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You are an expert at summarizing long articles. Proceed to summarize the following text: when it comes to drug therapy , intensivists have plenty of decision making every day including drug selection , dosing , administration , and monitoring strategies to optimize effective pharmacotherapy . even though the patient receives appropriate drug , a suboptimal dose or overdosing may result in either therapeutic failure or drug toxicity . the concept of having a clinical pharmacist in an intensivist - led multidisciplinary team evolved in the early 1980s in usa . plenty of studies revealed critical care pharmacist involved in a multi - professional healthcare team had constructive impact on the outcome of critically ill patients . in the modern day intensive care unit ( icu ) , the skills of a clinical pharmacist are characterized as a responsible caregiver , educator , researcher , and manager . critical care pharmacist addresses adverse drug events ( ades ) caused due to drug - related problems and medication errors . many prospective , controlled trials reveal significantly lower rates of ades and lesser days of hospitalization when a clinical pharmacist is integrated into an intensive care healthcare team . a study demonstrated reduction in rate of prescribing errors and preventable ades by 66% from 10.4 to 3.5 per 1000 patient days after clinical pharmacist intervention . this study was conducted to assess the impact and effectiveness of having a clinical pharmacist in an icu . this study aims to evaluate the clinical pharmacist interventions with a focus on optimizing the quality of pharmacotherapy and patient safety . even though the contribution of critical care pharmacist to improve the quality of patient care is accepted worldwide , many icus have not recognized this important reserve . this paper may be used to educate other healthcare professionals and administrators on impact of clinical pharmacist in the care of critically ill patients . the prospective , observational study was carried out in the medical , surgical / trauma icu and a high dependency unit at a 750-bedded tertiary care hospital . the icus in the study were under the supervision of a clinical pharmacist exclusively for the critical care areas . the study was carried over a period of 1 year from january 1 , 2013 , to december 31 , 2013 . all detected drug - related problems ( drps ) and interventions were categorized based on the pharmaceutical care network europe ( pcne ) system with minor changes according to the applicability in the hospital setting . critical care clinical pharmacy services in our hospital include active participation in physician rounds and review of treatment chart for appropriate indications , drug dosing , dosage form , drug duplication , drug interactions , and drug allergies . critical care pharmacist plays an important role in identifying , reporting , investigating , and preventing all types of medication errors and adverse drug reactions ( adrs ) . other interventions include correction and clarification of physician orders , providing drug and poison information , and recommending an alternative therapy . clinical pharmacist adjusts dose of drugs in pediatric , geriatric , renal , and hepatic failure patients . pharmacist also involved in optimizing antibiotic usage based on patient characteristics , site of infection , pharmacokinetics , dose adjustment , and de - escalation . clinical pharmacist also contributes in continuing education activities through teaching programs for doctors and nurses . this increases direct patient care practice abilities , creates awareness among intensive care team , and prevents medication errors . data collection was done by the clinical pharmacist on a daily basis and discussed with the icu chief at the monthly meeting . data analysis and results were presented as percentage and numerically coded for the ease of descriptive statistics using spss software version 20.0 by spss inc . , during the study period , average monthly census of 1032 patients got treated in all three icus . a total of 986 pharmaceutical interventions due to drug - related problems were documented , of which medication errors accounted for 42.6% ( n = 420 ) followed by 152 ( 15.4% ) drug of choice problem . manifested or potential drug - drug interactions were 149 ( 15.1% ) followed by 135 ( 13.7% ) y - site drug incompatibility , 47 ( 4.8% ) drug dosing problem , 45 ( 4.6% ) drug duplication , and 38 ( 3.8% ) adrs . all the 986 drug - related problems detected by the clinical pharmacist were categorized based on the pcne classification and percentage calculated . in table 1 , 29 ( 2.9% ) of the adrs identified were mainly due to antibiotics which included hypersensitivity reactions , thrombocytopenia , and interstitial nephritis while the other drugs were responsible for electrolyte imbalance , hyperthermia , and nephrotoxicity . thirty ( 3% ) serious and 17 ( 1.7% ) significant drug - drug interactions required clinical pharmacist intervention ; for which either the offending drug was stopped , dose was reduced , or an alternative drug was prescribed . remaining 102 ( 10.4% ) serious and significant drug - drug interactions were closely monitored for any potential manifestation . a total of 135 y - site drug incompatibilities were detected , of which 8 ( 0.8% ) were visible incompatibilities [ figure 1 ] . clinical pharmacist detected drug- related problems visible y - site drug incompatibility reported in our intensive care unit between cefepime and vancomycin the next most commonly addressed problems were related to drug of choice . seventy - eight ( 8% ) observations in this group to study were due to inappropriate drug or dosage form followed by drug use without clear indication and contraindication of the drug . drug duplication ( drugs of same therapeutic group or with same active ingredient ) identified by the clinical pharmacist was common with anti - hypertensives and proton pump inhibitors . drug dosing problems were next on the list with 35 ( 3.6% ) problems due to drug dose too low or too high and 12 ( 1.2% ) problems due to shorter or longer duration of treatment . in table 1 , 42.6% drug - related problems in our study accounted for medication errors . all medication errors were categorized based on the pcne classification and were within the benchmarks . in table 2 , clinical pharmacist interventions for drug - related problems were categorized based on the pcne classification . a total of 1182 interventions were made by the clinical pharmacist for drug - related problems . most of the interventions took place at the drug level which was propositions for modification in therapy . drug dosing adjustments done by the clinical pharmacist included 140 ( 11.9% ) renal dose adjustment , 62 ( 5.2% ) hepatic dose adjustment , and 17 ( 1.4% ) pediatric dose adjustment . glycemic control in the icu was also under the supervision of the clinical pharmacist which included 104 ( 8.8% ) insulin dosing modifications . remaining interventions at drug level included 64 ( 5.4% ) drug stopped or new drug started , 34 ( 2.9% ) instruction for drug use changed , and 28 ( 2.4% ) drug changed and alternatively used . interventions at the prescriber level comprised prescriber seeking clarification or drug information which was 10.4% ( n = 120 ) , and information given to prescriber without seeking clarification