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:
there has been a striking upsurge in tuberculosis ( tb ) vaccine research in china in recent years .
more than 80 papers reporting such research have been published since 2004 ( figure 1 ) , many in english language journals .
this has been driven and funded largely by chinese government agencies , since the scale of the tb problem and the difficulties in implementing fully effective control measures were recognized .
, we can note that there are at least two additional restricting factors limiting the progress of the field in china : few research groups have access to facilities for safely working with animals infected with a dangerous pathogenic organism such as the tubercle bacillus ; infrastructure for undertaking vaccine clinical trials to international standards is sparse . in consequence ,
the universal problem of how to select among the promising approaches and candidate vaccines is particularly acute in china .
nevertheless , the basic research problems are being tackled with some enthusiasm and creativity , and the new 5-year program to improve tb control that was announced by the chinese ministry of health on 1 april 2009 will have an impact .
the antigens investigated to date and the locations of research groups are listed in tables 1 and 2 , respectively .
a substantial body of work has gone into characterizing the immune responses to be found in tb infection and following vaccination .
the twin purposes of identifying candidate antigens for use in vaccines and diagnostic tests and of defining immunological markers for latent infection and disease states drive these studies .
these studies have not always been followed up with tests of protective or therapeutic efficacy in animal infection models .
the increased immunogenicity of mouse dendritic cells transfected with antigen heat shock protein 65 ( hsp65 ) has been tested in wuhan and in hong kong , and differences have been found in the polarizing effect of intracellular mycobacterium bovis bacille calmette  guerin ( bcg ) vaccine bacteria on antigen presentation by human adult and cord blood dendritic cells .
various forms of recombinant bcg expressing early secreted antigen 6 of mycobacterium
 tuberculosis ( esat6 ) , or antigen 85b ( ag85b ) and antigen rv3425 , or ag85b and esat6 with tumor - necrosis factor- , or esat6 and human granulocyte macrophage - colony stimulating factor ( gm - csf ) have shown enhanced immunogenicity .
recombinant m. smegmatis expressing m. tuberculosis culture filtrate protein 10 ( cfp10)/esat6 fusion protein was found stimulatory for macrophage inducible nitric oxide synthetase .
recombinant m. smegmatis and bcg strains have been made that can express cloned antigens at a range of different levels under the control of modified fura gene promoters .
other bcg recombinants expressing esat6 , esat6/interleukin 2 ( il-2 ) or ag85b / esat6 fusions have been made .
a range of known antigens has been tested for immunogenicity as mixtures , fusion proteins and peptides .
these include chimeric ag85b / esat6 with adjuvants monophosphoryl lipid a ( mpl ) and trehalose 6,6'-dimycolate , hsp16.3 with dimethyl - dioctadecyl - ammonium bromide / mpl ( dda / mpl ) adjuvant , fusion protein m. tuberculosis protein 64 ( mpt64)esat6 , resuscitation - promoting factor b ( rv1009 ) , or cfp10 , esat6 or rpfe ( rv2450 ) with nitrocellulose , or rv3772 and rv3425 with incomplete freund 's adjuvant ; or ag85b / mpt64190198/mtb8.4 plus a novel adjuvant of dda with bcg extract .
in - silico analysis of putative mhc class 1-restricted epitopes present in antigens encoded within the region of difference 1 ( rd-1 ) to rd-16 regions of m. bovis genome has revealed potential high - affinity hla binders and profiles of human humoral responses to 38-kda , mtb48 , cfp10/esat6 antigens have been defined .
screening of human immune sera against an expression library of m. tuberculosis open reading frames revealed three novel antigens among the top 20 most strongly recognized : rv1987 , rv3807c and rv3887c .
more than a dozen studies have used dna vaccination as a means of delivering antigens in immunogenicity tests . many have shown th1-biased immunogenicity without additional adjuvanting , for example with ag85b , ag85b / esat6 fusion , esat6/cfp10 fusion , mtb8.4/38-kda / ag85b fusion and epitopes from esat6 , ag85a , cfp10 and ag85b inserted within hsp65 .
targeting the expressed product for degradation via the ubiquitin pathway has been used to enhance mhc class 1 presentation of epitopes from mpt64 and 38-kda , mpt64 , and esat6 .
enhanced responses to encoded antigens have been obtained by additionally encoding cytokines , such as interleukin 21 ( il-21 ) , with ag85a or ag85a / esat6 , and gm - csf with ag85a .
inclusion of dna expressing il-12 enhanced prime / boost responses to bcg and to plasmids expressing ag85a and esat6 .
esat6 dna priming and protein boosting has also been shown to give enhanced th1 responses .
many antigen preparations have been tested for their capacity to protect against challenge infection with virulent m. tuberculosis .
subcutaneous esat6/cfp10 , or esat6/mpt64 fusion proteins on nitrocellulose protected mice against h37rv challenge , but not as effectively as bcg .
hsp65/il-2 fusion protein was found to elicit better protection than hsp65 given with dda / mpl adjuvant and protection was equivalent to that produced by bcg .
similarly , either hspx , a dormancy associated antigen , or synthetic epitope 91104 gave protection equivalent to bcg when given with dda / mpl .
/ mpt64190198/mtb8.4 fusion protein with dda adjuvant boosted protection against challenge in bcg primed mice .
a similar fusion protein in which mtb8.4 was replaced by hspx gave a similar boost , but boosting with a mixture of the two fusion proteins was even better .
a fusion protein of esat6 and ag85a also significantly boosted protection against h37rv in mice .
recombinant bcg expressing the ag85b / mpt64190198/mtb8.4 fusion protein gave slightly better protection to mice against h37rv challenge than parent bcg or bcg expressing rag85b alone .
recombinant bcg expressing a fusion protein of human interleukin ( hil)-12p70 and esat6 showed increased immunogenicity but less protective effect .
recombinant salmonella typhimurium that both expressed esat6/ag85b fusion protein and delivered it as a dna vaccine when given orogastrically gave protection similar to subcutaneous bcg and the combination was superior to either vaccine alone .
the earliest reports indicated protection in mice superior to bcg when a divalent construct expressing both ag85b and mpt64 , or a mixture of plasmids expressing ag85b , mpt64 , mpt63 and esat6 was used . the protection given by a mixture of three plasmids expressing mpt83 , ag85b and esat6
was enhanced by including dda adjuvant and an encoded fusion protein of ag85b and mpt64 was superior to the separately encoded antigens .
encapsulation in poly(lactide - co - glycolide ) microspheres with dda enhanced the protective efficacy in mice of dna - encoding ag85b / mpt64/mpt83 fusion antigen , and strikingly the dna mixed with dda was superior to bcg in protecting cattle against challenge .
inclusion of a plasmid expressing il-2 improved protection by this plasmid or by plasmid expressing mtb8.4 .
a mixture of plasmids encoding ag85b , mpt64 , mpt70 and tb10.4 boosted protection by bcg , as did a plasmid expressing a cfp21/mpt64 fusion protein .
ag85b or ag85a were superior to esat6 when compared separately for protection as dna vaccines .
dna expressing a fusion of mpb64/ag85b / esat6 was superior to a mixture of plasmids expressing the separate antigens and gave protection equivalent to bcg .
the protective effect of dna expressing hsp65 against bcg challenge was enhanced by incorporating epitopes of esat6 , ag85a / b and cfp10 within the hsp65 backbone .
the protective effect of hsp65 dna against h37rv challenge was increased by expression as a fusion with hil-2 , but did not surpass that of bcg .
expression of ag85b fused to bovine herpes virus 1 vp22 protein , which facilitates dissemination of antigen to adjacent cells , resulted in protection against h37rv challenge in mice that was better than protection by bcg .
few studies have been conducted with animals other than mice : a mixture of ag85b , hspx and cfp10/esat6 fusion together with cpg and aloh as adjuvant was immunogenic in mice but gave little protection against challenge with h37rv in guinea pigs ; in contrast , combined dna vaccines encoding antigens ag85b , mpt64 and mpt83 given with dda appeared to be better than bcg in protecting cattle .
interest in therapeutic vaccination has been sustained by clinical studies of a commercial chinese product , m. vaccae extract .
recent meta - analyses of published data concluded that this product gave significant benefit in preventing tb in people at high risk ( 13 studies ) , but there was only a minor benefit from treating new tb cases ( 54 studies ) . in a unique and contrasting approach
, a recombinant m. smegmatis delivering dna expressing human granulysin and murine il-12 was recently found to be therapeutic against h37rv infection .
most research into therapeutic vaccines for tb has focused on the use of naked dna vaccination .
dna had a significant therapeutic effect against h37rv in mice and the fusion hsp65/il-2 was significantly better .
treatment of infected mice with a dna vaccine expressing a fusion protein of mycobacterial hsp70 and leukocyte cluster of differentiation antigen 80 substantially reduced acid - fast bacteria and pathology in liver and spleen , whereas bcg had no effect .
although treatment with dna expressing ag85b was therapeutic , treatment with dna expressing mpt64 was not , and the mixture was less effective than the ag85b vaccine on its own , and inclusion of dna expressing il-12 gave a slight additional benefit .
mice infected with a clinical isolate resistant to isoniazid and rifampicin responded well to treatment with the drugs plus dna expressing chimeric ag85a / esat6 , and appeared to respond better to treatment with the drugs plus dna expressing ag85a than to the dna vaccine alone ; ag85a dna alone was at least as effective as ag85a plus rifampicin in treating mice infected with a strain resistant to rifampicin and isoniazid , ag85a
an immunogenic mixture of dna vaccines expressing ag85b , mpt64 and mpt83 has been found to work as a potent adjunct to isoniazid plus pyrazinamide therapy in mice and to be therapeutic in cattle infected with m. bovis , reducing both pathology and bacterial numbers ; a mixture expressing ag85b , mpt64 and hsp65 was similarly effective .
inclusion of immunostimulatory nucleotide motifs in the gene transcript enhanced the therapeutic efficacy of a plasmid expressing hsp65 when tested against h37rv in mice .
it is evident in considering this body of recent tb vaccine research in china that much of it has been tactical in nature , establishing credentials both nationally and internationally , and building new research bases . additionally , there are creative and insightful studies of particular relevance to the needs of china .
researchers are now able to exploit cutting edge technologies in designing new tb vaccines and are increasingly able to test the vaccines in relevant animal models of infection .
the evidence that dna vaccines can provide effective therapy for tb in cattle may be a significant pointer to the future .
the potential benefits of adding immunotherapies / therapeutic vaccines to tb chemotherapy have been recognized in china , but both preventive and therapeutic approaches against human tb await development of clinical trial capacity for their proper assessment .

