  junior obstetrician in vienna , ignaz philipp semmelweis ( 18181865 ) , discovered in 1847 that physicians carried infectious particles on their hands from the mortuary to the obstetrical clinic , causing puerperal fever and puerperal sepsis , and he introduced a  successful method for its prevention .
louis pasteur ( 18221894 ) found in 1879 that infection with streptococci was the most important cause of puerperal fever  .
scherer worked closely with the famous pathologist rudolf virchow ( 18211902 ) on several projects ( fig .  2 ) . in 1851
virchow performed an autopsy on a  patient who had died from leukaemia and offered scherer blood from this patient for analysis .
the results of this analysis were published the same year in the  verhandlungen der physikalisch - medicinischen gesellschaft in wrzburg  .
virchow and scherer had previously studied the spleens of patients who died from leukaemia , and were curious if they could find the same results in the blood .
scherer reached the conclusion that : the blood of this patient contains :  ameisensure , essigsure und milchsure , die gleichfalls von mir schon frher als in der milzflssigkeit vorkommend bezeichnet wurden
( formic acid , acetic acid , and lactic acid , as also found by me previously in fluids from the spleen ) .

2johann joseph scherer ( left ) and rudolf virchow ( right ) in 1849 johann joseph scherer ( left ) and rudolf virchow ( right ) in 1849
scherer 's observations inspired others to conduct further research , primarily in patients with leukaemia  [ 1922 ] , but also in patients with other conditions and diseases and in animal experiments with dogs and rabbits  .
while scherer found lactic acid in blood obtained after death during autopsy , mosler and krner   mention an observation made by carl folwarczny , published in the allgemeinen wiener medicinischen zeitung in 1858 , where blood was withdrawn from a  leukaemia patient during life , analysed according to scherer 's method , and found positive for lactic acid . in addition , carl folwarczny described in 1863 in his ' handbuch der physiologischen chemie '   that lactic acid can be found in the blood of patients with leukaemia , septicaemia ( pyaemia ) and in conditions leading to septicaemia like puerperal fever , the latter probably after scherer 's observations . in an extensive article , the berliner physician georg salomon  , who had serious doubts that the occurrence of lactic acid in blood was mostly related to leukaemia , proved in 1878 that lactic acid was also present in the blood of patients who were suffering and died from other diseases .
he studied blood obtained during autopsy from cadavers , but also blood from patients obtained by bloodletting or cupping , and in some cases he compared the blood before and after death .
he was able to demonstrate lactic acid in the blood of patients suffering from leukaemia , ( pernicious ) anaemia , congestive heart failure , chronic obstructive pulmonary disease , pleuritis , pericarditis , pneumonia and several solid malignant tumours .
gaglio   is often erroneously mentioned as the first author to find lactic acid in blood  [ 2729 ] .
he was able to demonstrate lactic acid in fresh arterial blood withdrawn from dogs and rabbits after bloodletting .
both gaglio and berlinerblau , however , neglected previous research , as indignantly described by salomon in 1888 [  ich erlaube mir , den inhalt meiner arbeiten , die von gaglio nur ganz flchtig , von berlinerblau gar nicht berhrt sind , in krze zu reproduciren
( i take the liberty of summarizing the contents of my work , which was mentioned only briefly by gaglio and not at all by berlinerblau ) ]  .
the japanese chemist trasaburo araki showed that the amount of lactic acid in exhausted muscle results from muscle activation  .
irisawa  , inspired by the results obtained by salomon and gaglio , obtained fresh blood of 11 dying patients with serious conditions . in six cases he found hyperlactataemia , in four cases normal values .
he speculated on the aetiology of hyperlactataemia , the most plausible cause being the severe hypoxia during the dying process . in an experiment in which he made a  dog anaemic for several days
, he found a  rise in lactic acid levels during the time leading up to death . in cambridge ( uk ) ,
walter morley fletcher ( 18731933 ) and frederick gowland hopkins ( 18611947 ) worked together on the metabolic changes occurring in muscular contractions and rigor mortis under anaerobic conditions , and found that lactate was the product of carbohydrate metabolism  .
their classic 1907 paper demonstrated rigorously that muscle contraction is accompanied by the anaerobic formation of lactic acid , which is removed aerobically , at a  rate depending on the level of exposure to oxygen  .
poul astrup and john severingshaus mentioned scherer 's 1851 article as first demonstration of lactic acid in blood , but overlooked the 1843 cases and folwarczny 's work  . in conclusion , scherer 's 1843 case reports   should be cited as the first description of lactic acid in human blood and also as the first demonstration of lactic acid as a  pathological finding in septic and haemorrhagic shock .
folwarczny , in 1858 , was the first to demonstrate lactic acid in blood in a  living patient .

Answer:
lactic acid was first found and described in sour milk by karl wilhelm scheele ( 17421786 ) in 1780 . the german physician
 chemist johann joseph scherer ( 18411869 ) demonstrated the occurrence of lactic acid in human blood under pathological conditions in 1843 and 1851 . in this article
 we honour the forgotten observations by scherer and describe the influence of scherer 's finding on further research on lactic acid at the end of the 19th century .
 we conclude that scherer 's 1843 case reports should be cited as the first description of lactic acid in human blood after death and also as the first demonstration of lactic acid as a  pathological finding in septic and haemorrhagic shock .
 carl folwarczny was , in 1858 , the first to demonstrate lactic acid in blood in a  living patient .


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:
fixed drug eruption ( fde ) is characterized by recurrent well - defined lesions in the same location each time the responsible drug is taken .
we report here a rare case of fde induced by atenolol , a beta - adrenoreceptor - blocking agent .
a 48-year - old tunisian woman was referred to our department for the appearance of five inflammatory plaques on both legs .
she had been treated for hypertension with atenolol ( hypoten , al - hikma pharmaceuticals , jordan ) 100 mg once a day for six weeks .
no other medications had been taken and she had not previously received beta - blocking agents .
physical examination revealed five well - demarcated reddish and round plaques with an itching and burning sensation on both legs ( figure 1 ) .
skin biopsy , taken from a lesion with no vesicular changes , showed focal necrosis of keratinocytes , hydropic degeneration of the basal cells , dermal edema and a perivascular lymphocytic infiltrate of the upper dermis .
topical desonide ( locatop ) was applied twice a day and skin lesions resolved within two weeks with a residual pigmentation .
6 weeks after complete resolution , patch testing was carried out according to the international contact dermatitis research group ( jacobs et al 1999 ) recommendations with 10% atenolol in petrolatum on a previously affected site of the right leg ( figure 2 ) and on normal skin of the back . a positive reaction ( + + )
was seen at d2 and d3 on the left leg but no reaction was detected on the back .
they mostly include nonsteroidal antiinflammatory drugs , nonopioid analgesics , sulphonamides , and tetracyclines ( savin 2001 ) .
topical provocation testing has been reported to be useful and safe for the diagnosis of fde when applied on previously affected sites ( alanko et al 1987 ; alanko 1994 ; lee 1998 ; ozkaya - bayazit et al 1999 ) .
different patch test methods ( open / occlusive ) and variations in their evaluation ( erythema of more than six hours duration / erythema and infiltration ) exist ( ozkaya 2008 ) .
beta - blockers - induced fde are very rare ( palungwachira and palungwachira 1999 ; zaccaria et al 2006 ) .
only two cases have been reported in the literature ( palungwachira and palungwachira 1999 ; zaccaria et al 2006 ) .
they were induced by atenolol ( palungwachira and palungwachira 1999 ) and propranolol ( zaccaria et al 2006 ) .
none of them was confirmed by patch testing or systemic provocation ( palungwachira and palungwachira 1999 ; zaccaria et al 2006 ) .
thus , to the best of our knowledge , we report herein the first case of fde induced by atenolol and confirmed by a positive patch test on previously affected sites .