was 6.3% ( n = 75 ) . about 94.8% ( n = 1121 ) was the acceptance rate for the propositions put forward to the clinician and remaining 5.2% ( n = 61 ) were rejected . clinical pharmacist interventions for drug - related problems in table 3 , a total of 577 clinical pharmacists answered drug and poison information queries were listed . majority of the drug information queries regarded drug dosing , indication , and guidelines , which was 34.1% ( n = 197 ) . poison queries included 47 ( 8.1% ) toxicokinetics , followed by management of poisoning and identification of the poison content . a critically ill patient is reviewed and treated by physicians from different specialties ; hence , polypharmacy is a very common practice in this setting . we presume that medication errors include most commonly transcribing and administration errors which occur at the level of nurses . indeed , prescribing errors and errors in drug application which occur at the level of the prescriber is often neglected . it is important to have a clinical pharmacist to review the treatment charts to rectify these issues . numerous published studies show the importance of clinical pharmacist intervention and active participation in multidisciplinary patient care rounds having significantly better patient outcome through quality patient care . interestingly , during the study period , 38 adrs were reported , and few of them were rare presentations . these results also coincided with a study by leape who concluded that the participation of clinical pharmacist in medical rounds improved adr reporting and reduced the rate of preventable ades . many studies from the critical care areas show significant evidence favoring better reporting and prevention of ades in the presence of clinical pharmacist . the acceptance of the clinical pharmacist 's interventions in our study was 94.8% which was well in accordance with other published data , where the acceptance rate ranges from 85.5% to 99% . critically ill patients are at risk of drug interactions due to the complexity in pharmacotherapy and use of different drug combinations . a study by reis evaluated the prevalence of potential drug interaction and its clinical significance in critically ill patients . the current study managed to contribute substantial information to the physicians regarding the manifested or potential drug interactions in the critical care unit . this included clinical pharmacist interventions due to drug interaction or the need for monitoring the patient . while most articles focus on drug interactions in critical care , drug incompatibility is also considered likely to harm the patients . as a result of incompatibility , the drug either loses its efficacy or precipitates . about 3.618.6% of incompatible drug combinations we have also documented 135 y - site drug incompatibilities which included eight visible incompatibilities . streamlining , dose optimization , and de - escalation of antibiotics in the presence of a clinical pharmacist are already proven and recommended to enhance antibiotic stewardship . in our study , clinical pharmacist interventions were effective in rationalizing use of antibiotics , especially in optimizing the dose . plenty of studies have proven reduced incidence of medication errors when pharmacist actively participates in multidisciplinary rounds . in this study , clinical pharmacist not only detected medication errors but also prevented and investigated all types of medication errors . a national survey by maclaren et al . from over 260 hospitals , compared clinical and outcome data with the clinical pharmacy services in the icu . they reported significant impact in terms of mortality , length of stay , and cost benefits in the presence of critical care pharmacist . parallel studies from maclaren and bond using the same data claimed statistically significant clinical and economical outcome associated with thromboembolic or infarct - related events ( tie ) in the presence of a clinical pharmacist . desirable activities of critical care pharmacist also include formulating guidelines for the critically ill patients , active participation in research , and educating the icu team . guidelines which have been developed and implemented by the clinical pharmacist in our icu includes protocols for pain , sedation , delirium , glycemic control , stress ulcer prophylaxis , deep vein thrombosis prophylaxis , y - site drug compatibility chart [ figure 2 ] , drug administration , dilution guidelines , and toxicological management protocols . once the protocols are formulated , all the members of the icu team are educated on how to use the protocol . most of these clinical pharmacist enforced protocols are nurse oriented , and hence , it becomes easy for optimizing patient care . the effectiveness of these guidelines is under the supervision of a critical care pharmacist , and it is well studied in western countries . y - site drug compatibility chart prepared for most commonly used intravenous drugs in intensive care unit though our study did not aim to show the economic benefit of clinical pharmacy services , it has definitely reduced drug costs and other treatment costs . drug cost reduction and treatment cost savings as a result of clinical pharmacist interventions have been assessed and proved in various other studies . clinical pharmacist as a part of multidisciplinary team in an icu was associated with a substantially lower rate of adverse drug event caused by medication errors , drug interactions , and drug incompatibilities . clinical pharmacists are essential to improve patient safety and outcome , reduce costs , and provide quality of care in critically ill patients .

background and objectives : a critically ill patient is treated and reviewed by physicians from different specialties ; hence , polypharmacy is a very common . this study was conducted to assess the impact and effectiveness of having a clinical pharmacist in an indian intensive care unit ( icu ) . it also evaluates the clinical pharmacist interventions with a focus on optimizing the quality of pharmacotherapy and patient safety.materials and methods : the prospective , observational study was carried out in medical and surgical / trauma icu over a period of 1 year . all detected drug - related problems and interventions were categorized based on the pharmaceutical care network europe system.results:during the study period , average monthly census of 1032 patients got treated in the icus . a total of 986 pharmaceutical interventions due to drug - related problems were documented , whereof medication errors accounted for 42.6% ( n = 420 ) , drug of choice problem 15.4% ( n = 152 ) , drug - drug interactions were 15.1% ( n = 149 ) , y - site drug incompatibility was 13.7% ( n = 135 ) , drug dosing problems were 4.8% ( n = 47 ) , drug duplications reported were 4.6% ( n = 45 ) , and adverse drug reactions documented were 3.8% ( n = 38 ) . drug dosing adjustment done by the clinical pharmacist included 140 ( 11.9% ) renal dose , 62 ( 5.2% ) hepatic dose , 17 ( 1.4% ) pediatric dose , and 104 ( 8.8% ) insulin dosing modifications . a total of 577 drug and poison information queries were answered by the clinical pharmacist.conclusion:clinical pharmacist as a part of multidisciplinary team in our study was associated with a substantially lower rate of adverse drug event caused by medication errors , drug interactions , and drug incompatibilities .