Answer:
it is now privately acknowledged that there may be little if any perceptible impact of the national bacille calmette  guerin ( bcg ) vaccination program on disease prevalence , despite the extensive coverage of the newborn infant population and likely benefit in the early years of life . a better preventive vaccine than bcg is now being sought by chinese researchers .
 urgency has been added to the control problem by the emergence of multidrug - resistant tuberculosis ( tb ) .
 furthermore , expensive second - line drugs seem unlikely to be made available by the government to treat drug - resistant cases , so attention in addition has turned to the potential of immunotherapy as an adjunct to chemotherapy .
 research trends are summarized here .


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:
from the first reported infected patient in may 2009 through january 2010 , a total of 740,835 patients in south korea were reported as having pandemic ( h1n1 ) 2009 virus infection .
a total of 225 patients ( 0.03% ) died of disease related to pandemic ( h1n1 ) 2009 . during this period ,
physicians in local clinics and tertiary hospitals sent specimens from 67 patients who were suspected of having drug - resistant pandemic ( h1n1 ) 2009 to the korea centers for disease control ; 11 patients ( 16% ) had drug - resistant virus ( figure ) .
after confirmation of drug resistance , epidemic intelligence service officers obtained clinical and epidemiologic data by medical record review and interviews with household contacts and attending physicians for all patients .
clinical course and outcome of 11 patients with oseltamivir - resistant pandemic ( h1n1 ) 2009 , south korea .
symptom aggravation was defined as influenza - related symptoms that worsened regardless of new infiltrations seen by chest radiography .
symptom improvement was defined as influenza - related symptoms ( nasal stiffness , sore throat , cough , myalgia , fatigue , headache , and fever ) that were absent or mild .
ed , emergency department . to investigate whether virus contained genetic markers associated with resistance to antiviral drugs , a conventional genotyping assay ( sequencing ) was performed , and neuraminidase ( na ) and matrix 2 genes were sequenced .
all 11 patients had virus with a histidine - to - tyrosine mutation at residue 275 of the na protein ( h275y ) ; 1 patient also had virus with an i117 m mutation ( figure ) .
detailed molecular epidemiologic data and genetic characteristics of the isolates are described elsewhere ( 2 ) . of the 11 patients ,
6 were < 59 months of age and 5 had underlying immunosuppressive conditions ; only 1 patient was immunocompetent and > 59 months of age ( table ) . three patients from whom samples before and after treatment with oseltamivir were available showed evidence of having acquired the h275y mutation during oseltamivir therapy .
none of the 11 patients received oseltamivir chemoprophylaxis . * specimens were obtained from oropharyngeal ( n = 7 ) and nasopharyngeal ( n = 2 ) swabs , nasopharyngeal washings ( n = 1 ) , and brochoalveolar lavage fluid ( n = 1 ) .
patients who had underlying diseases such as hiv infection , malignancy , liver cirrhosis , or chronic renal failure , or patients receiving immunosuppressive treatment .
 carbapenem - resistant pseudomonas aeruginosa ( patient 3 ) , carbapenem - resistant acinetobacter
 baumanii ( patient 4 ) , and penicillin - susceptible streptococcus pneumonia ( patient 10 ) .  of the 3 patients , 1 was infected with carbapenem - resistant p. aeruginosa ( patient 3 ) and 1 was infected with carbapenem - resistant a. baumanii ( patient 4 ) .
we also tested 100 persons who had contact with the 11 patients for possible transmission of drug resistance .
eight of 100 were confirmed as having been infected with pandemic ( h1n1 ) 2009 virus before the 11 patients were infected .
influenza - like illnesses developed in the 11 patients a median of 2 days ( range 17 days ) after the 8 contact persons were confirmed as having pandemic ( h1n1 ) 2009 .
five of the 8 contact patients were children ; none had an immunosuppressive condition or were given oseltamivir chemoprophylaxis before illness ; and 7 of 8 were < 59 months of age .
oseltamivir - resistance tests were not performed for these 8 patients because they all received oseltamivir therapy and their clinical symptoms resolved .
therefore , the possibility of transmitted resistance from contact patients was not demonstrated in this study .
all 11 patients were initially given the usual dose of oseltamivir ( 75 mg 2/day in adults ) .
after detection of oseltamivir resistance , treatment regimens were as follows : 3 patients were given high - dose oseltamivir ( 150 mg 2/day in adults ) , 3 patients were given combination therapy ( oseltamivir and amantadine ; oseltamivir and peramivir ; and oseltamivir , amantadine , and ribavirin , respectively ) ; 3 patients were given zanamivir nasally ; and 2 patients continued to receive oseltamivir .
seven of the 11 patients had complications during treatment : 6 had viral or secondary bacterial pneumonia and 1 had acute respiratory distress syndrome ( table ) .
patient 3 died 15 days after confirmation of infection with pandemic ( h1n1 ) 2009 virus and 10 days after the emergence of oseltamivir - resistant virus .
patient 4 died 15 days after confirmation of infection and 4 days after emergence of oseltamivir - resistant virus .
patient 8 , who was infected with virus that had h275y and i117 m mutations , died 18 days after confirmation of infection and 4 days after the emergence of oseltamivir - resistant virus .
our nationwide surveillance of drug - resistant pandemic ( h1n1 ) 2009 in south korea indicated that most patients were children ( < 59 months of age ) or immunocompromised .
all isolates had the h275y mutation in the na protein , and 1 isolate also had the i117 m mutation in the same protein .
our finding that oseltamivir resistance developed in immunocompromised patients is consistent with those of recent case reports that described development of oseltamivir resistance in immunosuppressed patients receiving this drug ( 3,4 ) .
a recent study in australia reported that 4 of 32 adult oncology and hematology patients were infected with oseltamivir - resistant virus with the h275y mutation ( 5 ) . in 3 of our patients ( patients 3 , 5 , and 11 ) drug - resistant
thus , we suggest that physicians be alert to emergence of oseltamivir - resistant pandemic ( h1n1 ) 2009 , particularly if there is treatment failure with oseltamivir or prolonged viral shedding is evident . more than half of our patients were < 59 months of age , indicating that a younger age may be a risk factor for infection with drug - resistant pandemic ( h1n1 ) 2009 .
clinical trials have reported oseltamivir resistance in < 5.5% of children with seasonal influenza ( 6 ) .
explanations for the higher rate of drug resistance in children than in adults are that children have a more protracted course of influenza , longer viral shedding times , and higher viral titers ( 7 ) .
another explanation might be that we can not rule out suboptimal dosing of oseltmaivir in children , although world health organization dose standards were used ( 8) and all pharmacies were given instructions on emergency compounding of oseltmaivir .
availability of pretreatment and posttreatment samples indicated that resistance to oseltamivir developed during treatment in > 3 patients .
one case report ( 9 ) , 1 report of a cluster of cases in vietnam ( 10 ) , and 1 outbreak in a hematologic ward ( 11 ) documented patient - to - patient transmission of oseltamivir - resistant virus .
one of our patients was infected with virus that had a novel na mutation ( i117 m ) .
a previous study indicated that the i117v mutation in avian influenza virus ( h5n1 ) was associated with low - level oseltamivir resistance ( 12 ) .
the i117 m mutation of na may contribute to oseltamivir resistance , but it is not clear whether isolates with these 2 na mutations have higher levels of resistance or virulence than the h275y na mutant .
we found few patients with drug - resistant pandemic ( h1n1 ) 2009 in south korea .
however , our study was based on the nationwide surveillance system for drug resistance among patients with suspected oseltamivir treatment failures , which is different from other surveillance systems , in which all isolated viruses are tested .
thus , we can not report the prevalence of drug - resistant pandemic ( h1n1 ) 2009 and risk factors for drug - resistant virus infection in south korea .
further studies are needed to monitor oseltamivir resistance , especially in immunosuppressed or pediatric patients when treatment failure with oseltamivir or prolonged viral shedding occur .