Answer:
fixed drug eruption ( fde ) is characterized by recurrent well - defined lesions in the same location each time the responsible drug is taken .
 we report here a case of multiple fde induced by atenolol in a 48-year - old woman confirmed by positive patch test in previously affected sites .
 beta - blockers - induced fde are very rare .
 only two cases had been reported in the literature . to the best of our knowledge ,
 this is the first case reported of atenolol - induced fde confirmed by a positive patch test .


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:
our survey covered all small molecule new molecular entity ( nme ) drugs that are intended for systemic use and were approved by the fda between january 2013 and august 2016 . the new drug application ( nda ) review documents ( drugs@fda , http://www.fda.gov/drugsatfda ) and product labels were examined for pbpkrelated information for the 85 products that met the above criteria .
there were a total of 18 products for which pbpk models were considered in the nda review documents ( tables
 14 ) . in the majority of cases , pbpk models were used for the prediction of the effect of metabolic enzyme mediated drugdrug interactions ( ddis ; figure
 1a ; tables
 14 ) .
importantly , the frequency of model use is consistent with the perceived level of reliability.1 , 3 , 5
  overview of physiologically based pharmacokinetic ( pbpk ) information in product labels or us food and drug administration ( fda ) review documents for drugs approved by the fda between january 2013 and august 2016 .
( a ) number of new molecular entities ( nmes ) with information of pbpk for respective areas of applications .
( b ) proportion of product labels / reviews containing pbpk information for drugs in all nmes , anticancer agents , and nmes with breakthrough therapy designation and/or accelerated approval status at the time of approval .
seven of eight nmes with pbpk and breakthrough / accelerated approval status were anticancer agents .
a key caveat of our survey was that it was limited to publicly available information .
the utilization of pbpk models for sponsor 's internal decisionmaking and earlier stage and postapproval regulatory interactions , such as postmarketing requirement ( pmr ) or supplementary nda , were not captured .
pbpk models have great potential to influence decisionmaking at different stages of drug development , such as initial dosing recommendations for pediatric clinical trials , design of ddi studies , etc.5 the current evaluation should be interpreted in the context of pbpk use during the final phase in the development of a new drug , because pbpk modeling strategies and the level of model validation can vary at different stages of drug development .
this survey also did not capture the potential value of cost and speed savings by using pbpk vs. conducting clinical studies .
interestingly , we observed wider acceptance of pbpk models in the field of oncology compared with other therapeutic areas ( figure
 1b ) . one possible explanation is the difficulty of conducting clinical ddi studies in oncology , due to ( 1 ) shortage of appropriate patient populations or ( 2 ) ethical and safety concerns over exposing healthy volunteers to oncology medications .
the first point is supported by the observation that three of eight nmes with pbpk in the nononcology field were for rare diseases ( such as eliglustat , macitentan , and obeticholic acid ) .
another possible explanation is that the higher levels of toxicity and narrower therapeutic windows for oncology drugs compared with drugs in other therapeutic areas warrant precise optimization of drug exposure .
it is also noteworthy that 7 of 10 anticancer agents were given regulatory incentives to accelerate drug development , either with breakthrough therapy designation or accelerated approval , which may have contributed to a greater reliance on pbpk simulations .
pbpk models have been most extensively used for the prediction of the effect of ddi or pharmacogenetic effect on the pharmacokinetics of nme as a victim ( figure
 1a ) . in particular , the extrapolation of the effect of strong inhibitors or inducers to less potent perpetrators constituted the majority of the applications ( 11 among 13 nmes ; table
 1 , ids 111 ) , and all applications resulted in labeling recommendations ( table
 1 ) . in these cases , existing clinical data with strong perpetrator(s ) were used to  anchor  the pbpk model performance , namely by accurately providing fraction metabolized by a particular enzyme , which provides a higher level of confidence in ddi prediction.1 , 5 for example , a fourfold dose reduction of ibrutinib was recommended for patients taking moderate cytochrome p450 ( cyp)3a inhibitors based on the pbpk model validated with clinical ddi data using strong perpetrators .
pbpk models in product labels or fda review documents : new drug as a victim of ddis or genetic variations cyp , cytochrome ; ddi , drugdrug interaction ; i d , identification ; nme , new molecular entity ; pbpk , physiologically based pharmacokinetic ; pmc , postmarketing commitment ; pmr , postmarketing requirement ; ugt1a1 , udpglucuronosyltransferase 1a1 .
the numbers in the reference column represent pubmed i d ( if physiologically based pharmacokinetic models were published in scientific journals ) .
the elimination pathways for all the 11 nmes involve cyp3amediated metabolism , whereas two are metabolized by cyp2d6 in addition to cyp3a .
this observation is not surprising , considering that cyp3a and cyp2d6 are involved in metabolism of a large proportion of marketed drugs , and wellestablished probe perpetrators are available for these two enzymes . for two cyp3a and cyp2d6 dual substrates , aripiprazole lauroxil and eliglustat , complex interactions involving the inhibitors of these enzymes and cyp2d6 genotype
anchoring of model prediction with both a strong inhibitor and an inducer has been conducted in most cases , but there were two cases in which model validation with inhibitors was used for the prediction of inducer effect ( cobimetinib , panobinostat ) , both of which resulted in a conservative labeling language of avoiding concomitant use with the strong inducers .
this may suggest that the required level of pbpk model qualification depends on the context of pbpk application . because modification of recommended dose in the product label
application of pbpk,2 the use of a certain amount of clinical pharmacokinetic data as an external validation dataset has generally been required for including dosing recommendations in the product label .
the case of belinostat is intriguingalthough there were no external data , the simulation performed by the fda during the nda review resulted in label language recommending a 25% reduction in the starting dose for homozygous carriers of a genetic polymorphism of its major metabolic enzyme , udpglucuronosyltransferase 1a1 .
this is likely , in part , because the recommended starting dose is equal to the maximum tolerated dose .
pmr to definitively examine the effect of pharmacogenetic alteration on belinostat pharmacokinetics and safety was included in the nda approval .
therefore , even when the pbpk approach could not obviate the conduct of a dedicated clinical study , the model can inform the optimal use of medications .
the second most frequent use of pbpk modeling is to predict the ddi potency of an nme as a perpetrator ( inhibitor / inducer ; table
 2 ) .
four nmes ( ids 1417 ) have successfully utilized a pbpk modeling approach to demonstrate the lack of a clinically significant effect on the metabolic pathways of interest for the particular drug .
one method was to use a negative clinical ddi result with other cyp enzymes as an external validation ( alectinib , panobinostat ) , whereas another was to use a sensitivity analysis on inhibition parameters ( alectinib , canagliflozin ) . in the case of lenvatinib ,
an external model validation was seemingly not performed , presumably supported by general perception that pbpkbased prediction of mechanismbased inhibition leads to overestimation of ddis.5 these observations based on limited cases suggest that required levels of model validation could be flexible , and that we may expect wider application of pbpk in this category .
pbpk models in product labels or fda review documents : new drug as a perpetrator of drugdrug interactions cyp , cytochrome ; ddi , drugdrug interaction ; i d , identification ; mate , multidrug and toxin extrusion transporter ; nme , new molecular entity ; oct2 , organic cation transporter 2 ; pbpk , physiologically based pharmacokinetic ; pmc , postmarketing commitment ; pmr , postmarketing requirement .
the numbers in the reference column represent pubmed i d ( if physiologically based pharmacokinetic models were published in scientific journals ) .
there were two nmes with pbpk models for which additional dedicated clinical ddi studies with cyp3a substrates were requested as pmr . for ceritinib ,
in addition , neither of these two nmes had supporting clinical data to verify model performance .
further examples will be needed to evaluate the ability of the pbpk approach to quantitatively predict positive ddi effects.1