You are an expert at summarizing long articles. Proceed to summarize the following text: toxocara vitulorum is an intestinal ascarid parasite of cattle and water buffaloes ( bubalus bubalis ) . although the parasite may occur worldwide , it is of particular economic importance in tropical and subtropical regions , mainly due to lacking or inefficient control . t. vitulorum causes morbidity and mortality in calves , which typically become infected early post - partum by ingesting larvae excreted in the colostrum and milk . after a prepatent period of 3 - 4 weeks , the ingested larvae have matured to adult worms in the calf s duodenum that produce a large number of eggs , during a patent period of about 4 weeks . at the age of 8 weeks , most infected calves are able to clear the parasite due to strengthened and acquired immunity . cambodia , a southeast asian country , has a tropical climate characterized by distinct rainy and dry seasons . agriculture is the major work sector in cambodia , and within this sector , livestock is the third largest subsector , behind crop production and fisheries . cattle ( mainly bos indicus ) and water buffaloes ( bubalus bubalis ) provide draught power , manure used as fertilizer or biogas , and increasingly , animal protein and income from trade . nevertheless , the ruminant sector is characterized by smallholder farmers rearing limited numbers of animals in traditional production systems . as a result , the animals are highly susceptible to endemic diseases , including t. vitulorum and other gastrointestinal parasites , resulting in substandard agricultural output . the aim of this study was to investigate the prevalence and associated risk factors of t. vitulorum infection in buffalo and cattle calves in cambodia . the study was conducted in 3 provinces , i.e. , pursat , kampong chnnang , and kampong cham , located in central cambodia from june till october 2011 . in each province , the age of the animals was registered as either 28 days , 28 - 56 days , or > 56 days . each fecal sample was examined for the presence of eggs of t. vitulorum and strongyle eggs and eimeria spp . oocysts by the mcmaster technique with a sensitivity of 50 eggs per gram of feces ( epg ) . the consistency of the fecal sample was scored as being either normal , or soft , or watery . t. vitulorum prevalence and corresponding exact 95% confidence intervals ( ci ) were calculated for the entire sample and for the different provinces , species , age groups , fecal consistencies , and co - infection categories . additionally , the results of the t. vitulorum fecal egg counts were summarized by their arithmetic mean and sd . association of t. vitulorum prevalence with species , age group , fecal consistency , and co - infection category was assessed with a generalized linear mixed model for binary data , using adaptive gaussian quadrature with 25 quadrature points . a final multivariable model was obtained through a backwards selection procedure , at a significance level for removal of 5% . the study was conducted in 3 provinces , i.e. , pursat , kampong chnnang , and kampong cham , located in central cambodia from june till october 2011 . in each province , the age of the animals was registered as either 28 days , 28 - 56 days , or > 56 days . each fecal sample was examined for the presence of eggs of t. vitulorum and strongyle eggs and eimeria spp . oocysts by the mcmaster technique with a sensitivity of 50 eggs per gram of feces ( epg ) . the consistency of the fecal sample was scored as being either normal , or soft , or watery . t. vitulorum prevalence and corresponding exact 95% confidence intervals ( ci ) were calculated for the entire sample and for the different provinces , species , age groups , fecal consistencies , and co - infection categories . additionally , the results of the t. vitulorum fecal egg counts were summarized by their arithmetic mean and sd . association of t. vitulorum prevalence with species , age group , fecal consistency , and co - infection category was assessed with a generalized linear mixed model for binary data , using adaptive gaussian quadrature with 25 quadrature points . a final multivariable model was obtained through a backwards selection procedure , at a significance level for removal of 5% . a total of 517 animals were subjected in this study . of these , 64 were found to excrete t. vitulorum eggs in their feces ( 12.4% ; 95% exact ci : 9.7 - 15.5 ) . the mean fecal egg count was 2,798 epg ( sd=16,351 ; range=0 - 224,400 ) . table 1 shows descriptive statistics by the province , species , age group , fecal consistency , and co - infection category . the final multivariable generalized linear mixed model showed a higher odds of t. vitulorum infection for buffalo versus cattle , for animals aged 4 - 8 weeks versus younger and older ones , and for animals with strongyle infection ( table 2 ) . to our knowledge , this is the first report on t. vitulorum infections in buffalo and cattle calves from cambodia . compared to those countries , the prevalence observed in our study is relatively low ( 12.4% ) . in thailand , srikitjakarn et al . found a t. vitulorum prevalence of 58% in calves during their first 3 months of life . more recently , holland et al . observed a prevalence of 8% in vietnamese calves aged 1 - 2 months , and rast et al . found a prevalence of 22.6% in buffalo and cattle calves aged <3 months in northern lao pdr . in our study , the main risk factors for t. vitulorum infection appeared to be host species and , not surprisingly , age . the apparent association with strongyle prevalence might be explained as an artefact due to the collinearity between strongyle infection and age ( results not shown ) . indeed , strongyle infections tend to be more common in older animals . roberts reported clinical signs in toxocariasis , especially in buffalo calves . they included , poor hair coat , eczema , stools resembling white scour and having a foul smell , inappetency with intermittent colic and bloat . more recent literature reports that calves with toxocariasis could have either pale colored or black diarrhea , or could be asymptomatic . in our study further studies are needed to determine the contribution of t. vitulorum towards the overall clinical impact of disorders in calves of less than 3 months . in conclusion , t. vitulorum is important in cambodia , especially in buffalo cattle and animals between 4 - 8 weeks of age . farmers should be aware of the potential impact of this parasite , and treat their animals appropriately . anthelmintic treatment with either pyrantel or benzimidazoles at the age of 2 - 3 weeks has proved to be very effective in eliminating t. vitulorum both in cattle and buffalo calves in cambodia ( data not shown ) and should be recommended to livestock owners in order to prevent potential pathologies caused by this parasite .

the prevalence and associated risk factors of toxocara vitulorum infection in buffalo and cattle calves was studied in 3 provinces in central cambodia . fecal samples were collected from 517 calves between the age of 1 - 15 weeks and processed for nematode egg counts by a modified mcmaster method . a total of 64 calves were found to excrete t. vitulorum eggs in their feces ( 12.4% ; 95% exact ci : 9.7 - 15.5 ) . the mean fecal egg count was 2,798 epg ( sd=16,351 ; range=0 - 224,400 ) . a multivariable generalized linear mixed model showed higher odds of t. vitulorum infection for buffalo versus cattle , for animals aged 4 - 8 weeks versus younger and older ones , and for animals with strongyle infection . there was no association with fecal consistency . farmers should be aware of the potential impact of t. vitulorum , and treat their calves at the age of 2 - 3 weeks with anthelmintics such as benzimidazoles or pyrantel .