Answer:
eleven patients with drug - resistant pandemic ( h1n1 ) 2009 were identified in south korea during may 2009january 2010 .
 virus isolates from all patients had the h275y mutation in the neuraminidase gene .
 one isolate had the i117 m mutation .
 of the 11 patients , 6 were < 59 months of age , and 5 had underlying immunosuppressive 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:
an 18-year - old man was referred to our clinic for the evaluation of blurred vision involving the left eye that had manifested four days previous . he had no specific medical , ocular , or trauma history .
the subject 's best - corrected visual acuity was 1.0 in the right eye and 0.9 in the left eye .
vf ( central 10 - 2 sita - standard strategy ) was measured with a humphrey field analyzer ii ( zeiss - humphrey , san leandro , ca , usa ) under continuous monitoring .
the oct demonstrated disruption in the photoreceptor inner and outer segment ( is / os ) junction and undulation of the rpe with backscattering ( fig .
2c ) , but the oct findings did not reveal improvement compared to the initial findings ( fig .
the oct demonstrated a recovery of continuity in the photoreceptor is / os junction , as well as decreased rpe irregularity with minimal backscattering ( fig .
arpe is an acute , transient , foveal disturbance of unknown cause and which affects young adults .
because of scarce case reports and an infrequent prevalence of the disease , the diagnosis can be difficult without suspicion .
fluorescein angiography ( fa ) is a critical test for the differential diagnosis of arpe .
unfortunately , we could not obtain fa data because t he patient had signs of an anaphylactic reaction , such as dizziness and difficulty breathing , immediately after the fluorescein injection .
therefore , we made a diagnosis based on the fundus findings in combination with the oct and other characteristics of the disease .
white dot syndromes , especially multiple evanescent white dot syndromes ( mewds ) , should be considered in the differential diagnosis of arpe .
white dot syndromes are characterized by multifocal white lesions and are accompanied by mild vitritis .
mewds differs from arpe in that the lesions are located outside the macula in the posterior pole , and electroretinogram ( erg ) findings are abnormal .
the main lesions responsible for mewds cause damage to the photoreceptor outer segment but not the rpe . in our case
, there was a single white dot lesion that was limited to the juxtafoveal region ; also , erg , which was performed on the first visit , showed normal findings . in acute posterior multifocal placoid pigment epitheliopathy ( apmppe ) ,
multiple , large placoid lesions start in the posterior pole and extend to the post - equatorial fundus , often accompanied by prodromal flu - like symptoms . our patient 's lesions were discrete clusters of a few subtle , small grey spots that resolved without scarring within three months after onset .
in contrast , the lesions in patients with apmppe are replaced by rpe changes upon resolution .
the oct demonstrated rpe involvement , which was similar to the previously reported oct findings .
based on these findings , other diseases were ruled out and the patient was diagnosed with arpe .
hsu et al .   first described the oct findings of patients with arpe using time domain oct ( oct3 ; carl zeiss ) as a hyper - reflectivity involving the outer nuclear layer , photoreceptor , and rpe .
hyper - reflectivity has not yet been evaluated with sd - oct . in our case
, we found a definite disruption in the is / os junction , as well as an undulation of the rpe according to sd - oct .
because sd - oct can provide better image resolution than oct3 , we believe that the disruption of the is / os junction with sd - oct presented as a hyper - reflectivity of the outer retina with oct3 . as reported by hsu et al . , the thickness of the hyper - reflectivity decreased with increased resolution , and we found a decreased length of the is / os disruption based on the serial observations of the oct findings .
the rpe irregularity also decreased as the symptoms improved and as the threshold of the visual field increased . on the basis of these findings
, the morphologic changes in inflammation related to arpe do not seem to be permanent .

Answer:
we investigated the case of a young man with blurred vision in his left eye .
 his visual acuity was slightly decreased , and ophthalmoscopy disclosed a gray - white lesion in the macula .
 he had no systemic or ocular history .
 on the visual field test , the threshold sensitivity was decreased in the corresponding region .
 spectral domain optical coherence tomography ( oct ) demonstrated a disruption in the photoreceptor inner and outer segment ( is / os ) junction and undulation of the retinal pigment epithelium ( rpe ) with backscattering .
 we re - examined the patient after two weeks and after three months without any treatment . visual acuity and visual field results were gradually normalized , and oct demonstrated the recovery of continuity in the photoreceptor is / os junction , as well as decreased rpe irregularity with minimal backscattering .
 we used spectral domain oct instead of time domain oct ( oct3 ) so that we could provide better image resolution of the acute retinal pigment epitheliitis ( arpe ) .
 finally , we observed recovery of the functional and anatomical changes in the arpe patient with a resolution of the condition within three months following the initial examination , using oct and visual field tests .


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:
several studies reported histophatological observations during influenza a / h1n1 2009 pneumonia : the major finding was diffuse alveolar damage ( dad ) [ 14 ] .
type ii pneumocytes were considered the main target of influenza a / h1n1 infection . a limited number of observations described in vivo samples , such as bronchoalveolar lavage ( bal ) [ 68 ] .
therefore , it may play a role in further understanding the pathogenesis of new viral strains . in this case
series we present the results of bal performed in three patients with severe influenza a / h1n1 2009 pneumonia complicated by acute respiratory distress syndrome ( ards ) .
between august and december 2009 we performed a bronchoscopy - guided bal of three patients admitted to the san gerardo hospital , monza , italy , for influenza a / h1n1 virus pneumonia with subsequent development of ards .
all three patients required intensive care unit ( icu ) admission and received mechanical ventilation ( mv ) and extracorporeal respiratory support ( ecmo ) .
influenza a / h1n1 diagnosis was confirmed by a / h1n1 virus rna detection on nasal swab samples using influenza a / h1n1 2009 rrt - pcr ( real - time reverse - transcriptase - polymerase - chain - reaction ) assay ( genexpert ) .
bal differential cell count on cytocentrifugate was performed in the light microscopy ( lm ) by counting about 300 cells in random fields at 400x magnification .
demographics , comorbidities , severity on admission , microbiological isolations , and outcome for each patient are described in table 1 .
antiviral therapy with oseltamivir ( 150  mg twice daily ) was started at hospital admission simultaneously with rrt - pcr assay and was continued until rrt - pcr assay on nasal swab turned negative .
large , atypical cells with plasmocytoid appearance were observed in all three specimens with similar percentages ( 8 , 9 , and 6% , resp . ) . at lm
, they appeared as large , plasmoblastic / plasmocytoid - like cells with eccentric nuclei and paranuclear vacuoles , high ratio nucleus / cytoplasm , and intensely basophilic cytoplasm .
immunocytochemical analysis on cytocentrifugate showed that these cells were negative for cd20 ( b lymphocyte marker ) and cd138 ( plasma cell marker ) .
ultrastructural examinations at transmission em allowed us to observe multilamellar osmiophilic bodies in the cytoplasm of plasmoblastic / plasmocytoid - like cells .
em showed in these cells small round cytoplasmic inclusions with irregular surface and a diameter around 60  nm ( figure 2 ) .
they also showed cytoplasmic vesicles with a diameter around 100  nm and an irregular electron - dense core ( figure 3 ) .
the main characteristic of the bal of our patients with influenza a / h1n1 pneumonia associated with ards was the presence of large cells with a plasmoblastic / plasmocytoid - like appearance , identified at em as atypical type ii pneumocytes .
the first hypothesis regards the reparative action that type ii pneumocytes may have in dad . in our cases ,
stanley described morphological atypias , such as increased nuclear - cytoplasmic ratio , in type ii pneumocytes found in bals during ards .
these atypical pneumocytes are usually aggregated in clusters and are supposed to have a reparative role .
all our patients developed ards and we observed pneumocytes aggregated in clusters in the bals performed earlier ( cases numbers 2 and 3 ) . according to this first hypothesis , the atypical cells we observed could be described as reactive immature type ii pneumocytes .
type ii pneumocytes have been described as the main target of influenza a / h1n1 2009 infection .
nakajima et al . in 2012 described four autopsy cases of influenza a / h1n1 with a histopathological pattern of acute dad who presented with influenza virus antigen - positive type ii pneumocytes , perhaps indicating a direct role of the virus - infected cells in the acute alveolar damage .
no specific cytophatic effect or viral inclusion has been described so far at lm in lung tissue specimens during influenza pneumonia .
several observations have been performed via em on autopsy specimens . during the recent influenza pandemic , mauad et al . found type ii pneumocytes with vesicles , approximately 100  nm in diameter , with an electron - dense center .
bal and colleagues described cytoplasmic inclusions in pneumocytes , which ranged in diameter from 74 to 82  nm and showed surface spikes characteristic of influenza virus .
em observations of our specimens revealed some atypical pneumocytes showing both small round cytoplasmic inclusions with an irregular surface and small vesicles ( similar to those described by bal and mauad ) .
according to this second hypothesis , atypical type ii pneumocytes could be a specific morphological marker of influenza virus infection . from the data collected so far
, we can not favor one explanation ; in fact , they could coexist in cases of severe influenza a / h1n1 pneumonia associated with ards .
limitations of the present study include the following : first , the paucity of cases analyzed ; second , we did not perform immunohistochemical staining for h1n1 antigens on bal samples . the description of bal in a control group of patients with ards not associated with h1n1 pneumonia is beyond the scope of this case series .
however , other authors described bal cytology in non - h1n1 ards , and although they reported morphological atypias in type ii pneumocytes , they did not describe these peculiar plasmoblastic / plasmocytoid - like cells [ 10 , 12 , 13 ] .
the collection of the airway specimens of patients number 2 and number 3 , in which the nosocomial pathogens were isolated , took place after bal was performed .
therefore , these pathogens most likely did not affect the cellularity in bal . in conclusion ,
plasmoblastic / plasmocytoid - like type ii pneumocytes characterize the bal of our patients with influenza a / h1n1 2009 pneumonia associated with ards .
they could represent a pathognomonic marker of influenza virus pneumonia as well as reparative cellular activation after dad .
more observations of bal cytology in patients with influenza pneumonia are needed to understand their characteristics and role .