most of the pbpk applications on absorptionrelated pharmacokinetic changes were exploratory and did not impact the labeling recommendation ( table
 3 ) .
altered panobinostat absorption was not observed  with drugs that elevate the gastric ph in pbpk simulation .
pbpk models in product labels or fda review documents : drug absorption ara , acid reducing agents ; auc , area under the curve ; cmax , peak plasma concentration ; fda , us food and drug administration ; i d , identification ; nme , new molecular entity ; pbpk , physiologically based pharmacokinetic ; pgp , pglycoprotein .
the numbers in the reference column represent pubmed i d ( if pbpk models were published in scientific journals ) .
other pbpk applications observed in the nda review documents include prediction of the effect of hepatic impairment ( hi ; table
 4 ) , but pmrs were issued for three of four nmes to conduct or complete dedicated clinical studies , presumably because of the low level of reliability.1 in the case of obeticholic acid , the effect of hi on hepatic exposure was explored with pbpk simulations , and this helped to inform the dosing recommendation in patients with hi .
pbpk models in product labels or fda review documents : other areas of pbpk applications cyp , cytochrome ; ddi , drugdrug interaction ; hi , hepatic impairment ; i d , identification ; nme , new molecular entity ; oatp , organic aniontransporting polypeptide ; pbpk , physiologically based pharmacokinetic ; pmr , postmarketing requirement .
the numbers in the reference column represent pubmed i d ( if physiologically based pharmacokinetic [ pbpk ] models were published in scientific journals ) .
the regulatory impacts of pbpkbased predictions have been limited in areas other than metabolismbased ddis and pharmacogenetics , such as in transportermediated ddis or effect of acid reducing agents .
accumulated experience of pbpk application in these areas will help to establish the level of confidence necessary to inform regulatory decisions .
also , some degree of model validation with clinical data using the nme has generally been required for highimpact regulatory decisions.2 currently , validation of system components , such as hepatic metabolic activity in patients with renal impairment , based on other molecules that share same elimination pathways has not been considered sufficient .
such limitations have impeded the application of pbpk models to replace clinical studies for evaluating socalled  intrinsic factors ,  such as in pediatric populations , to evaluate ethnic differences in pharmacokinetics , or in patient populations with organ impairment .
the authors believe that future verification efforts of pbpkbased prediction performance with cross learning from other molecules , including both xenobiotics and endogenous biomarkers , will greatly expand the use of pbpk beyond ddi and pharmacogenetic applications and will contribute to acceleration of new drug development .

Answer:
physiologically based pharmacokinetic ( pbpk ) modeling can be used to predict drug pharmacokinetics in virtual populations using models that integrate understanding of physiological systems .
 pbpk models have been widely utilized for predicting pharmacokinetics in clinically untested scenarios during drug applications and regulatory reviews in recent years . here , we provide a comprehensive review of the application of pbpk in new drug application ( nda ) review documents from the us food and drug administration ( fda ) in the past 4 years .


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:
dr . coyne - beasley receives research funding from merck & co. none of these funds were used in the conduction or completion of the research contained in this manuscript .
this article was supported by grants from the national institutes of health 1r01ai113305 - 01 ( cates pi ) , and by the north carolina translational and clinical sciences institute , through support from the national center for advancing translational sciences ( ncats ) , national institutes of health , grant award number 1ul1tr001111 .
the content is solely the responsibility of the authors and does not necessarily represent the official views of the nih .

Answer:
a significant barrier to the delivery of hpv vaccine is reluctance by both healthcare providers and parents to vaccinate at age 11 or 12 , which may be considered a young age .
 this barrier has been called  vaccine hesitancy  in recent research . in this commentary
 , we suggest using social marketing strategies to promote hpv vaccination at the recommended preteen ages .
 we emphasize a critical public health message of a sexually transmitted infection ( sti ) as preventable and vaccination against hpv as a way to protect against its consequences .
 the message tackles the issue of vaccine hesitancy head on , by saying that most people are at risk for hpv and there is a way to prevent hpv 's serious consequences of cancer .
 our approach to this conversation in the clinical setting is also to engage the preteen in a dialog with the parent and provider .
 we expect our emphasis on the risk of sti infection will not only lead to increased hpv vaccination at preteen ages but also lay important groundwork for clinical adoption of other sti vaccines in development ( hiv , hsv , chlamydia , and gonorrhea ) as well as begin conversations to promote sexual health .