You are an expert at summarizing long articles. Proceed to summarize the following text: the incidence of malignant tumours , particularly epithelial , increases with age , and consequently most cases are observed between 50 and 60 years of age . however , some solid tumours are likely to appear in the reproductive age , and thus it is possible that they will occur during pregnancy . the coexistence of cancer and pregnancy can delay making a diagnosis , especially for those with breast cancer . it is more difficult to assess the effect of pregnancy on prognosis in malignant tumours malignant tumours in pregnant women are very rare , but they are a serious problem women are increasingly postponing the decision about motherhood ( the age of primapara in europe increased in the last decade by two years on average ) , so we should expect a growing number of such cases during pregnancy . diagnostic and therapeutic procedures should be carried out carefully , taking into account the risk factors associated with both woman and foetus . the optimal management should include the proper assessment of oncological and obstetric risk , clear decision - making process both for the patient and for the child , the appropriate treatment , and careful observation after its completion , based on close interdisciplinary collaboration between an oncologist , obstetrician , and neonatologist . the treatment of gynaecologic cancers complicating pregnancy entails the need to consider the maintenance of pregnancy but also the potential loss of the ability to reproduce as a result of the conducted therapy . the retrospective data took into account both invasive and pre - invasive cancers , and in other cases also cancers diagnosed after birth . undoubtedly , it is the most common cancer in pregnancy among all gynaecological malignant growths [ 35 ] . pregnancy does not have a negative impact on prognosis and the therapeutic outcomes are the same as in non - pregnant women [ 3 , 5 ] . screening for cervical cancer is an important part of prenatal care . many guidelines recommend performing the papanicolaou ( pap ) test in all women at the moment of diagnosing pregnancy , although its interpretation during pregnancy can be difficult due to frequent erosions , inflammations , and the presence of decidual cells , which might be confused with atypia ( the so - called arias - stella reaction ) . generally , the test has the same importance as in patients who are not pregnant . after finding the abnormal result of the pap test the changes of low degree regress in about 60% cases and remain unchanged in about 30% . the progression to more advanced changes ( cin3 ) is rare and occurs in a maximum of 6% of patients . in disorders of high degree , such as cin3 if there is no evidence of invasion , no treatment should be implemented during pregnancy and the entire therapy can be postponed until after the birth . in patients with no invasive changes , monitoring is recommended using colposcopy performed in each trimester with repeated biopsy in cases suspected of progression [ 3 , 5 ] . the indications for conisation in pregnancy are more limited , due to the risk of severe complications of surgery such as bleeding ( including death ) in up to 15% of patients , miscarriage , premature labour , or premature rupture of membranes . this risk increases with the advancement of gestation , thus if there is a suspicion of micro - invasive or invasive changes , conisation or excision of the changes using a large diathermy loop should be carried out in early pregnancy . the choice of therapeutic method depends on the dimensions of the cervix , the preferences of the gynaecologist , and the expected progression of pathology . the choice of treatment must always be discussed with the patient and should be consistent with the patient 's beliefs . the management in the case of invasive cervical cancer depends on : 1 ) the size of tumour , 2 ) the state of the lymph nodes , 3 ) the stage of pregnancy , and 4 ) the histological subtype . the basic histological subtypes , i.e. squamous cell carcinoma , adenocarcinoma , and glandular - squamous carcinoma , have similar prognosis and should be similarly treated , as opposed to the more rare and poor prognosis type , i.e. small cell carcinoma . in the latter case it is necessary if possible to terminate pregnancy and the patient should be immediately subjected to the optimal therapy . in the past , abortion and radical therapy of cancer was the treatment of choice in the case of cervical cancer in the first and second trimester of pregnancy . at present , the aim is to maintain pregnancy , particularly in patients with the disease at an early stage , without lymph node involvement . staging , including the status of regional lymph nodes , must be properly carried out . magnetic resonance imaging ( mri ) is the best imaging technique for this purpose , which can be performed without contrast in the evaluation of cervical cancer [ 36 ] . in all the cases , the examination was conducted before conisation using the camera 1.5-t . the patients were examined in the supine position and did not receive any contrast agent . two radiologists evaluated the following : the local condition ( parametritis , uterus , bladder , and rectum ) , the visibility of changes , the size of changes , and the intensity of signal compared to the uterine and cervical muscles as well as the lymph nodes of the abdomen and pelvis . in addition , the test took into account imagining problems caused by the movements of the foetus . after determining the degree of progression , making therapeutic decisions , and implementing the treatment , the control mri examinations were repeated every four weeks until the 30 week of gestation [ 3 , 7 ] . the guidelines of the european symposium on urogenital radiology state that it is possible to provide a contrast agent ( gadolinium derivative ) in a pregnant woman , which can improve the visualisation of small lesions in mri . the most up - to - date guidelines describe the gadolinium as possible to use only if it is absolutely essential [ 6 , 7 ] . the features of cervical cancer in mri during pregnancy are similar to those found in patients who are not pregnant . however , we ought to remember that in non - pregnant women , cervical tumours are usually hyperintense compared to the muscles of the uterus , while in pregnancy the normal cervix can be hyperintense , causing the tumour to look isointense or even hypointense . in all of the described cases , mri had a significant impact on the therapeutic decisions [ 3 , 7 ] . the pet - ct examination , which is used to assess the extent of lesions in locally advanced cervical carcinoma , is contraindicated in pregnancy . this is firstly due to the exposure to a high dose of ionising radiation ( ct ) and because of the higher uptake of the radionuclide in the liver of the foetus with a longer retention than in the maternal liver ( pet ) . this was demonstrated in animal studies ( pregnant monkeys ) [ 3 , 5 , 8 ] . histopathological evaluation of the lymph nodes remains the gold standard in the assessment of regional lymph nodes . the involvement of lymph nodes affects therapeutic decisions and can change the course of pregnancy [ 3 , 4 ] . the society of american gastrointestinal and endoscopic surgeons ( sages ) has developed guidelines describing laparoscopic procedures in pregnant women . pelvic lymphadenectomy is a valid diagnostic procedure in the first and second trimester of pregnancy in patients with early cervical cancer . the rate of involved pelvic lymph nodes is comparable to that seen in non - pregnant women at the same level of progression . the histological evaluation of the lymph nodes collected from pregnant patients should be carried out by a qualified and experienced pathologist because some of the changes in the pelvic lymph nodes associated with the development of decidua can mimic metastasis to the lymph nodes , especially in squamous cell carcinomas . the immunohistochemistry test ( with the assessment of cytokeratins ) allows the disease to be distinguished from physiological changes occurring during pregnancy . sentinel node detection using radiocolloid is not recommended in pregnant women with cervical cancer , although some researchers believe that this procedure is technically feasible in this group of patients [ 3 , 4 , 9 ] . approximately 70% of cervical cancers coexisting with pregnancy are detected at stage i according to figo . at this stage , if there are no metastases to the lymph nodes , there are two possible methods of management : 1 ) close clinical observation ( in order to rule out tumour progression ) and the postponement of treatment until maturity of the foetus ; then the treatment is implemented after birth , 2 ) sparing surgical treatment of cervical tumour to preserve the uterus and pregnancy . at stage ia , the first method of treatment is associated with a very good prognosis . in this stage conisation alone the laparoscopic evaluation of the lymph node status is probably the best criterion for proceeding at stages ib1 in the case of negative lymph nodes , patients with tumours smaller than 2 cm may be subjected to careful observation and implementation of treatment after birth ; either simple trachelectomy or large conisation should be considered [ 35 ] . in locally advanced cervical cancer , a