Answer:
we present the results of bronchoalveolar lavage ( bal ) performed in three patients with severe influenza a / h1n1 pneumonia complicated by acute respiratory distress syndrome ( ards ) .
 light microscopy analysis of bal cytocentrifugates showed the presence of characteristic large , mononuclear , plasmoblastic / plasmocytoid - like cells never described before . via transmission electron microscopy , these cells were classified as atypical type ii pneumocytes and some of them showed cytoplasmic vesicles and inclusions .
 we concluded that plasmoblastic / plasmocytoid - like type ii pneumocytes might represent a morphologic marker of a / h1n1 influenza virus infection as well as reparative cellular activation after diffuse alveolar damage .


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:
Synthesis of (\xc2\xb1)-Idarubicinone via Global Functionalization of Tetracene

Paper sections:

The Streptomyces-produced type II polyketides doxorubicin (l)1 and daunorubicin (2)2 are among the most effective and most often used chemotherapeutics owing to their broad-spectrum of anticancer activity (Figure 1).3 For example, doxorubicin (l) is used for the treatment of breast and bladder cancers, childhood solid tumors, soft tissue sarcomas, and aggressive lymphomas.4 Similarly, daunorubicin (2) is primarily used as an antileukemic drug for multiple myeloma, acute myeloid leukemia, acute lymphocytic leukemia, and Kaposi's sarcoma.5 Although extremely effective, anthracyclines threaten patients with cumulative dose-dependent cardiotoxicity, severely limiting their long-term application as well as their use in patients with pre-existing cardiovascular risk.6 Therefore, significant research efforts have been devoted to the identification of derivatives with improved pharmacological properties.7 The successful result of one such medicinal chemistry campaign is idarubicin (3),8 an FDA approved anticancer agent with superior therapeutic efficacy and reduced cardiotoxicity relative to daunorubicin (2).9

The need for tailored analogs has made anthracyclines the subject of rigorous investigation within the synthetic community.10 Thus, many innovative pathways to the aglycon anthracyclines (anthracyclinones) have been established, all of which rely upon annulation to forge one of the rings (see Figure 2a). The most commonly employed unifying disconnection is C-ring annulation, achieved through cycloadditions, cationic cyclizations, or anionic processes (Figure 2a, left inset).11 Moreover, cycloadditions were also explored to forge other rings of the tetracyclic core of these molecules (Figure 2a, right insets).12 Herein, we report a conceptually different, nonannulative approach to anthracyclinones, starting from a simple aromatic hydrocarbon via a global functionalization strategy (Figure 2b). Specifically, (±)-idarubicinone (4) was synthesized from tetracene (5), an ideal aromatic precursor containing the essential tetracyclic framework, through a manifold of arene functionalizations and a site-selective dearomative elaboration.

Following this global functionalization strategy, we commenced our studies by exploring functionalization reactions of tetracene (5), which would establish the proper oxidation states of the internal rings B and C within idarubicinone (4) (Figure 3). Thus, inspired by a similar transformation reported on anthracene, we achieved the first oxidation of 5 with catalytic amounts of cobalt(II) tetraphenylporphyrin (CoTPP, 5 mol %) and phenyliodine(III) sulfate as an oxidant,13 delivering 5,12-tetracenequinone (6) in 77% yield. Although this transformation proceeded readily, the second oxidation to the corresponding 6,11-dihydroxy-5,12-tetracenequinone derivative 7 proved more challenging. Several oxidants known for direct arene oxidation, such as CAN, Frémy's salt, hypervalent iodine reagents, or oxidizing metal complexes,14 were found to be unsuitable for this transformation. This setback was not surprising, as this type of peri-oxidation remains a largely unsolved synthetic challenge owing to the high oxidation potential of quinones. Therefore, we decided to evaluate C–H activation, anticipating that the quinone carbonyl groups would serve as weakly coordinating directing groups for the peri-(C-6) and (C-11) positions15. After examining several carbonyl-directed hydroxylation protocols, we developed a one-pot procedure involving a modification of Ru-catalyzed sp2 C–H oxygenation pioneered by Ackermann ([Ru(cymene)-Cl2]2 and PIFA),16 followed by sequential one-pot hydrolysis and methylation to give desired product 7. Control experiments revealed that this functionalization likely proceeds through the peri-selective formation of ruthenacycle intermediate I-1, delivering phenol derivative, which underwent further oxidation to the hydroquinone stage in the presence of excess PIFA.17

With arene oxidation completed, which set the required oxidation state of the B and C rings, we turned our attention to the dearomative functionalization of the terminal ring A. We have recently reported a series of dearomatization strategies that employ visible-light-promoted para-cycloaddition between arenes and the arenophile N-methyl-1,2,4-triazoline-3,5-dione (MTAD, 8) and subsequent in situ manipulation of the resulting cycloadducts.18 With polynuclear arenes, we consistently observed highly site-selective cycloadditions onto the terminal rings. Because tetracenequinone derivative 7 contains two such regions, rings A and D, amenable to cycloaddition with MTAD, another level of complexity to this process was introduced. However, based on previous studies, we know that the relevant mechanistic feature of this process is a photoinduced charge- and electron-transfer from the arene to the arenophile;19 therefore, the HOMO of the arene should dictate the site-selectivity in polynuclear aromatic settings. Accordingly, computational studies (at the B3LYP/def2-TZVPPD level of theory) of 7 predicted a strong bias for the A ring, which has profoundly larger HOMO orbital coefficients, (see Figure 3, bottom inset for the corresponding HOMO surface). Indeed, this prediction correlated well with experiment, as we observed exclusive cycloaddition onto the A-ring to provide intermediate 9. With this site-selective dearomatization, we explored several strategies to introduce the remaining two carbon atoms needed to complete the idarubicinone framework. We found that the arenophile-based cycloaddition in combination with in situ Rh-catalyzed alkene hydroboration (7 → [9] → 10) installed the boron moiety as a suitable handle for the introduction of the requisite acetyl group. Several hydroboration procedures were evaluated, but ultimately the cationic rhodium complex [Rh(cod)2BF4] with 1,4-bis(diphenylphosphino)butane (dppb) and catecholborane provided the best outcome (for optimization details, see Table S1 in Supporting Information).20 Although catecholborane was essential for the hydroboration step, the inherent instability of the resulting alkyl catechol boronic ester required immediate transesterification of catechol to pinacol to enable product isolation in higher yields.21 Importantly, following this protocol, we were able to prepare multigram quantities of boronic ester 10 in a single pass in 55% yield and an endo/exo 3:1 dr (see Figure 3, bottom inset for an X-ray diffraction structure of 10).

Elaboration of organoborate 10 to the full skeleton of idarubicinone required installation of a two-carbon fragment through a seemingly straightforward B-alkyl Suzuki coupling reaction. However, since several standard Pd- and Ni-catalyzed reaction conditions failed,22 we decided to explore the C–C bond forming strategies involving the rich chemistry of boron 1,2-metalate rearrangements. Particularly, we were keen to explore Zweifel olefination with lithiated ethoxyvinyl ether,23 which would provide rapid access to the C-9 acetyl group. Nevertheless, a major pitfall of this design was the presence of the quinone and its general incompatibility with organolithium reagents. Indeed, prospecting experiments involving boronic ester 10 and 1-ethoxyvinyllithium resulted in the addition of organolithium species to quinone, delivering a mixture of products without any traces of the desired olefinated product. To address this chemoselectivity issue, we developed a one-pot process that involved in situ masking of the quinone. Thus, a tetrahydrofuran (THF) solution of boronic ester 10 was sonicated with Zn powder in the presence of trimethylsilyl chloride (TMSCl), resulting in the formation of a fully protected bis-hydroquinone.24 This intermediate was exposed to a freshly prepared 1-lithioethyl vinyl ether to form the boronate complex I-2, which was immediately subjected to Zweifel olefination by addition of iodine and base.25 Concurrently with olefination, the excess iodine also oxidized the labile silylated hydroquinone back to the quinone, and workup of the reaction mixture with an aqueous HCl solution hydrolyzed the newly introduced vinyl ether to the corresponding methyl ketone 11. Remarkably, this one-pot operation involved several distinct transformations and was performed on a multigram scale in 72% yield.26

Although the arenophile-mediated dearomative hydroboration and subsequent Zweifel olefination introduced the desired methyl ketone, this sequence also installed a bridging urazole moiety, which had to be strategically transmuted to reveal the fully decorated A ring of idarubicinone (4). This task was partially accomplished by treatment of ketone 11 with base followed by Me2SO4, initiating β-elimination of urazole at position C-10 with subsequent methylation of the urazole hydrazyl nitrogen, furnishing α,β-unsaturated ketone 12 in 79% yield. The N-alkylation of the urazole motif proved necessary to prevent undesired side reactions during subsequent manipulations (for details, see Table S2 in Supporting Information). Finally, subjecting olefin 12 to Mukaiyama hydration conditions27 selectively introduced the tertiary alcohol at position C-9, as α-ketol product 13 was obtained in 70% yield as a single diastereoisomer. Notably, the use of recently reported silane, PhSiH2(Oi-Pr),28 was beneficial for high conversions of this hydrogen-atom transfer process.