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 report a case of sle - associated myopericarditis in a young male without clear evidence of viral infection based on viral markers in blood .
the patient 's cardiac function dramatically improved after treatment with steroids without any additional complications .
a 19-year - old male was admitted to the combined armed forces hospital with a 7-day history of fever , cough , dyspnea , orthopnea , and chest pain .
based on the chest radiograph and computed tomography , he was diagnosed with a pericardial effusion and pneumonia ( fig .
1a ) , and was transferred to our hospital for evaluation of the cause and treatment .
his blood pressure was 110/70 mmhg , pulse rate was 112 beats / min , respiratory rate was 24 breaths / min , and body temperature was 38. jugular veins were engorged . on cardiac auscultation , the cardiac rhythm was regular and rapid , summation gallops were heard at the cardiac apex , and there were pericardial friction rubs along with left lower sternal border in the sitting position .
bilateral pretibial pitting edema was present on admission . on admission , blood tests showed white blood cell count of 5,420/mm , hemoglobin 10.6 g / dl and platelet count of 94,000/mm .
c - reactive protein was 4.59 mg / l ( normal , 0 - 3 mg / l ) .
the blood chemistry revealed blood urea nitrogen to be 24.0 mg / dl , creatinine 1.1 mg / dl , total protein 5.7 g / dl , and albumin 2.6 g / dl .
the levels of cardiac markers were elevated ; troponin - i 0.87 ng / ml ( normal , 0 - 0.05 ng / ml ) and myoglobin 371 ng / dl ( normal , 16.3 - 96.5 ng / dl ) .
an electrocardiogram ( ecg ) revealed sinus tachycardia and diffuse t - wave inversion in which leads ( fig .
echocardiography demonstrated severe left ventricular systolic dysfunction { left ventricular ejection fraction ( lvef ) was 18% } with severe global hypokinesia and preserved wall thickness ( fig .
a large amount of pericardial effusion was observed 13 mm anterior to the right ventricle , 18 mm around the right atrium and 2 mm posterior to the lv .
at first , we suspected viral myopericarditis , and started conservative treatment for congestive heart failure and pericarditis .
but , there was no improvement in lvef as well as in the clinical findings . viral markers for cytomegalovirus , coxsackie virus b type 2 , herpes simplex virus , and epstein - barr virus were all negative . during conservative treatment
, he complained of new - onset ankle joint pain and tender erythematous swellings in both the ankles .
the immunofluorescence tests were positive for anti - nuclear antibody ( 1 : 640 titre ) , anti - dsdna antibodies ( 683.4 iu / ml ) , and anti - extractable nuclear antigen antibodies ( anti - sm , anti - rnp , anti - ro , and anti - la ) , and the complement level was low ( table 1 ) .
we concluded that the patient had sle according to the american rheumatism association / american college of rheumatology classification criteria for sle . on the 13th day of admission
, we started treatment with high - dose glucocorticoids ( methylprednisolone 1,000 mg intravenously daily for three days followed by 1 mg / kg per day in divided doses ) . on follow - up examination , ecg showed normalization of t - wave inversion ( fig . 2c ) and echocardiography obtained just before discharge showed improved systolic function ( fig .
chest x - ray also showed improving consolidation in both the lung fields and cardiomegaly ( fig .
complement 3 was normalized and anti - dsdna antibodies decreased from 683.4 iu / ml to 383.8 iu / ml ( who u / ml , normal 0 - 93 ) .
he was discharged on the 33rd day of admission with oral prednisolone , and he visited the outpatient department 1 month later . in this 1 month , he had no symptoms .
echocardiography revealed normal lvef , without significant valvular disease and pericardial effusion compared to the last examination ( table 2 ) .
subsequently , the steroid medication was tapered and it was planned to maintain him on sle - specific treatment in the rheumatologic department .
sle is an autoimmune inflammatory disease of unknown etiology that affects various parts of the body , including all components of the cardiovascular system.1 ) the prevalence of lupus ranges from approximately 40 - 150 cases per 100,000 in the usa.2 ) in adults , the female - to - male ratio is 7 - 15 : 1.3 ) cardiac involvement in sle may comprise of involvement of the pericardium , myocardium , endocardium , heart valves , and coronary or pulmonary arteries.4 ) pericardial involvement is the most frequent cause of symptomatic cardiac disease5 ) and is the most common echocardiographic finding in sle patients .
the pericardium can be involved by acute and chronic inflammatory changes ; granular deposition of immunoglobulin and c3 , demonstrated by direct immunofluorescence,6 ) supporting the role of immune complexes in the development of pericarditis .
myocarditis is an uncommon , often asymptomatic manifestation of sle with a prevalence of 8 - 25% in different studies.7 ) global hypokinesis may be an echocardiographic indication of myocarditis and is present in approximately 6% of sle patients.8 ) the gold standard for diagnosing myocarditis in sle remains the endomyocardial biopsy.9 ) however , an endomyocardial biopsy is invasive with procedure - related risks and the diagnostic yield is low in 10 - 20% of cases , so it is not powerful enough to confirm the diagnosis.10 ) lupus myocarditis can be diagnosed based on clinical suspicion and echocardiographic evidence of a reduced lvef and segmental or global wall motion abnormality , once the other etiologies , such as viral and ischemic cardiomyopathy , have been excluded.9)11 ) immunofluorescence studies demonstrate fine granular immune complexes and complement deposition in the walls and perivascular tissues of myocardial blood vessels , supporting the hypothesis that lupus myocarditis is an immune complex - mediated disease .
lupus myocarditis , although mild , has to be treated immediately with high - dose corticosteroids . in the most severe forms ,
it is necessary to use intravenous pulse corticosteroid therapy ( methylprednisolone 1 g / day for three consecutive days ) followed by high doses of oral prednisone .
immunosuppressants , namely cyclophosphamide or azathioprine , and intravenous igg may be beneficial in the treatment of myocarditis.5 ) early mechanical circulatory supports help to save the life and prevent multi - organ failures in patients with fulminant myocarditis.12 ) in the present case , the patient was initially diagnosed with myopericarditis on the basis of his symptoms , diffuse t - wave inversion on ecg , elevated cardiac markers and echocardiographic findings .
however , there was no improvement in his symptoms and the common cardiotrophic viral markers were all negative . also , the patient had pericarditis , thrombocytopenia and proteinuria .
because the previous typical clinical signs and the positive immunofluorescence tests were suitable for making the diagnosis of sle , we confirmed the diagnosis of myopericaditis associated with sle in this patient .
after a provisional diagnosis of myopericarditis with sle was made , he was treated with intravenous corticosteroid pulse therapy ( methylprednisolone 1 g / day for three consecutive days ) followed by high doses of oral prednisone .
after 3 days of steroid therapy , the patient 's signs and symptoms were stabilizing and echocardiographic findings were improved .
initially , we had considered myopericarditis to be caused by viral infection ; however , the final diagnosis was myopericarditis during presentation of primary sle based on the clinical manifestations , echocardiography , immunofluorescence tests and good response to steroid therapy . because the treatment of sle induced myopericarditis
should be needed for some specific therapy such as corticosteroid , this case shows that careful investigation is needed for search of the cause of myopericarditis in a young male , and not only viral infection but also autoimmune disease should be investigated for . in this report
, we described the first case of a korean young male sle patient in whom the first manifestation was of myopericarditis and treatment with glucocorticoids resulted in a good clinical outcome .