decision is taken about neoadjuvant chemotherapy or chemoradiotherapy . in pregnant women , the choice of this therapeutic method entails the need to terminate pregnancy prior to the implementation of therapy . in exceptional cases , where surgical abortion is not feasible ( e.g. due to the large mass of cervical tumour ) , radiation therapy can be started during pregnancy . neoadjuvant chemotherapy ( nact ) alone and the maintenance of pregnancy is an alternative to the combined treatment ; in such cases , surgical treatment ( or chemoradiation ) is implemented after birth . in stage ib2 and higher most women described to date have been treated with cisplatin and paclitaxel ( 175 mg / m ) . cisplatin may be administered every seven days at a dose of 2050 mg / m or every 21 days at a dose of 50100 mg / m ( usually 75 mg / m ) the second scheme is currently considered the standard for the treatment in pregnancy . there are also several reports on alternative using carboplatin ( auc 57.5 ) , which may be an option to reduce nephrotoxicity , especially in patients with a positive history of pre - eclampsia [ 3 , 5 , 6 , 9 ] . the patient should be presented with all therapeutic options , be aware of the risks , and take an active part in the final decision - making . most of the changes detected in imaging studies during pregnancy in the uterus or ovaries are benign and are usually detected at a routine ultrasound check - up during the pregnancy observation [ 3 , 5 , 6 , 10 , 11 ] . sometimes these changes manifest themselves suddenly , giving symptoms of acute abdomen in the course of ovarian torsion , rupture or intraperitoneal bleeding [ 3 , 5 ] . diagnosis and treatment of a pathological mass found in the appendages depend on the radiological image . there are different scales and ultrasound evaluation systems of pathological lesions , but it is not certain whether their value is the same as in pregnancy practice . a suspicion of malignant nature of the change is based upon : the size ( the changes measuring 5 cm and more require surgical intervention ) , morphological assessment of the tumour , and the presence of changes outside the ovary . it may be useful to use the colour - doppler imaging technique in order to obtain a picture of the blood vessels and thus improve the quality of ultrasound [ 36 , 10 ] . computed tomography of the pelvis is contraindicated because of the high levels of ionising radiation and the associated risk to the foetus . magnetic resonance imaging is preferred to accurately assess the pelvis during pregnancy [ 3 , 4 , 6 , 8 , 10 ] . in the case of ovarian cancer , however , one must remember that during pregnancy it may be ( like other tumour markers ) physiologically elevated , especially in the first trimester ( with a dozen or so per cent of pregnant women the level of ca-125 may be higher than 65 iu / ml ) . the level of ca-125 normalises during the second and third trimester , but it grows rapidly immediately after birth . therefore , the evaluation of ca-125 marker in pregnant women is not helpful in the first trimester of pregnancy , but it can be useful in the second and third trimester [ 3 , 4 , 8 ] . some authors suggest that inhibin b , amh , he4 , and ldh physiologically should not be elevated and can be used in oncologic assessment . but we should also remember that higher levels of tumour markers are associated with non - oncological obstetric complications such as miscarriage , preeclampsia , or hellp . in 1 out of 6001500 pregnancies , a pathological change in the appendages approximately 3% of these patients are diagnosed with malignant tumour of the ovary ; however , non - epithelial tumours have been most commonly observed ( embryonic and of the sex cords origin ) tumours of low - grade . the treatment depends on the size of tumour , the morphological image ( assessed using imaging testing or during surgery ) , histological subtype , progression of the disease , the course of pregnancy , and the expectations of the patient . the use of laparoscopic techniques can reduce the perioperative mortality rate , but we should remember that these procedures should be performed in compliance with all the standards designed to prevent the spread of tumour cells during surgery . the ideal procedure is to collect the specimens from the peritoneum together with the removal of the ovary and fallopian tube on the affected side with the analysis of the frozen fragments further investigation depends on the outcome [ 35 ] . ovarian tumours of low malignant potential have a very good prognosis and most patients are treated only surgically , without chemotherapy . if the surgical exploratory evaluation finds serous ovarian tumour of low malignant potential , it is necessary to resect the tumour and all grossly visible abnormal changes . if the contralateral ovary is macroscopically normal , it should be left [ 35 ] . in the absence of macroscopic peritoneal involvement , the routine assessment of progression should be carried out without lymphadenectomy ( cytology , random peritoneal specimens , resection or biopsy of the omentum , appendectomy in the case of mucous tumours ) . all changes found outside the ovary should be removed in order to assess the progression and histological subtype . another surgical evaluation should be carried out in the case of serous tumours of low malignant potential with the accompanying micropapillary tissue . this procedure may be deferred for a period of time after birth provided that the disease is diagnosed after the 2024 week of gestation . before the 20 week of pregnancy , the laparoscopic evaluation seems to be the safest option . in the case of malignant ovarian tumours , the maintenance of pregnancy and chemotherapy should always be individually discussed the final decision depends on the biological features and the stage of the disease ( histological subtype , differentiation , progression , including the involvement of the lymph nodes , tumour size , the presence of the disease in the peritoneum ) and of course , as always , the will of the patient [ 3 , 4 , 10 ] . in most patients with non - epithelial cancer ( embryonal or of the sex cords origin ) , these patients report more complaints than patients with epithelial tumours , including pain , bloating , and symptoms of acute abdomen . over 90% of patients are diagnosed at the first stage . in order to take a decision to perform the surgery maintaining fertility , a full evaluation of the progression inside the peritoneal cavity indications for adjuvant chemotherapy and the treatment regimens are similar to those in non - pregnant women bep ( bleomycin , etoposide , cisplatin ) is the program of choice [ 3 , 5 , 10 ] . epithelial ovarian cancers are rare in pregnant women and their treatment poses the most difficulties . the prognosis in these tumours is worse than in non - epithelial , in two thirds of patients there is the spread to the peritoneum and the lymph nodes and most patients require chemotherapy . standard adjuvant chemotherapy should be considered for high - grade stage i and any stage ii disease [ 3 , 5 , 6 , 9 ] . the surgical treatment is complicated because it should include the resection of appendages , peritoneal metastasis , and lymph nodes . if a decision is taken to maintain pregnancy , the preservation of the uterus with evaluation of the disease progression in the peritoneal cavity is a primary procedure that should be offered . during the initial surgical procedure , only the suspicious lymph nodes should be removed . the invasive cytoreductive surgical treatment leads to the termination of pregnancy because of the need for hysterectomy such a procedure should be proposed when the diagnosis of epithelial ovarian cancer is made at stage iii during the first or second trimester of pregnancy [ 3 , 9 ] . in some patients with peritoneal dissemination , it is possible to maintain pregnancy and use neoadjuvant chemotherapy ( carboplatin and paclitaxel ) there was no damage to the foetus if chemotherapy was administered in the second and third trimester . however , the observation of patients after the treatment described in the available reports is very short [ 3 , 4 , 6 , 810 ] . the risk of birth defects as a result of chemotherapy administered during pregnancy is high in the first trimester of pregnancy , especially between the 2 and 8 weeks of pregnancy , and therefore therapeutic abortion and the need to defer the treatment should be discussed with each patient . the cytostatic treatment of ovarian tumours in the second and third trimester of pregnancy should be in