This hydration achieved the proper oxidation state of the A-ring, and the only difference between intermediate 13 and idarubicinone (4) at this stage resided in two hydroquinone protecting groups and the urazole moiety instead of a hydroxy group at the C-7 position. Although deprotection of methyl ethers to hydroquinone proceeded without any difficulties using BCl3 (13 → 14, 98% yield), the removal of the urazole proved to be an arduous task. Eventually, the inspiration for the direct urazole-to-hydroxy exchange was found in the Moore hypothesis for the biological mode of reactivity known as bioreductive alkylation.29 Thus, it was proposed that anthracyclines undergo in vivo quinone reduction and subsequent C-7 amino sugar elimination, producing a reactive species in the form of a phenylogous quinone methide. Moreover, this concept was demonstrated in solution with several anthracyclines, which formed the corresponding semiquinone intermediates upon subjection to specific reducing agents.30 The direct translation of these findings to our system, for example the addition of sodium dithionite to precursor 14, did not eliminate the urazole; however, after the addition of base (NaOH) we observed elimination and exclusive formation of 7-deoxyidarubicinone (15) under anaerobic conditions. This result was in accordance with the literature, since deoxygenated anthracyclinones were commonly observed upon reduction of anthracyclines.31 Mechanistically, the reduction of quinone 14 to hydroquinone, followed by base-induced elimination of the urazole, likely formed the semiquinone methide I-3, which after protonation gave the deaminated product 15. However, we noticed that in the presence of oxygen, this reactive intermediate underwent competitive oxidation,32 delivering idarubicinone (I-3 → 4). Accordingly, short exposure of 14 to an aqueous solution of sodium dithionite and NaOH, followed by rapid saturation of reaction mixture with oxygen, provided (±)-idarubicinone (4) and (±)-7-deoxyidarubicinone (15) in 31% and 57% yield. Although extensive optimization of this protocol did not result in a higher ratio of desired anthracyclinone 4 to 15 (for details, see Table S3 in Supporting Information), this deoxygenated side-product could be readily converted to aglycone 4 in one or two steps using known protocols.33

In summary, we have described a functionalization-based approach to (±)-idarubicinone (4) from tetracene (5). The salient feature of this strategy is a judicious orchestration of two arene functionalizations and dearomatization, introducing the functionality of the A, B, and C rings of the anthracyclinone skeleton. Specifically, Co- and Ru-catalyzed arene oxidations, site-selective arenophile-mediated dearomative hydroboration, and subsequent Zweifel olefination provided the fully decorated anthracyclinone framework. Moreover, adjustment of the A ring, including a formally redox neutral urazole-to-hydroxy exchange delivered (±)-idarubicinone (4) in 8 operations and 2% overall yield from tetracene (5).

Importantly, by employing a simple polynuclear hydrocarbon aromatic starting material, the described work also presents a notable departure from previously reported syntheses of anthracyclinones in which annulations were critical to the overall synthetic design. In fact, polynuclear arenes are not commonly considered in synthetic planning for construction of stereochemically complex scaffolds. However, through the development and application of new methods, the present study provides a compelling case in which tetracene serves as an ideal template for imprinting of desired functionality. Thus, the range of available polynuclear arenes, as well as numerous functionalization opportunities, can be combined to render this global functionalization approach an appealing and complementary entry for the preparation of other type II polyketide-like compounds.

Answer: Anthracyclines are archetypal representatives of the tetracyclic type II polyketide natural products that are widely used in cancer chemotherapy. Although the synthesis of this class of compounds has been a subject of several investigations, all known approaches are based on annulations, relying on the union of properly prefunctionalized building blocks. Herein, we describe a conceptually different approach using a polynuclear arene as a starting template, ideally requiring only functional decorations to reach the desired target molecule. Specifically, tetracene was converted to (\xc2\xb1)-idarubicinone, the aglycone of the FDA approved anthracycline idarubicin, through the judicious orchestration of Co- and Ru-catalyzed arene oxidation and arenophile-mediated dearomative hydroboration. Such a global functionalization strategy, the combination of site-selective arene and dearomative functionalization, provided the key anthracycline framework in five operations and enabled rapid and controlled access to (\xc2\xb1)-idarubicinone.


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:
gastrointestinal stromal tumors ( gists ) are the most common mesenchymal , nonepithelial tumors of the gastrointestinal tract in adults between 40 and 50 years of age [ 1 , 2 ] . as per seer analysis ,
only 1% of 1,458 gist cases are esophageal in origin , with an incidence of 5170% in the stomach ; 2536% in the small intestine ; 57% in the colon , rectum and appendix , and 13% in the esophagus [ 1 , 2 , 3 ] .
they are generally small and asymptomatic , but occasionally can be large and produce dysphagia . a review of the literature revealed a case of a large esophageal gist presenting with dyspnea .
however , here we report a rare case of a small esophageal gist in a patient with dyspnea who presented with a mediastinal mass on chest x - ray and was initially diagnosed by a pathologist as having leiomyosarcoma and referred for chemotherapy .
1 ) . a ct scan of the chest with contrast revealed a hypodense , soft tissue mass / lymphadenopathy in the posterior mediastinum measuring 2.0  3.0 cm , contiguous with the esophagus ( fig .
2 ) , suggestive of neoplastic etiology . further imaging with pet revealed a mediastinal soft tissue mass / lymph node and a standardized uptake value ( suvmax ) of 5.1 .
the patient underwent a bronchoscopy and mediastinoscopy with fine - needle aspiration of the mass .
pathology showed increased cellularity with moderate nuclear atypia and pleomorphism with a mitotic count of 23 mitoses/10 high - power fields .
the ki67 index was 35% and , finally , the sample was reported as spindle cell well - differentiated leiomyosarcoma ( fig .
the patient was referred to us for further management . given the possibility of a gist ,
thoracotomy findings showed the mass in the posterior mediastinum , which was dissected free from the trachea and inferior aspect of the aorta .
six weeks after surgery , a repeated pet - ct scan showed no recurrence . on further follow - up
gists are rare , accounting for 0.13.0% of all gastrointestinal neoplasms and 5.7% of sarcomas . initially ,
gist applied to neoplasms displaying only c - kit ( cd117 ) , but the diagnosis is based on histopathology and immunohistochemistry .
a total of 95% of gists express kit or dog 1 and have mutations in kit or platelet - derived growth factor receptor ,  polypeptide .
the kit - positive cells in abdominal soft tissues include mast cells in the wall of the gastrointestinal tract ; the interstitial cells of cajal ( intestinal pacemakers ) around the myenteric plexus were thought to be the origin of gists .
gists typically present in adults 4050 years of age and predominantly in the stomach and intestine .
a comprehensive review of 11 case reports ( table 1 ) and case series with esophageal gists showed that only 1 patient presented with dyspnea and a large posterior mediastinal mass ( 27 cm ) ; 3 further masses were detected on routine chest x - ray [ 3 , 4 ] .
our patient presented with vague , progressive shortness of breath , with the unusual finding of a small mediastinal mass on chest x - ray .
esophageal gists commonly present with dysphagia but bleeding , perforation , back pain , anorexia , regurgitation and weight loss have been reported .
dyspnea with the finding of a small tumor on chest x - ray is rare .
further , pet - ct can help to differentiate gists from sarcoma , but our case showed an suvmax of 5.1 which can misclassify it as sarcoma [ 3 , 8 ] .
initial biopsy and testing created a diagnostic dilemma because immunohistochemistry did not include cd117 immunostaining and diagnostic imaging was inconclusive .
we present this case to raise physician awareness of such a rare presentation , so that the possibility of gists is considered in these situations , and cd117 testing be done if sarcoma histology is obtained .
surgery is the mainstay of treatment of localized gists ; targeted therapies like imatinib have shown overall survival benefit in high - risk patients after surgery [ 9 , 10 ] . and in unresectable and metastatic disease , it has been approved as primary treatment .
the pdgfra mutation d842v , sporadic wild - type gists , mutations with succinate dehydrogenase or braf - mutated gists are unlikely to respond to imatinib .
ongoing trials involve sorafenib , nilotinib , pazopanib , regorafenib and cediranib for advanced gists [ 11 , 12 , 13 , 14 , 15 ] .
future trials with combined or sequential use of tyrosine kinase inhibitors with other medications and personalized therapy after tumor molecular subtyping are promising in the management of gists .
our case report highlights the consideration of gists in the differential diagnosis of posterior mediastinal masses and emphasis on the necessity of cd117 staining in those situations which can alter the therapeutic and prognostic implication for the patient .