Answer:
myocardial involvement with clinical symptoms is a rare manifestation of systemic lupus erythematosus ( sle ) , despite the relatively high prevalence of myocarditis at autopsies of sle patients . in this review ,
 we report the case of a 19-year - old male sle patient who initially presented with myopericarditis and was successfully treated with high dose of glucocorticoids .


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:
proliferative vitreoretinopathy ( pvr ) remains the major complication after retinal detachment surgery [ 13 ] .
pvr was identified as an independent clinical entity in 1983 by the retina society terminology committee and a classification was created , based on the condition formerly named  massive vitreous traction  or  massive periretinal proliferation  [ 57 ] .
this classification divided pvr into four stages , a , b , c , and d , apparently by increasing its severity , from minimal to massive pvr ( table 1 ) . nevertheless , this classification had numerous limitations .
it did not consider the location of the vitreoretinal traction and the magnitude of the contraction .
in addition , some of the stages provide a false idea of severity ; for instance , d4 caused by a localized epiretinal membrane could be more easily treated by surgery than a c1 caused by intraretinal changes [ 8 , 9 ] . in 1989 , the silicone study group introduced a new classification   including some characteristics , such as the location , anterior or posterior , and the type of contraction ( table 2 ) .
classification was then updated in 1991   according to modifications proposed by the silicone study group and also by other authors   ( table 3 ) .
this classification appears to be difficult to use in clinical practice and may not offer any special advantage for decision - making in relation to the treatment of the disease .
moreover , the classifications might have prevented advances in the understanding of the disease pathogenesis .
for instance , because the retina society committee defined pvr as a  proliferative disease ,  many treatments based on the inhibition of cell proliferation were developed for more than 20 years , none of which appears to have produced a significant clinical advance .
therefore , a review of both the classification and the pathogenesis of pvr appears to be appropriate to aid the development of new treatments .
there is a clinical impression that over the last 15 years clinicians have abandoned current pvr classifications .
thus , the purpose of this study has been to evaluate the current use of pvr classifications in papers dealing with clinical practice and therapy as an indirect measure of the degree of usefulness of existing classifications .
a search in pubmed for papers published between january 2000 and january 2014 was undertaken by two independent researchers .
inclusion criteria comprised human studies published in english , french , and spanish on pvr or retinal detachment with specific mention to pvr .
prospective randomized and nonrandomized clinical studies , retrospective clinical studies , short series , and pilot studies were included .
a manual search of related articles was also performed through references reported in each article .
we also analyzed how the different authors interpreted the classifications , comparing the results they provided with the original description .
therefore , we investigated if they used all the characteristics ( grade [ a , b , c ] , pvr localization , extension in hours , and type ) of the updated retina society classification or if they were used only partially .
furthermore , it was also noted whether classifications were used both before and after an eventual pvr pharmacological or surgical treatment .
data were extracted using a custom - made data sheet performed with agreement between authors .
preliminary search identified a total of 219 publications , 81 of which were eliminated as they did not fulfill the inclusion criteria .
35 articles ( 25,4% ) did not undergo detailed analysis because there was no reference to the type of pvr classification used by the authors or because no classification was used ( generic terms such as initial or severe pvr or simply pvr were adopted , without using any grading system ) .
103 publications ( 74,6% ) used standardized pvr classifications and they were analyzed in detail .
the most used classification was the updated retina society classification   ( 58 cites ; 56,3% ) , followed by the first retina society classification   ( 35 cites ; 33,9% ) .
in addition , 3 authors ( 2,9% ) used modified or customized classifications [ 1315 ] . in 4 publications ( 3,8% ) , errors in the stated classification
were identified [ 13 , 1618 ] : in two papers [ 16 , 18 ] , the authors cite the updated retina society (  91 ) but in fact they used the first retina society classification (  83 ) , koerner et al . , after citing the updated retina society classification used a customized one , and roldn - pallars et al .
cite the two retina society classifications at the same time . among the papers using the updated retina society classification , the most documented was grade c pvr ( 48 articles , 83% ) , while grades b and a were less frequently documented ( 15 ( 26% ) and 7 ( 12% ) articles , resp . ) .
of the publications documenting only c grade , the classification of subtypes was infrequently used . in 5 of 48 publications ( 10,4% )
, there was a full c grade description in terms of localization ( anterior or posterior ) , extension ( in clock hours ) , and type ( focal , diffuse , subretinal , circumferential , or anterior displacement ) .
a similar finding was observed when authors used the first retina society classification ( 35 papers ) : only c and d grades were frequently reported ( 27 and 10 papers , resp . ) , while grades a and b were infrequently used ( 4 and 7 articles , resp . ) .
when the silicone study classification was used , only grade c was mentioned ( in 2 out of 4 articles ) .
finally , there were 2 publications ( 1,9% ) in which the standard classifications were used to assess changes in pvr status after any treatment , reporting pvr grade before and after it [ 19 , 20 ] .
the remaining authors used the classifications only to describe pvr status , rather than using them to analyze the improvement or worsening of the previous stage after the applied treatment .
classifications of pvr were developed to provide clinicians with a useful tool to compare results of treatments .
they are , to date , purely descriptive and do not reflect the pathobiology of this complex vitreoretinal disease .
the original classification of 1983 , which was relatively simple to use , induces errors in the estimating severity in some cases .
as mentioned , d grades were based on the ophthalmoscopic appearance of the detached retina , and experience demonstrated that some of these cases could be relatively easily solved by peeling localized epiretinal membranes although , in some cases , classified as c , intraretinal severe changes prevent reattachment , unless complicated surgical techniques were used .
subsequent classifications [ 10 , 11 ] were more detailed and therefore more complicated to use on a routine basis .
they incorporated the anterior pvr forms , which add severity to the case , but until now no one has incorporated the intraretinal changes , observed in many surgical retinal samples [ 8 , 9 ] , which may prevent the anatomical reattachment of the retina and require retinectomy .
another important limitation is that they do not provide information on the activity of the process , although it has been observed that pvr progresses through several stages [ 13 ] .
this may be crucial in estimating the risk of reproliferation after surgery or when surgeons schedule removing silicone oil , and no data on the chronology of events is included in any classification .
furthermore , current classifications are not prognostic and do not correlate with visual prognosis or anatomical success after surgical treatment
. moreover , some of these classifications can be difficult to use in clinical practice , due to their complexity ( grade , localization , extension , type , etc . ) and because they may not provide useful information they have been largely abandoned by clinicians .
our findings in this study demonstrate that , in clinical research , investigators are using them inconsistently and reporting limited observations of stages ( mostly grade c ) .
some authors simply do not use any , preferring generic terms , such as minimal , moderate , and severe pvr [ 21 , 22 ] .
furthermore , early stages of pvr ( named as grades a and b ) , which are common to all classifications , are not used , and most authors refer only to most advanced stages , basically grade c [ 20 , 23 ] . moreover
, the presence of classification errors could indicate that there is confusion concerning their use [ 13 , 1618 ] .
an important relevant finding is that only a limited number of clinicians appropriately and fully use the current updated classification of 1991 [ 2427 ] , while the majority of authors avoid using the added characteristics of localization , extension , and type , limiting the description to the grade .
in addition , many colleagues still use the first reported classification , probably because although it presents many limitations , it is easier to use compared to the last version [ 23 , 28 ] .
additionally , some authors decided to use alternative classification , probably to avoid problems evaluating pvr stages .
the use of multiple classifications makes the efficient communication between clinicians and the comparison of different studies very problematic .
as mentioned , one of the aims of this study was to evaluate the usefulness of these classifications for pvr management with surgery and other adjunctive treatments .
unfortunately , many ophthalmologists did not use the normalized classifications for comparing the outcomes using non - clearly defined terms such as pvr recurrence [ 29 , 30 ] .
our findings showed the inconsistent and limited use of the current pvr classifications suggesting that it may be of benefit to produce a revised classification incorporating , if possible , the new knowledge on pvr which has been published since 1991 , pointing out new potential targets for therapeutic agents distinct from those , mainly proliferative agents , targeted by the original description of this disease .
thus , it is possible that we could reduce its prevalence after retinal detachment surgery and to improve the anatomical and functional results of this disease which resists the attempts of both basic researchers and clinicians for more than 30 years .