accordance with the standards applicable in non - pregnant patients , both in the case of non - epithelial and epithelial tumours . usually , the premature termination of pregnancy is not necessary if the disease is well controlled with chemotherapy . previously published reports described only single cases of birth defects and their relationship with chemotherapy is not clear [ 3 , 11 ] . most reported cases concern the safe use of bleomycin , carboplatin , taxanes , and vinca alkaloids . newborns demonstrated neutropaenia , hair loss , and impaired hearing due to the use of cisplatin within three weeks before childbirth . a case of ventriculomegaly was reported in a newborn of a mother treated with bep regimen . there are no reports on the use of topotecan in pregnant women , and data concerning gemcitabine are very scarce it is suspected of having the ability to inhibit intrauterine growth [ 3 , 11 ] . there are only a few reports of the application of this antibody during pregnancy in ophthalmic treatment without a negative impact on the course of the pregnancy and the development of the foetus . certainly , however , the systemic administration of anti - angiogenic therapy can not be recommended during pregnancy [ 3 , 4 , 8 ] . the data on this topic come from individual case reports , of which at least half were diagnosed in the course of uterine bleeding after childbirth . in other cases , the diagnosis was made while determining the cause of miscarriage . in most cases , well - differentiated cancer was observed without or with minimal invasion of the myometrium [ 5 , 8 , 11 , 12 ] . endometrial cancer diagnosed before fertilisation changes the intrauterine environment to one that makes fertilisation extremely difficult ; on the other hand , pregnancy has a protective effect on endometrial tumour growth . it is suspected that the rare phenomenon of the coexistence of pregnancy and endometrial cancer may correspond to the presence of immature endometrium , resistant to progesterone . cancer can occur focally in the immature basal cells , which do not respond to hormonal stimulation . the radical removal of reproductive organs is the standard treatment of endometrial cancer , but in the majority of patients with endometrial cancer at stage i according to figo , the long - term prognosis is successful , and after discussing with them further maternity plans , they can undergo sparing therapy ( curettage with the subsequent regular check - up with endometrial biopsy ) . this malignant tumour is very rare in premenopausal women , although the incidence of invasive squamous cell carcinoma of the vulva in women under 40 years of age is growing due to hpv and hiv infections [ 4 , 5 , 8 ] . radical vulvectomy with inguinal lymphadenectomy is the basic therapeutic option in cancer of the vulva in pregnancy . the use of blue dye is not recommended during pregnancy due to a high risk of severe allergic reactions . undergoing surgery is a relative contraindication to vaginal birth [ 4 , 5 ] . less extensive treatments are laser therapy or surgical excision of the changes like vulvar intraepithelial neoplasia ( vin ) or partial vulvectomy with the sentinel node procedure in the case of invasive cancers with clinically non - suspicious regional lymph nodes [ 5 , 9 ] . the treatment of vulvar cancer in pregnant women is not different in principle from that performed in non - pregnant women , but the advancement of pregnancy is important and should be taken into account before taking the final medical decision . in the third trimester , vascularisation of the vulva significantly increases , which also increases the operational risk ( high mortality rate ) ; therefore , if a diagnosis is made after the 36 week of pregnancy , surgery should be postponed until after the birth . if the inguinal lymph nodes are involved , the prognosis is unfavourable and immediate treatment is crucial . here vulva melanoma in pregnant women should be treated in the same way as in non - pregnant . patients with poor prognosis should be informed of the high risk of recurrence , the possibility of death and the high risk of metastasis appearance in the foetus ( 22% ) . primary carcinoma of the vagina is a rare gynaecological cancer , more often observed as secondary to the involvement of the vulva , cervix , endometrium , bladder , colon , or rectum . histologically , primary vaginal cancers are squamous cell ( up to 90% ) , adenocarcinomas ( up to 10% ) , and occasionally melanomas and sarcomas leiomyosarcoma and rhabdomyosarcoma . it is believed that intrauterine exposure to diethylstilbestrol can cause clear cell carcinoma of the vagina in young women . the coexistence of vaginal cancer and pregnancy is very rare and described in casuistic reports . the microscopic evaluation includes the assessment of smears and biopsies taken during colposcopy . in order to assess the severity of the disease in pregnant women , the following examinations can be safely performed : cystoscopy , procto - rectoscopy , abdominal ultrasound , and conventional chest x - ray with abdominal protection . because of the rarity of the disease , there are no guidelines for dealing with pregnant women . the treatment should be planned individually , depending on the progression of cancer , the stage of pregnancy , and the possibility of its maintenance . childbirth , if it occurs , should be carried out , of course , by caesarean section . it is not known whether the postponement of treatment due to pregnancy significantly changes the prognosis in patients with this diagnosis regardless of the coexistence of pregnancy , advanced disease has a decidedly poor prognosis and the five - year survival rate is low . the diagnosis of malignant tumour in pregnancy is a dramatic event that overshadows the joy of the forthcoming motherhood . usually , these women are diagnosed with genital cancer , breast cancer , lymphatic system neoplasm , or melanoma . historically , the diagnosis was associated with the need to terminate the pregnancy . today , although unskilled doctors still propose the only therapeutic option , abortion is not the only solution . thanks to the efforts of many experts , reports in recent years have been summarised and collected creating guidelines that would enable , at least in some cases , the maintenance of pregnancy and the effective treatment of cancer , especially gynaecological cancers and breast cancer . the patient should have the opportunity to decide about the fate of her pregnancy and it should not be affected by the moral beliefs of the doctor . the task of the professionals , who look after such a special patient , is to provide the woman with access to the most current and reliable knowledge in order to allow her to take a conscious decision on further management . from the moment of taking a decision to start the treatment and maintain pregnancy , the patient must be provided with the multidisciplinary care of highly qualified doctors cooperating with each other , who know and understand the complexity of coexistence of cancer and pregnancy [ 3 , 4 , 6 , 9 , 1113 ] . thanks to the publications in recent years , summarised in this paper , it is possible to avoid making hasty , tragic decisions enabling pregnant women affected by cancer to fight not only for their own health , but also for the birth of a healthy child .

the coexistence of malignant tumour and pregnancy is a state of simultaneous occurrence of two completely contradictory philosophical and biological phenomena the development of a new life and a life - threatening terminal illness . finally , a physician in fact the whole team of doctors is facing the fight for two lives : of the mother and her unborn child.the incidence of malignant disease in pregnancy is 0.05 to 0.1% . this condition is a major challenge for physicians because there are no randomised studies that could be the basis to choose the therapeutic methods the medical knowledge merely comes from case reports , registries , and observational studies.the following cancers most often coexist with pregnancy : gynaecological neoplasm ( especially cervical and ovarian cancer ) , breast cancer , lymphatic system neoplasm , and melanoma.formerly , the diagnosis was clearly the necessity of abortion . today although unskilled doctors still propose the only therapeutic option termination of pregnancy is not the only solution.the past few years have seen the updating of reports and guidelines for the management of pregnant women with cancer . this paper is a review and summary of the information from these publications .