Answer:
gastrointestinal stromal tumors ( gists ) are the most common mesenchymal tumors of the gastrointestinal tract and are predominant in the stomach and intestine but rare in the esophagus . here
 , we report a case of esophageal gist which presented as a mediastinal mass on chest x - ray and dyspnea .
 the case was initially diagnosed as leiomyosarcoma , which could create a diagnostic dilemma . therefore , recognizing this uncommon presentation as a mediastinal mass with esophageal gist is important in the differential diagnosis .


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:
appropriate placement of dental implants is essential for esthetic and restorative aspects.12 the development of computer - assisted guided surgery has helped realize restoration - driven implant placement.3 contemporary guided implant surgery systems are generally based on cone - beam computed tomography ( cbct ) and computer - aided design and computer - assisted manufacturing ( cad / cam ) technologies .
cbct visualizes anatomic structures without superimposition , which enables 3-dimensional ( 3d ) diagnosis and treatment planning.456 cad / cam technologies improve the fabrication of surgical guides by reducing manual work and facilitating transfer of the planned implant position to the guide template.7 accurate placement of implants makes it possible to deliver restorations to the patient 's mouth on the day of the surgery.89 accordingly , these advancements have optimized implant treatment to be more predictable , less invasive , and faster from both a surgical and a prosthodontic point of view.1011 surgical guide templates are categorized based on the extent of drilling restriction.12 nonlimiting design is simplistic ; although such guides serve as imaging indicators for marking the entry point of drilling , they do not limit the angulation or the depth of drilling motion .
however , in general , hole enlargement and implant placement are still performed freehand by the surgeon .
most surgical guides with partially limiting design are converted from a radiographic template that is used to evaluate the surgical bone site and devise a surgery plan . completely limiting design
is the most advanced type of guide , restricting the drilling process and placement of implant in three dimensions .
this design concept reduces the need for decision making during surgery , thereby leading to more predictable results of implant placement .
contemporary cad / cam - based surgical guides are included in this category.1314 the accuracy of a guided implant surgery system is defined as the deviation between the planned and placed position of the implant.15 the accuracy of the entire procedure is a quantitative evaluation of positional and angular discrepancies in 3d coordinates.16 the measurements are performed using image superimposition of pre- and postoperative ct images.17 possible sources of error include factors such as digitizing , superimposition , machining process , the guide design concept , and the operator 's experience .
1819 in a recent in vitro study , van assche and quirynen reported a noticeable tolerance of surgical implant instruments within the metal sleeve.15 this tolerance is caused by the gap between the drill and the guide sleeve , which allows rotation of the drill in the sleeve .
unwanted lateral osteotomy may occur when the drill is not parallel to the sleeve during the drilling ; therefore , this type of error is defined as an intrinsic error.20 on the other hand , if there is no tolerance , the friction generated from mechanical components hinders the drilling process , which might result in sleeve deformation .
recently , a direct drill - guiding implant surgery system with a completely limiting design was developed .
this system features shank - modified drills that use the shank portion of surgical instruments as a guiding component to limit drilling motion with little tolerance .
moreover , a guide sleeve is incorporated in the stereolithographic surgical guide design , which eliminates the need for additional insertion of metal guide sleeves into the guide template .
the purpose of this study was to investigate the accuracy of this newly developed guided implant surgery system in partially edentulous patients using prospective clinical design and geometric analyses.2122
eleven patients ( 5 men , 6 women ; aged 2175 years ; mean age 46 years ) requiring implant placements in partially edentulous jaws were included in this study .
a total of 21 implants ( anyone ; megagen implant , gyeongbuk , korea ) were placed .
patients with a history of debilitating systemic disease or requiring ridge augmentation with bone grafting were excluded from the study .
the study was approved by the institutional review board of the hospital ( 2014 - 11 - 020 ) .
a conventional impression was taken , and a stone cast was fabricated for each patient .
the surface image of the cast was then digitized into surface tessellation language ( stl ) format using a desktop scanner ( ceramill map 400 ; amann girrbach , koblach , austria ) .
images of the underlying bone were obtained using a cbct scanner ( pax - flex3d ; vatech co. , hwasung , korea ) with a field of view of 120  85 mm , voxel size of 0.2 mm , and exposure conditions of 90 kvp , 10 ma , and 24-second pulsed scan . during cbct image taking , patients were directed to bite a radiopaque datum tray ( megagen implant , gyeongbuk , korea ) in centric occlusion .
the cbct data were saved in digital imaging and communications in medicine ( dicom ) format .
the datum tray was also digitized into a stl file using the desktop scanner ( ceramill map 400 ; amann girrbach , koblach , austria ) .
the solid block portion of the datum tray was used as a medium for superimposition of the surface image and underlying bone image .
the dicom file and the two stl files were imported into an implant - planning software program ( r2gate 1.0 ; megagen implant , gyeongbuk , korea ) where the image merging and virtual surgery were performed .
the image - merging process was performed with manual registration by selecting three anatomic landmarks from the dentition .
the position of the implant was determined based on the underlying bone and virtual restoration ( fig .
2 ) and fabricated using a 3d printer ( perfactory 4 ddp ; envisiontec , dearborn , mi , usa ) .
the direct drill - guiding system in this study uses shankmodified drills whose structure has 3 parts : the stopper part , the guide part , and the drilling part ( fig .
the stopper structure of the drill corresponds with the stepped structure of the internal surface of the sleeve and restricts the drilling depth when the two structures are joined .
the guide part of the drill closely accommodates the sleeve of the guide , which limits the orientation of the drilling motion .
the guide part of the drill has the uniform diameter and length ; this feature eliminates the need for additional internal tubes .
the handpiece connector and ratchet connector are instruments for inserting the implant fixture after osteotomy . as the component for depth control , the handpiece connector has the stopper structure , and the ratchet connector has a horizontal marking to indicate the correct depth of insertion .
the sleeve structure of this system is incorporated into the design of the guide template , so the guiding component is created together with the guide body when the template is fabricated ( fig .
each drilling was performed until the stopper of the drill contacted the rim of the guide template .
all implants were placed by a single operator . to obtain the positional information of the placed implant , postoperative cbct scanning was conducted using the same settings as the preoperative scan .
the accuracy of the guided surgery system was evaluated at the abutment level by comparing the virtual abutments of the planned and placed implants ( fig .
the actual position of the abutment was determined based on the actual position of the implant in the postoperative cbct scan .
the outcome parameters were horizontal deviation , vertical deviation , and angular deviation , and the values were calculated using the centerlines of the abutments and reference points in 3 dimensions .
all data were reported as the mean  standard deviation and visualized via bar graphs .
the kruskal - wallis test and mann - whitney u test were used to compare the amounts of deviation among 3 planes .
the means and standard deviations of horizontal deviation were 0.593  0.238 mm in the mesiodistal direction and 0.691  0.344 mm in the buccolingual direction .
the mean vertical deviation was 0.925  0.376 mm in the occlusogingival direction , which was significantly larger than the horizontal deviations ( p = .018 ) .
however , there was no significant difference between the two horizontal deviations ( p = .421 ) .
as for angular deviation , the values were 2.024  0.942 degrees in the mesiodistal direction and 2.390  1.142 degrees in the buccolingual direction ( fig .
the direct drill - guiding system in this study showed higher accuracy in implant placement by using shank - modified drills and a stereolithographic surgical guide that reduces the tolerance of surgical drills inside the guide sleeves . in a recent systematic review ,
the mean horizontal deviation of implant placement compared to the planned position was reported as 1.2 mm,23 whereas the direct drill - guiding system showed a mean deviation of 0.642 ; thus , this system is approximately twice as accurate as other systems in terms of horizontal linear deviation .
the angular deviation of the direct drill - guiding system in this study was less than the general value of angular deviation reported in the systematic review .
these findings correspond well with those reported by cassetta et al.,14 who evaluated the effects of limiting the tolerance between the drill and guide sleeve on the total error of implant placement .
to minimize tolerance , two tubes were used ; a guide tube was attached to the head of the surgical handpiece , and a master tube was embedded in the surgical guide . because the diameter of the guide tube was only 0.05 mm smaller than that of the master tube , these tubes fit closely during the drilling procedure .
these mechanics allowed only in - and - out motion , restricting the lateral movement of the drill . as a result ,
the accuracy of the system with the guide tube was superior to that of the system without the guide tube .
the direct drillguiding system in the present study has a similar mechanism for reducing tolerance .
therefore , it can be inferred that the direct guiding components play a key role in limiting drill movement and that tolerance control is essential for increasing the accuracy of the guided surgery system .
even when the sleeve of the guide template limits the blade part of the drill , a certain amount of gap is inevitable to allow the rotation of the drill within the sleeve.20 the deviation caused by the gap when the drill is not turning can be calculated theoretically by the interrelationship between the sleeve and drill angulation.24 basically , to increase the positional concordance of the planned and placed implants , it is important to use the drill in a centric position and parallel to the internal wall of sleeve.71525 however , it is not easy to keep a drill in the correct position because visibility and manipulability of the drill is limited in the narrow intraoral space .
meanwhile , the use of longer sleeves has been suggested as a mechanical approach to reduce the tolerance of surgical instruments .
although the above - mentioned parallel drilling and use of longer sleeves are helpful for increasing the accuracy of implant placement , the sleeve should still have some amount of tolerance to prevent friction when the drill is rotating .
in other words , the gap between the drill and the guide sleeve is unavoidable , which leads to errors in implant placement . as an alternative for guiding a drilling part of drill through a sleeve ,
koyanagi26 suggested the use of two orthodontic wires and tubes to connect the head of the handpiece with the guide template . since the wires slide along the tube , the drill advances as planned during the osteotomy .
the guide system tested in the present study is based on a different working mechanism and consists of modified drills that use the shank part of drill as a guiding surface . since the guiding surface makes direct contact with the inner surface of sleeve , the tolerance of the drill is markedly decreased .
this direct contact can be maintained during drill rotation because both contact parts have smooth surfaces with low the friction coefficient .
the combination of the shank - modified drill and sleeve - incorporated stereolithographic guide template therefore completely restricts the implant instruments and leads to more accurate implant placement .
the depth control of instruments is an essential element of a guide system with a completely limiting design.27 the addition of a stopper physically restricts the depth of the osteotomy by allowing drill advancement only to the level of the stopper.2829 this depth control enhances safety by preventing drills from intruding on vital anatomic structures such as the maxillary sinus and inferior alveolar nerve.30 the stopper is also useful for placing the implant at the planned depth , which not only improves treatment convenience but also enables immediate placement of the coronal restoration.31 in general , the mean vertical error of previous implant guide systems was reported as 0.5 mm.19 however , the guide system in the present study showed less accurate outcomes in the depth parameter .
although the ratchet connector has a reference line to indicate the stop point , it lacks a physical stopper .
accordingly , the vertical positioning of implant is influenced by the operators ' visual and tactile senses .
thus , to improve the accuracy of this system in the vertical dimension , inclusion of a stopper structure on the ratchet connector is recommended .
the accuracy of guided implant surgery is influenced by procedures that transfer the digital virtual plan to the surgical site.19 possible individual errors originate from intrinsic sources , which include issues with radiography quality , file conversion , cad software , and the tolerance between mechanical components ; and extrinsic sources , which relate to the fit of surgical guide , the mucosal thickness at the surgical site , the position of the edentulous area , and the surgeon 's experience .
this study revealed the error in the accuracy of the newly developed guided implant surgery system . since the data were obtained from clinical cases , the outcome values are clinically valid and meaningful .
thus , controlled in vitro experiments or large - size clinical prospective trials will be needed in the future to analyze these effects .
to our knowledge , this is the first clinical report to evaluate the accuracy of a direct drill - guiding system for implant placement .
the present study confirms that the use of shank - modified drills and sleeve - incorporated stereolithographic templates is an effective way to improve the accuracy of implant placement by minimizing mechanical tolerance of the instruments .