Answer:
purpose . to evaluate the current and suitable use of current proliferative vitreoretinopathy ( pvr ) classifications in clinical publications related to treatment
 . methods .
 a pubmed search was undertaken using the term  proliferative vitreoretinopathy therapy  .
 outcome parameters were the reported pvr classification and pvr grades .
 the way the classifications were used in comparison to the original description was analyzed .
 classification errors were also included .
 it was also noted whether classifications were used for comparison before and after pharmacological or surgical treatment .
 results .
 138 papers were included .
 35 of them ( 25.4% ) presented no classification reference or did not use any one .
 103 publications ( 74.6% ) used a standardized classification .
 the updated retina society classification , the first retina society classification , and the silicone study classification were cited in 56.3% , 33.9% , and 3.8% papers , respectively .
 furthermore , 3 authors ( 2.9% ) used modified - customized classifications and 4 ( 3.8% ) classification errors were identified .
 when the updated retina society classification was used , only 10.4% of authors used a full c grade description .
 finally , only 2 authors reported pvr grade before and after treatment . conclusions .
 our findings suggest that current classifications are of limited value in clinical practice due to the inconsistent and limited use and that it may be of benefit to produce a revised classification .


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:
primitive neuroectodermal tumor ( pnet ) , a highly aggressive tumor of the kidney is a rare malignancy with only few cases being reported in literature .
boys and men are more likely to suffer rpnet ( renal pnet ) , and the sex ratio ( male : female ) is about 3:1 .
it usually presents at an advanced stage , with distant metastasis and is associated with a poor prognosis .
we report in this paper , a case of primary renal pnet in a young male .
a 39-year - old male presented with complaints of hematuria and heaviness in the right flank since 15 days . physical examination revealed a soft lump in the right hypochondrium .
ultrasound examination of the abdomen showed an irregular cystic structure in the right kidney at lower pole with few internal echoes .
ct scan of the abdomen demonstrated a large significantly enhancing right renal lower polar mass with necrosis with thrombosis in right renal vein . on the basis of these clinico - radiological findings , diagnosis of right side renal cell cancer
gross examination revealed a friable , grayish - white , lobulated mass ( 7  5 cm ) with multiple foci of hemorrhage and necrosis .
the mass extended from mid to lower pole of the right kidney and infiltrated into the renal pelvis and was limited to the renal capsule the renal vein and ureter were free of the tumor .
there was a thrombus inside the renal vein , which was not adherent to intima of renal vein .
microscopically , the tumor was composed of monotonous sheets of round cells with scant cytoplasm , hyperchromatic vesicular nuclei , coarse chromatin and few conspicuous nucleoli , transverse by thin fibrous bands infiltrating and entrapping the renal glomeruli and tubules [ figure 1 ] .
on immunohistochemistry , the tumor cells were positive for cd99 [ figure 2a ] , fli-1 [ figure 2b ] , nse [ figure 2c ] , and synaptophysin [ figure 2d ] , but negative for desmin , ck , ema , and lca .
a diagnosis of pnet was made based on the above findings , and patient was started on vac ( vincristine , adriamycin , and cyclophosphamide ) alternating with ie ( ifosfamide and etoposide)-based adjuvant chemotherapy regimen which he tolerated well .
after 6 cycles of chemotherapy , a pet scan showed absence of any metabolically active focal uptake in whole body .
chemotherapy with vac ( vincristine , actinomycin d , and cyclophosphamide ) alternating with ie ( ifosfamide and etoposide ) for a year was planned .
section showing malignant round cells arranged in pattern sheets infiltrating and entrapping the renal glomeruli and tubules { figure 1a : h&e ; 100 , figure 1b : h&e ; 200 } ( a ) the tumor cells express membranous expression of cd99 { dab ; 200 } ( b ) the tumor cells express nuclear positivity for fli-1{dab ; 200 } ( c ) the tumor cells express cytoplasmic positivity for neuron - specific enolase ( nse ) { dab ; 200 } ( d ) the tumor cells expressing cytoplasmic positivity for synaptophysin { dab ; 200 }
the primitive neuroectodermal tumor ( pnet ) , was first recognized by arthur purdy stout in 1918 , and is a member of the family of  small round - cell tumors .  pnet arising in the kidney was first reported by mor in 1994 .
primitive neuroectodermal tumors occurs preferentially in the soft - tissues of the paravertebral region and chest wall , less frequently in extremities , with a slight male predominance .
rpnet appears to be an unique clinical entity that behaves more aggressively than pnet arising at other sites .
the presenting symptoms and images of rpnet are non - specific and similar to other renal tumors .
rpnet show a male predominance with 85% cases being diagnosed during the second to fourth decade .
it is an aggressive tumor that tends to recur locally and to metastasize to lymph nodes , lung , liver , bone , and bone marrow , which entail a worse prognosis .
the differential diagnosis of rpnet includes other small round cell tumors like neuroblastoma , adult nephroblastoma , malignant lymphoma , rhabdoid tumor , small cell carcinoma and monophasic , poorly differentiated , round cell variant of synovial sarcoma , carcinoid , rhabdomyosarcoma , clear cell sarcoma of the kidney , the small cell variant of osteosarcoma , and desmoplastic small round cell tumor .
grossly , rpnet are typically very large tumors with about 65% measuring > 10 cm in diameter .
they tend to be grayish in color , encapsulated , and contain focal areas of hemorrhage or necrosis .
microscopically , the tumor is composed of sheets of round cells ; individual cells have a round nucleus with a distinct nuclear membrane , fine powdery chromatin , and 1 or 2 small nucleoli .
the cytoplasm is ill - defined , scanty , usually pas - positive , and mitosis are variable .
perivascular pseudo rosettes and homer - wright rosettes are common . to better address the diagnosis ,
immunohistochemical markers to be used to confirm diagnosis are cytokeratin ( for nephroblastoma , small cell carcinoma , and synovial sarcoma ) , lca ( for lymphoma ) , nse / chromogranin a ( for neuroblastoma ) , and cd-99 for pnet .
cd99 ( the product of mic2 gene ) greatly aids in recognizing the es / pnet family of tumors .
many pnet also stain for neural markers , including nse , leu-7 , s-100 protein , synaptophysin , and pgp9.5 .
the most frequent translocation in pnet is t(11;22)(q24;q12 ) , detected in approximately 90% of cases , resulting in ews - fli fusion gene .
the overall survival in patients who had localized rpent was longer than that in the patients who had rpent with regional nodes or distant metastases .
the role of radiotherapy is not clear , but it may be advocated in locally advanced disease and involvement of gerota 's fascia .
post - operative chemotherapy for rpent is usually used and can improve the prognosis of rpnet .
the most commonly used chemotherapeutics are adriamycin , etoposide , dactinomycin , vincristine , cyclophosphamide , and ifosfamide . a multimodality management is recommended .