You are an expert at summarizing long articles. Proceed to summarize the following text: hemophilia a ( ha ) results from the partial or complete deficiency of functional factor viii ( fviii ) protein caused by a wide range of heterogeneous mutations in the factor 8 ( f8 ) gene . being an x - linked recessive disorder , females are generally not affected , although they can be carriers of this disorder . a classical female hemophilia is possible only when a carrier female marries a hemophilic male , of which there are only few reports in the literature.[24 ] few other reports of homozygous female ha are mainly due to de novo mutations in one or both the x chromosomes . blood was collected by peripheral venous puncture at a 1:10 volume ratio in 3.8% trisodium citrate . activated partial thromboplastin time ( aptt ) factor viii activity ( fviii : c ) of each sample was determined by one - stage aptt - based assay in a semiautomated coagulometer ( diagnostica stago , asnieres , france ) . plasma von willebrand factor antigen level ( vwf : ag ) was measured by enzyme - linked immunosorbent assay ( diagnostica stago ) . multiplex polymerase chain reactions spanning all the 26 exons were carried out and conformation - sensitive gel electrophoresis ( csge ) was used to screen the mutations . amplicons were run on a 12.5% gel ( acrylamide : 1 , 4-bis acroylyl piperazine 99:1 ) incorporating mild denaturants ( 10% ) ethylene glycol , 15% formamide and electrophoresed overnight at 80v dna sequencing was performed on both strands using the big dye terminator cycle sequencing v1.1 ready reaction kit and an automated abi dna sequencer ( applied biosystems , carlsbad , california . we report a case of homozygous female ha with moderate fviii deficiency ( moderate fviii deficiency 5.5% fviii : c , vwf : ag 120% ) , born of a 1 consanguineous marriage . she presented to our center with severe bleeding diathesis following delivery of her first child and a history of prolonged bleed from cuts and injuries . the mother ( a carrier of ha ) of the proband was married to a hemophilic who died of excessive bleeding in a road accident and was undiagnosed but his two brothers were diagnosed with moderate deficiency of ha ( f viii : c 4.8% and 5.7% ) . her two brothers were affected and the sister was found to be a carrier of ha . pedigree of an extensive family with classical female hemophilia a sequencing of this exon revealed a missense mutation corresponding to c.1315g > a , which results in the amino acid substitution corresponding to p.gly420ser that fits well with the clinical manifestation of the patient [ figure 2 ] . the mother was shown to be a heterozygous carrier of the mutation , while the two affected brothers , uncles and nephews also showed the same mutation . they were found to be cross - reacting material ( crm ) negative [ table 1 ] . a missense mutation c.1315g > a ( p.gly420ser ) in moderate hemophilia a genotypic phenotypic correlation it was inferred that the father of this index case was also affected and carried the same mutation as that of the index case . the mutation has earlier been reported to be associated with moderate and severe ha , causing polarity change in the protein coil thus influencing the secondary structure of the protein . female carriers of ha normally do not exhibit a moderate to severe phenotypic expression of the disease . however , a number of other pathophysiological mechanisms may account for the phenotypic expression of very low fviii : c levels in females . these include ( i ) skewed inactivation of the x chromosome leading to predominant expression of the mutated allele as a result of a preferential inactivation of the x chromosome with the wild - type f8 gene , ( ii ) turner syndrome , ( iii ) translocation or ( iv ) males with a female phenotype due to mutation in the sex - determining region y ( sry ) gene on the y chromosome , i.e. swyer syndrome combined with a mutation in the f8 gene . in the present report , we have presented homozygosity of the f8 gene mutation resulting in clinical manifestation of ha in a female . in india , as consanguineous marriages are very common in certain communities ( up to 30% ) , the likelihood of encountering female hemophilia is higher , although this is the first case of ha encountered out of 1600 hemophilia families registered in our comprehensive haemophilia care center . genetic diagnosis in such cases is not necessary as all the male children will be affected and daughters are obligatory carriers .

background : hemophilia a ( ha ) , being an x - linked recessive disorder , females are rarely affected , although they can be carriers.aims:to study the mutation in f8 gene in an extended family with a homozygous female ha.materials and methods : all the seven affected members ( six males and one female ) were initially screened by conformation sensitive gel electrophoresis ( csge ) and direct dna sequencing.results:a homozygous missense mutation c.1315g > a ( p.gly420ser ) was identified in exon 9 of f8 gene in homozygous state in the affected female born of 1 consanguinous marriage and in all the affected male members of the family . her factor viii levels was found to be 5.5% , vwf : ag 120%.conclusion : in india , as consanguineous marriages are very common in certain communities ( up to 30% ) , the likelihood of encountering female hemophilia is higher , although this is the first case of ha out of 1600 hemophilia families registered in our comprehensive haemophilia care center . genetic diagnosis in such cases is not necessary as all the male children will be affected and daughters obligatory carriers .

You are an expert at summarizing long articles. Proceed to summarize the following text: malignant central nervous system ( cns ) germ cell tumors ( gcts ) are uncommon , accounting for less than 1% of primary brain tumors , and occur predominantly during childhood . the incidence of cns gcts has been reported to exhibit a marked association with race , appearing to be more common in asian countries than in the west [ 1 - 13 ] . however , the majority of previous reports were based on single institution experiences rather than the general population . recently , a population - based comparison study between japan and the united states found no significant difference in the incidence of malignant cns gcts between these two countries . in contrast , the central brian tumor registry of the united states ( cbtrus ) report published in 2014 stated that asians / pacific islanders ( age - standardized rate [ asr ] , 0.19 ) were associated with a higher incidence rate of cns gcts than caucasian ( asr , 0.10 ) and african - american ( asr , 0.07 ) individuals in the united states . thus , the existence of racial differences in the incidence of cns gct remains unclear . the aim of this study was to determine the korean nationwide incidence and survival rate for primary malignant cns gcts . using the korea central cancer registry ( kccr ) database , we reported the precise cns gct incidence by age , sex , histological type , and topography in korea , as well as the survival rate during 2005 - 2012 . in 1999 , the kccr expanded cancer registration to cover the entire population under the population - based regional cancer registry program . national cancer incidence reports for diseases diagnosed since 1999 began to be published in 2005 , and the incidence data for 2012 was 97.7% complete . as gcts are often malignant , we included only malignant gcts diagnosed between 2005 and 2012 in this study . we were able to collect more reliable and accurate data describing cns tumors because , from 2005 onward , information regarding malignant whole - brain and cns tumors was registered separately from that of benign and borderline tumors . for survival analysis , we included gcts registered between 2005 and 2010 , and followed these cases until december 31 , 2013 . gcts were identified using the international classification of diseases for oncology ( third edition ) , and were selected using the primary sites c70.0-c72.9 and c75.1-c75.3 . tumors were classified into two groups : pineal ( c75.3 ) and nonpineal ( c70.0-c72.9 and c75.1-c75.2 ) . tumors were grouped by histology codes into germinoma ( 9060 , 9061 , 9064 , and 9065 ) , nongerminomatous gct ( 9070 , 9071 , 9081 , 9085 , and 9100 ) , and teratoma ( 9080 , 9082 , and 9084 ) . the national cancer center institutional review board approved this study ( ncc2015 - 0223 ) . crude rates were calculated by dividing the total number of cases in a given time period by the entire population , and were expressed per 100,000 persons . the male - to - female ( m : f ) incidence rate ratios ( irrs ) were calculated by dividing the age - adjusted incidence rates of male participants by those of female participants . for survival analysis , we used only data for patients with tumors that were diagnosed between 2005 and 2010 , and excluded cases that could not be followed because of mismatched personal identification numbers and cases in which gcts were not the primary tumors . the overall 1- to 5-year survival rates of gct patients , as well as survival by sex , age group , primary site , and histological type were calculated using the life - table method . 