Answer:
purposea recently introduced direct drill - guiding implant surgery system features minimal tolerance of surgical instruments in the metal sleeve by using shank - modified drills and a sleeve - incorporated stereolithographic guide template .
 the purpose of this study was to evaluate the accuracy of this new guided surgery system in partially edentulous patients using geometric analyses.materials and methodsfor the study , 21 implants were placed in 11 consecutive patients using the direct drill - guiding implant surgery system .
 the stereolithographic surgical guide was fabricated using cone - beam computed tomography , digital scanning , computer - aided design and computer - assisted manufacturing , and additive manufacturing processes .
 after surgery , the positional and angular deviations between planned and placed implants were measured at the abutment level using implant - planning software .
 the kruskal - wallis test and mann - whitney u test were used to compare the deviations ( =.05).resultsthe mean horizontal deviations were 0.593 mm ( sd 0.238 ) mesiodistally and 0.691 mm ( sd 0.344 ) buccolingually .
 the mean vertical deviation was 0.925 mm ( sd 0.376 ) occlusogingivally .
 the vertical deviation was significantly larger than the horizontal deviation ( p=.018 ) .
 the mean angular deviation was 2.024 degrees ( sd 0.942 ) mesiodistally and 2.390 degrees ( sd 1.142 ) buccolingually.conclusionthe direct drill - guiding implant surgery system demonstrates high accuracy in placing implants .
 use of the drill shank as the guiding component is an effective way for reducing tolerance .


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:
eosinophilic gastritis is an extremely rare disease that is characterized by eosinophilic infiltration of the various layers of the gastrointestinal tract in the absence of any definite causes of eosinophilia .
patients with eosinophilic gastritis have diverse symptoms , including abdominal pain , emesis , abdominal distension , and weight loss .
these symptoms are associated with eosinophilic infiltration of the various layers of the gastrointestinal tract .
the disease has to be distinguished from generalized eosinophilic disorder presenting with involvement of other organs .
a 52-year - old female patient visited another hospital because of epigastric pain and tenderness .
she had no history of allergic diseases such as eczema or atopy , or food or drug allergies .
, she had undergone esophagogastroduodenoscopy ( egd ) , which revealed multiple focal ulcerative lesions with diffuse discoloration and edematous change of the rugae in the gastric fundus , cardia , and upper body ( fig .
the symptoms had been recalcitrant to treatment with proton pump inhibitors , fasting , and fluid .
she had reported no nausea , vomiting , hematemesis , or melena . on admission ,
her blood pressure was 110/60 mm hg , pulse rate 76 beats per minute , respiratory rate 22 breaths per minute , and body temperature 36.2. physical examination revealed tenderness of the epigastric area .
her white blood cell count was 22,770/mm with markedly increased eosinophils ( 5,009/mm , 22% ) .
the c - reactive protein concentration was 13.95 mg / dl . her other blood chemistry test results were normal .
the tests for viral markers included hepatitis a , b , and c virus and human immunodeficiency virus ; those for autoimmune antibodies included anti - nuclear , anti - double stranded dna , and anti - neutrophilic cytoplasmic antibodies ; and those for tumor markers included -fetoprotein , carbohydrate antigen 19 - 9 , and carcinoembryonic antigen .
the serological test for toxocara antibodies ( igg ) was positive , whereas those for echinococcus , paragonimus westermani , sparganumi , and trichinella antibodies were negative .
the chest and abdomen radiographic examinations were normal . to investigate the cause of the epigastric pain and tenderness ,
abdominal computed tomography was performed , which revealed severe edematous wall thickening with focal localized low attenuation of the fundus and cardia of the stomach ( fig .
she underwent a repeated egd , which showed diffuse necrotic change in the fundus , cardia , and upper body ( fig .
a biopsy specimen was obtained during egd ; a rapid urease test ( clotest ) revealed no evidence of helicobacter pylori . on histopathologic evaluation ,
the gastric surface was found to be eroded and the underlying lamina propria showed dense eosinophilic infiltration .
she was treated with empirical intravenous antibiotics ( cefoperazone and metronidazole ) immediately after her transfer because infectious gastritis was not ruled out .
although she was treated with a broad - spectrum anthelmintic ( albendazole ) , antibiotics , proton pump inhibitor , and prokinetic agent during the next 5 days , her symptoms became worse .
eosinophilic gastritis was diagnosed according to the clinical pictures , laboratory findings , and endoscopic findings .
she was immediately started on methylprednisolone ( 62.5 mg / day ; this dose was maintained for 7 days ) .
therefore , she underwent a repeated short - term follow - up egd that showed regenerative epithelial tissue with peeling off , of the necrotic tissue ( fig .
she underwent a repeated egd that showed the replacement of white color scar tissue ( fig .
currently , she is being treated with 30 mg / day prednisone and is showing considerable clinical improvement .
eosinophilic gastroenteritis is an uncommon and rarely reported disorder characterized by eosinophilic infiltration of the various tissue layers of the digestive tract in the absence of any definite causes of eosinophilia , without eosinophilic infiltration in other organs .
the diagnosis of eosinophilic gastroenteritis is based on the following criteria : the presence of gastrointestinal symptoms , histological presentation of eosinophilic infiltration in tissue layers of the digestive tract , presence of high eosinophil count in ascites , and no evidence of parasitic infection or eosinophilic involvement of extraintestinal organs .
eosinophilic gastroenteritis can involve any portion of the gastrointestinal tract from the esophagus to the rectum , and the stomach is the most commonly involved organ , especially the antrum . in eosinophilic gastritis ,
the endoscopic features are rather extensive : rugal fold thickening , erythema , friability , nodularity , gastric outlet obstruction , gastric ulcer , and even a normal mucosa .
although not clearly defined , the common pathophysiological mechanism of this disease is associated with eosinophilic infiltration and degranulation in specific tissue layers of the digestive tract .
this eosinophilic recruitment and activation regulated by diverse cytokines is a part of the host immune mechanism in the gastrointestinal mucosa ; however , it can be a type of serious allergic or inflammatory reaction in the deeper tissue layers of the gastrointestinal tract . although there is no treatment consensus on eosinophilic gastroenteritis ,
several studies report good results with steroids in dosages from 20 to 40 mg / day , for 6 to 8 weeks [ 7 - 10 ] . in some case studies ,
leukotriene modifiers such as montelukast or mast cell stabilizers such as sodium cromoglycate have been proposed to be helpful for symptomatic improvement .
antihistamines such as ketotifen or immunosuppressants such as mycophenolate mofetil are also used in the treatment of eosinophilic gastroenteritis ; however , their therapeutic effects are not clear and would require more studies .
although rare , eosinophilic gastritis should be considered in the differential diagnosis of patients with gastrointestinal symptoms and peripheral blood eosinophilia .
lymphoma of the stomach , gastric cancer , and crohn disease involving the stomach may demonstrate endoscopic features similar to those of eosinophilic gastritis .
gastrointestinal parasitic infection should be considered in patients with abdominal discomfort , weight loss , and peripheral eosinophilia . in particular , infestations by hookworms ,
ascaris , strongyloides , toxocara , trichuris , and intestinal capillaria should be considered in patients from endemic areas . in this case , the concentration of the antigen - specific ige to the a. simplex was 0.57
moreover , the serology for toxocara antibodies ( igg ) was positive . however , this is not clinically significant in korea because koreans often consume raw fish , which causes repeated exposures to anisakis .
in addition , she had not had contact with any animals , including dogs and cats , at least for several years .
moreover , she was treated with albendazole for 5 days , and her symptoms had become worse . after steroid treatment , the symptoms disappeared and the eosinophil count decreased to the reference range .
moreover , the follow - up egd showed regenerative epithelial tissue with peeling off , of the necrotic tissue
. she had undergone several egds that showed diffuse necrotic change in the fundus , cardia , and upper body .
the etiology includes thromboembolism and occlusion of major arterial supply , ingestion of corrosive agents , volvulus of the stomach , endoscopic hemostatic injections , and infectious gastritis . in this case
thus , the possible cause of gangrene could be infection , and she was treated with empirical intravenous antibiotics ( cefoperazone and metronidazole ) .
however , she was treated with broad - spectrum antibiotics during the next 5 days , and her symptoms became worse .
the necrotic portion of the gastric high body is very vulnerable site of retching injury .
this retching injury is called prolapse gastropathy syndrome , a clinical syndrome involving the invagination of part of the gastric mucosa into the lower esophagus .
direct trauma to the mucosa occurs when the gastric mucosa becomes incarcerated through the lower esophageal sphincter .
in addition , the endoscopic findings and histopathologic results were not compatible to prolapse gastropathy syndrome . on the basis of the clinical picture , laboratory findings , and therapeutic results , we concluded the diagnosis of eosinophilic gastritis presenting as necrotizing gastritis in our patient .
this case highlights the reality of eosinophilic gastritis presenting as necrotizing gastritis , and that endoscopy and histopathological examination of the biopsies are the most useful tools for the diagnosis of eosinophilic gastritis presenting as necrotizing gastritis .
eosinophilic gastritis should be considered in the differential diagnosis in patients with necrotic gastritis who do not respond to empirical treatment .