Answer:
primitive neuroectodermal tumor of the kidney is a rare entity .
 very few cases of primary renal pnet have been reported to date .
 most literature about rpnet is isolated case reports .
 we report a case of rpnet in a 39-year - old male with a pre - operative diagnosis of renal cell carcinoma with renal vein thrombosis .
 the patient underwent radical nephrectomy with thrombolectomy , and histopathological examination revealed a highly aggressive tumor composed of monotonous sheets of round cells .
 tumor cells were positive for cd 99 and fli-1 , hence confirming the diagnosis of primitive neuroectodermal tumor .
 post - surgery , patient was given vac / ie - based adjuvant chemotherapy . in view of highly aggressive nature of this tumor ,
 prompt diagnosis and imparting effective chemotherapy regimen to the patient is required , and it is important to differentiate pnet from other small round - cell tumors because of different therapeutic 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:
invasive meningococcal disease ( imd ) is due to infection with the gram - negative bacterium neisseria meningitidis ( n. meningitidis ) .
although fulminant septicemia is less common , it is highly fatal , even if treated .
approximately 500  000 cases occur worldwide annually , resulting in approximately 50  000 deaths and severe long - term complications in up to 20% of survivors .
deafness , intellectual and learning impairment , epilepsy , and other neurological deficits are frequent sequelae that lead to long - term reduction in quality of life . according to the world health organisation ( who ) estimates , the overall notification rate of imd in europe ranges from 0.214 cases per 100  000 in the general population .
although the rates of imd can be low in european and other industrialized countries , the disease is potentially devastating , with a case mortality rate that has remained at about 510% despite treatment . in europe ,
the highest numbers of confirmed imd cases are reported in children younger than 5 y of age ( 7.37 per 100  000 ) , followed by children aged 1524 y ( 1.44 per 100  000 ) .
most of these cases of imd occur sporadically , although small local outbreaks are not uncommon .
while the majority of imd infections are caused by n. meningitidis serogroups a , b , c , x , w-135 , or y , their relative prevalence has varied considerably over time and by geographical location , making trends in disease epidemiology unpredictable . in europe , the majority of imd cases ( 85% ) are caused by serogroups b and c , while serogroup y is the third most frequently reported cause ( 3% in 2008 , and 4% in 2009 ) .
overall , the number of cases of imd attributable to serogroup y increased by 42% across european countries between 2007 and 2009 . however , the incidence of n. meningitidis infection due to serogroup c has declined since the introduction of the meningococcal group c conjugate vaccine ( mcc ) in some european countries while the incidence of imd across europe has also changed .
active surveillance is crucial to assess the epidemiology and burden of imd , as well as the impact of vaccination . in european countries , in which adequate surveillance systems have been in place for > 10 y
, long - term surveillance has detected large reductions in meningococcal serogroup c disease following the introduction of the mcc .
however , the scarcity of comprehensive country - specific data on the current burden of meningococcal disease in turkey arises from the lack of homogenous surveillance system , making it difficult to understand and to predict the dynamic changes in serogroup - specific epidemiology .
meningococcal conjugate acwy vaccine is used for both individual protection ( e.g. , target groups such as hajj pilgrims , military recruits , or teenagers in the united states ) and mass campaign vaccinations .
it is established that mcv has a great impact in reducing meningitis if used at large scale , such as the use of menc conjugated vaccine in the uk . while commonly used meningococcal vaccines in europe cover serogroups a , c , y , and w-135 , an effective vaccine against serogroup b has not been available until recently . a quadrivalent protein - based serogroup b vaccine developed by novartis vaccines and diagnostics has been licensed in the eu for infant vaccination . although its use has not been implemented in large - scale vaccination programmes , phase iii studies have demonstrated that the vaccine has the potential to protect against 78% of all imd - causative serogroup b strains .
lack of systemic surveillance data on serogroup - specific meningococcal epidemiology complicates the decision to be made by health authorities with regard to implementation and choice of available meningococcal vaccines .
the purpose of this review is to provide up - to - date information on the epidemiological situation regarding the burden of imd in turkey .
in turkey , data available on the burden of imd at the national level are based on records collected by the turkish statistical institute ( tsi ) and by the ministry of health .
according to ministry of health data , between 1989 and 1999 , the incidence of imd varied between 1 and 35 cases per 100  000 and the mortality rate varied between 0.71 and 2.62 per million cases .
the tsi reports that meningococcal infections were responsible for 10.2% ( 1336 ) of all deaths in children under 5 y of age in year 2008 .
tsi reports 21 , 14 , and 15 deaths from meningococcal infections in all age groups in 2010 , 2011 , and 2012 , respectively based on icd-10 coding system .
these contradictory data might be due to either the notification procedure ( report of death due to imd or report of newly identified imd cases ) or the identification of causes .
the current situation on meningococcal epidemiology may be better reflected by the prospective multicenter sentinel surveillance for childhood bacterial meningitis conducted by 2 groups since year 2005 .
one of the investigator - initiated sentinel surveillance studies was conducted by ceyhan et al . between february 16 , 2005 , through february 15 , 2006 , for acute bacterial meningitis among children admitted to 12 participating hospitals from 7 geographic areas and 12 health centers in 9 cities .
this study reports that n. meningitidis was the leading cause of bacterial meningitis in children aged < 1 y ( 56.5% ) followed by those aged 14 y. among the samples that were positive for n. meningitidis following pcr analysis , serogroup w-135 was the cause of most infections59 ( 42.7% ) cases were due to serogroup w-135 , 43 ( 31.1% ) were due to serogroup b , 3 ( 2.2% ) were due to serogroup y , and 1 ( 0.7% ) was due to serogroup a. there were no cases with a positive result for serogroup c. in this study , serogroup w-135 was also more common in children aged 416 y , while serogroup b was slightly more common in children aged <3 y. n. meningitidis serogroup w-135 was more prominent than the other meningococcal serogroups in the southeast anatolia while n. meningitidis serogroup b was much more common in the marmara ( northwestern turkey ) and the central region . during ongoing surveillance by ceyhan et al . between 20072009 , while the overall imd incidence was stable , the prevalence of imd due to serogroup b was reported to increase to 35% and the prevalence of serogroup w-135 decreased .
interestingly , the same group states that during the first 9 mo of 2011 , serogroup w135 was the predominant serogroup , followed by serogroup a , and serogroup b was observed in only 2.5% of cases .
another nationwide prospective rt - pcr - based surveillance for childhood bacterial meningitis was conducted between july 2006 and january 2009 and the turkish ministry of health with participation of 37 referral hospitals located in 23 cities in 7 geographic regions of the country .
rt - pcr detected bacterial dna in 246 ( 29% ) of 841 csf specimens from children with suspected bacterial meningitis , of which 131 ( 53% ) were due to streptococcus pneumoniae , 47 ( 19% ) were due to neisseria meningitidis , and 40 ( 16% ) were due to hemophilus influenzae type b. in this study , 29 ( 62% ) of 47 n. meningitidis isolates were determined as serogroup b , 2 ( 4% ) serogroup c , 1 ( 2% ) serogroup x , 1 ( 2% ) serogroup a , 1 ( 2% ) serogroup w135 , and 13 ( 28% ) other serogroups ( undetermined ) .
sixteen ( 32% ) of n. meningitidis were detected from the marmara ( north - western turkey ) region and only 5 ( 11% ) from the southeast anatolia .
to prevent imd among young infants , protection needs to be achieved early in life . since the introduction of the first meningococcal conjugate vaccines in 1999
, remarkable progress has been made in reducing the morbidity and mortality caused by meningococcal disease .
studies have demonstrated that meningococcal c conjugate ( mcc ) vaccination confers protection in infancy ( 012 mo ) from the first dose but this protection is short - term .
however , administration of a booster dose early in the second year of life results in longer protection .
the burden of imd is the highest among infants aged < 1 y ( 2.6 cases per 100  000 persons ) in the us . among infants younger than 1 y of age , more than 50% of cases
it was recently reported that bacterial meningitis was most frequently observed in the first 7 mo of life , regardless of the etiologic agent .
all meningococcal meningitis cases occurred in those < 6 mo of age and mostly in those <3 mo of age .
all cases in the youngest infants were due to meningococcal serogroup b and w135 in turkey .
if meningococcal vaccines against men b and serogroups a , c , w135 , y with early infant indications may also be registered , we would have an opportunity to protect young infants starting from 2 mo of age in turkey .
the growing - complexity of national immunization programme ( nip ) in turkey has resulted in as many as 4 required injections during a single healthy baby visit .
the number of injections in a well - baby visit in the us is up to 7 .
protecting against vaccine preventable meningococcal serogroups will result in an increase in the number of injections up to 6 in turkey , but this is acceptable when we compare with developed countries ( table 1 ) current nip schedule .
contrasting data obtained from different surveillance studies may be related to regional differences in the weight of subjects enrolled from different regions of the country or methods used .
argues that higher rates of serogroup w-135 since 2005 in their earlier study is due to 100  000 turkish hajj pilgrims traveling to saudi arabia every year , which was also seen in malaysia and singapore .
the results reported by bakir et al . showing the predominance of serogroup b may be explained by the millions of the turkish diaspora living in europe , where serogroup b is predominant , who travel back and forth to the country many times annually .
this is a more likely explanation of the existing sero - epidemiology because other explanations of the sharp decrease of serogroup b imd from 35% down to 2.5% in only a few years in the absence of serogroup - specific vaccination are unlikely .
this variation may also reflect the introduction and implementation of detection techniques such as the pcr .
sero - epidemiology data on imd in 2 different surveillance studies in turkey at the same time periods had different results .
this complicates the decision to be made by health authorities on the implementation and the type of meningococcal vaccine to be chosen . in the light of available surveillance data in turkey , a vaccine effective against meningococcus serogroup b as well as serogroup
systematic continuous surveillance is warranted to measure the urgency of need and effectiveness of a vaccination program for imd . the who recommends the introduction of appropriate large - scale meningococcal vaccination programmes in countries with high ( > 10 cases/100  000 population / year ) or intermediate ( 210 cases/100  000
population / year ) imd incidence rates , and in countries with frequent epidemics . in countries with lower imd incidence rates ( < 2 cases/100  000 population / year ) , vaccination is recommended for defined risk groups , including children and young adults residing in close communities , laboratory workers at risk of exposure , travelers to high - endemic areas and immunodeficient individuals .
overall , each country should choose the appropriate vaccination program depending on the locally prevalent serogroup of n. meningitidis .
conjugate vaccines are preferred over polysaccharide vaccines due to their potential for herd protection , immunologic memory and their increased immunogenicity , particularly in children < 2 y of age .

Answer:
each country chooses the appropriate vaccine against imd depending on the locally prevalent serogroups of n. meningitides .
 frequency of each meningococcal serogroup varies considerably over time and by geographical location . despite the majority of imd cases ( 85% )
 are caused by serogroups b and c in europe , true prevalence of serogroup b imd cases in turkey is unclear . in one of the recent studies , the sharp decrease of serogroup b imd from 35% down to 2.5% in a few years despite the absence of vaccination is confusing .
 millions of european turkish people travels from europe to turkey every year who could most probably carry serogroup b. it is obvious that a nationwide active surveillance is crucial to assess the the true epidemiology and burden of imd which has a major impact on the choice of vaccine type and age interval the vaccination to be implemented .