Answer:
eosinophilic gastroenteritis is very rare disorder that is characterized by eosinophilic infiltration of the gastrointestinal tract in the absence of any definite causes of eosinophilia .
 it is associated with various clinical gastrointestinal manifestations , and depends on the involved layer and site .
 we report a case of eosinophilic gastritis presenting with severe necrosis .
 the symptoms disappeared immediately after beginning steroid treatment , and the eosinophil count decreased to the reference range .
 the patient showed eosinophilic gastritis characterized by necrotic change such as necrotizing gastritis .
 it is a unique presentation of eosinophilic gastritis . to the best of our knowledge ,
 no case of eosinophilic gastritis characterized by necrotic change such as necrotizing gastritis has been previously reported in korea .


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:
road traffic crash ( rtc ) is the main cause of non - intentional injuries and the second cause of deaths after ischemic heart diseases in iran .
it accounts for more than 10% of total mortalities and about 23,000 deaths , in average , per year during the last decade .
this is approximately equal to the number of deaths caused by the 2003 bam earthquake , one of the worst natural disasters of recent decades .
these facts have made the rtc as a man - made disaster and real public health concern in iran . in line with the fourth i.r .
iran 's national development plan ( ndp ) , the fifth ndp for 2011 - 2015 has emphasized on development of rural infrastructures , including rural asphalt roads . although this development has led to more traffic in rural roads , no significant improvement is observed in safe driving behavior and construction of roads in rural areas .
in addition , compared with urban areas , rural people use older cars with less safety standards .
the monitoring by traffic police and coverage of emergency medical services ( ems ) are also lower in rural roads than main roads . this article aims to provide the iranian policy makers with information on the burden of deaths that are caused by rural rtcs and demonstrates its association with expansion of the rural roads .
we applied a retrospective analysis of secondary data to demonstrate the association of rural rtcs deaths with expansion of the rural roads in iran .
the variables of interest included length of road ( rural and urban ) , number of death ( caused by rural and urban rtcs ) and number of population .
the sources that we used for data collection were the iran 's high commission of road safety ( hcrs ) for length of road ( km ) , the iran 's forensic medicine organization ( fmo ) for the number of rtcs death and the iran 's statistical center for population data .
international classification of diseases-10 is the basis for coding the causes of death by fmo . for the purpose of analysis
, we illustrated the trends of length of rural road from 2005 to 2010 and their corresponding mortality .
rates of traffic death in rural and urban roads were also estimated per 100,000 populations .
 for trend was the test of significance and p < 0.05 was considered as statistically significant .
spss statistical software for windows ( version 11.0 , chicago , il ) was used for statistical analysis .
the number of rtc deaths in rural roads increased from 1,672 in 2005 to 2,206 in 2010 .
this was parallel to construction of the rural asphalt roads that was increased from 56,424 to 86,519 km during the same period [ figure 1 ] .
the trend analysis showed a positive association between these two variables (  for trend = 3.93 , df = 1 , p = 0.04 ) .
length of rural asphalt roads and number of deaths caused by rural road traffic crashes , iran , 2005 - 2010 the expansion of urban asphalt roads was also on an increasing trend from 71,711 to 77,964 km , but the number of traffic deaths in these roads decreased from 26,083 in 2005 to 21,043 in 2010 . from 2005 to 2010 , adjusted for 100,000 populations , the number of traffic deaths in urban roads decreased from 37.0 to 28.0 , while this number increased from 2.4 to 2.9 in rural roads [ figure 2 ] .
our study showed an increasing trend of the rtc deaths in iran 's rural roads and its positive association with expansion of the rural roads .
this is while , at the same period , the rate of traffic death in urban roads was on a decreasing trend .
therefore , expansion of the road network is one of the most important prerequisites for development of economics and infrastructures in rural areas , the policy makers should take preventive measures in rural roads to improve the safe driving condition . in this line ,
iran 's ministry of road and urban construction is the lead agency for the hcrs .
traffic police , ems and car factories are the main stakeholders of this national coordination body . to reduce the rate of deadly traffic crashes in rural roads , taking the coordinated measures by the hcrs ' members
the hcrs may also rely on the successful experience in decreasing the rate of urban rtc deaths . according to available literature ,
the risk factors of deadly rtcs in rural roads of iran are unsafe roads , excessive speed , risky driving caused by inadequate knowledge and inappropriate risk perception , no use of seat belt and using of old cars with low safety equipments .
effectiveness of the enforcement measures for control of rtcs in iran is rated six out of 10 , according to the world health organization .
this is expected to be even lower in rural roads as they are less controlled by traffic police compared with freeways , highways and main roads .
timely and quality provision of medical care is essential for saving lives in a rtc . in 2010 ,
the national emergency medical service was only able to cover 15% of minor roads , including rural areas . according to national ems , in addition to the current 1,028 ems stations ,
rural rtc is a concern not only in developing countries like iran , but also it accounts for the considerable number of death in developed countries . for instances , in germany ,
britain and the us , about two third of all rtc related fatalities occur on rural roads , which score badly when compared to the high quality motorway network in those countries .
all these have said , there are evidences that fortunately show how the preventive measures can be effective in reducing rural rtcs . for example , in germany , reinforcement of speed limits and development of additional passing lanes were found effective .
the expansion of rural asphalt roads exposes the people of rural areas with risk of severe rtc if effective preventive measures are not taken . to prevent from this threat , the iranian policy makers need to take the followings into consideration : public awareness , improving the safety of roads and vehicles , law enforcement , increasing coverage of police and ems

Answer:
background : the 5th iran national development plan , 2011 - 2015 , has emphasized on expansion of rural asphalt roads . this article aims to illustrate the trend of deaths caused by rural road traffic crashes ( rtcs ) and its association with length of the rural roads in iran.methods:we carried out a retrospective analysis on secondary data for the period from 2005 to 2010 . the iranian forensic medicine organization , high commission for road safety and iran 's statistical center were the sources for the number of rtc death , length of the road and population data , respectively.results:number of rtc deaths in rural roads increased from 1,672 in 2005 to 2,206 in 2010
 .
 this was associated with expansion of the rural asphalt roads ( p = 0.04 ) .
 the construction of urban asphalt roads was also on an increasing trend , but the number of traffic deaths in these roads decreased from 26,083 in 2005 to 21,043 in 2010 .
 adjusted for 100,000 populations , the number of traffic deaths in urban roads showed a decrease from 37.0 to 28.0 , while this number increased from 2.4 to 2.9 in rural roads during the study period.conclusions:although expansion of rural roads would contribute to economic development in rural areas , it exposes people to risk of severe rtcs if effective preventive actions are not taken . to prevent this threat
 , the iranian policy makers need to take the followings into consideration : public awareness , improving the safety of roads and vehicles , law enforcement , increasing coverage of police and emergency medical services .