9.2 ( sas institute inc . , cary , nc ) and stata 11.0 ( statacorp lp , college station , tx ) in 1999 , the kccr expanded cancer registration to cover the entire population under the population - based regional cancer registry program . national cancer incidence reports for diseases diagnosed since 1999 began to be published in 2005 , and the incidence data for 2012 was 97.7% complete . as gcts are often malignant , we included only malignant gcts diagnosed between 2005 and 2012 in this study . we were able to collect more reliable and accurate data describing cns tumors because , from 2005 onward , information regarding malignant whole - brain and cns tumors was registered separately from that of benign and borderline tumors . for survival analysis , we included gcts registered between 2005 and 2010 , and followed these cases until december 31 , 2013 . gcts were identified using the international classification of diseases for oncology ( third edition ) , and were selected using the primary sites c70.0-c72.9 and c75.1-c75.3 . tumors were classified into two groups : pineal ( c75.3 ) and nonpineal ( c70.0-c72.9 and c75.1-c75.2 ) . tumors were grouped by histology codes into germinoma ( 9060 , 9061 , 9064 , and 9065 ) , nongerminomatous gct ( 9070 , 9071 , 9081 , 9085 , and 9100 ) , and teratoma ( 9080 , 9082 , and 9084 ) . the national cancer center institutional review board approved this study ( ncc2015 - 0223 ) . crude rates were calculated by dividing the total number of cases in a given time period by the entire population , and were expressed per 100,000 persons . the male - to - female ( m : f ) incidence rate ratios ( irrs ) were calculated by dividing the age - adjusted incidence rates of male participants by those of female participants . for survival analysis , we used only data for patients with tumors that were diagnosed between 2005 and 2010 , and excluded cases that could not be followed because of mismatched personal identification numbers and cases in which gcts were not the primary tumors . the overall 1- to 5-year survival rates of gct patients , as well as survival by sex , age group , primary site , and histological type were calculated using the life - table method . 9.2 ( sas institute inc . , cary , nc ) and stata 11.0 ( statacorp lp , college station , tx ) . the kccr database included 654 cases of primary malignant gcts of the brain and cns diagnosed between 2005 and 2012 . the annual average number of registered cases was 81.8 , and the overall asr for cns gct was 0.179 per 100,000 people ( annual percent change , 0.71% ; p=0.732 ) ( table 1 ) . the incidence of all malignant gcts was significantly higher in male participants ( 0.263 per 100,000 people ; 95% confidence interval [ ci ] , 0.240 to 0.286 ) than female participants ( 0.089 per 100,000 people ; 95% ci , 0.075 to 0.104 ) . when ranked according to age , the majority of malignant tumors were reported in the young adult ( 15 - 29 years , 47.1% ) and pediatric ( 0 - 14 years , 45.3% ) age groups . the pediatric group had the highest incidence rate ( 0.434 per 100,000 people ) , followed by the young adult group ( 0.365 ) and the adults aged 30 years and over group ( 0.021 ) . approximately 65.4% of gcts were located outside the pineal region , while the rest were located in the pineal region . the majority ( 76.0% ) of tumors however , when stratified by site , the m : f irr for pineal region tumors was 13.62:1 compared to an irr of 1.87:1 for tumors located in a nonpineal region ( table 3 ) . among the patients with gct , 46 patients eventually died during the follow - up period . the 5-year observed survival rate was high for all gcts , at 91.2% ( table 4 ) . these rates showed no statistically significant differences between male and female participants ( male participants , 90.9% ; female participants , 92.3% ; p=0.658 ) ( fig . 1a ) , age groups ( 0 - 14 years , 90.7% ; 15 - 29 years , 91.8% ; 30 years and over , 90.6% ; p=0.912 ) ( fig . 1b ) , or primary sites ( pineal , 91.5% ; nonpineal , 91.1% ; p=0.843 ) ( fig . however , there was a significant difference according to histological type ( germinoma , 95.3% ; nongerminomatous gct , 77.6% ; teratoma , 76.5% ; p < 0.001 ) ( fig . the kccr database included 654 cases of primary malignant gcts of the brain and cns diagnosed between 2005 and 2012 . the annual average number of registered cases was 81.8 , and the overall asr for cns gct was 0.179 per 100,000 people ( annual percent change , 0.71% ; p=0.732 ) ( table 1 ) . the incidence of all malignant gcts was significantly higher in male participants ( 0.263 per 100,000 people ; 95% confidence interval [ ci ] , 0.240 to 0.286 ) than female participants ( 0.089 per 100,000 people ; 95% ci , 0.075 to 0.104 ) . when ranked according to age , the majority of malignant tumors were reported in the young adult ( 15 - 29 years , 47.1% ) and pediatric ( 0 - 14 years , 45.3% ) age groups . the pediatric group had the highest incidence rate ( 0.434 per 100,000 people ) , followed by the young adult group ( 0.365 ) and the adults aged 30 years and over group ( 0.021 ) . approximately 65.4% of gcts were located outside the pineal region , while the rest were located in the pineal region . the majority ( 76.0% ) of tumors however , when stratified by site , the m : f irr for pineal region tumors was 13.62:1 compared to an irr of 1.87:1 for tumors located in a nonpineal region ( table 3 ) . among the patients with gct , 46 patients eventually died during the follow - up period . the 5-year observed survival rate was high for all gcts , at 91.2% ( table 4 ) . these rates showed no statistically significant differences between male and female participants ( male participants , 90.9% ; female participants , 92.3% ; p=0.658 ) ( fig . 1a ) , age groups ( 0 - 14 years , 90.7% ; 15 - 29 years , 91.8% ; 30 years and over , 90.6% ; p=0.912 ) ( fig . 1b ) , or primary sites ( pineal , 91.5% ; nonpineal , 91.1% ; p=0.843 ) ( fig . however , there was a significant difference according to histological type ( germinoma , 95.3% ; nongerminomatous gct , 77.6% ; teratoma , 76.5% ; p < 0.001 ) ( fig . the incidence of cns gcts is known to be higher in asia , japan , and korea than in other areas of the world . in particular , cns gcts account for relatively high proportions of pediatric brain tumors in east asia , 7.8% in japan , 14.0% in taiwan , 7.9% in china , and 9.5% in korea , whereas their frequencies in north america and europe are less than 3% . according to the cbtrus report , the overall incidence of malignant cns gcts between 2007 and 2011 was 0.07 per 100,000 in the united states , with the asian / pacific islander group associated with a higher cns gct incidence rate ( 0.19 per 100,000 ) than caucasian and african - american participants . in children , the incidences of cns gct , including benign tumors , were 0.21 per 100,000 in total and 0.21 , 0.14 , and 0.51 per 100,000 in caucasian , african - american , and asian/ pacific islander populations , respectively . goodwin et al . also described differences in the incidence of pediatric gcts according to race ( caucasian , 1.29 per 100,000 ; african - american , 0.33 per 100,000 ; and asian , 2.6 per 100,000 ) . moreover , the childhood incidence of primary cns gcts in a regional survey in kumamoto prefecture in southern japan was found to be 0.45 per 100,000 . these data suggest that an asian genetic background is strongly associated with the development of cns gct . however , a recent study demonstrated that the incidence of cns gct in japan was not significantly higher than that in the united states . mccarthy et al . estimated the incidence of malignant cns gcts diagnosed during 2004 - 2006 in 14 population - based registries representing 31.8% of the total population of japan and analyzed the surveillance epidemiology and end results program database for 17 population - based cancer registries covering 26% of the population of the united states . unexpectedly , they found the incidence of malignant cns gcts in japan ( 0.096 per 100,000 ) to be similar to that in the united states ( 0.075 per 100,000 ) , and showed the same sex - based patterns by location . the incidence of cns gcts in japan was low compared to those reported in previous studies . these results prompted us to investigate the actual nationwide population - based incidence of cns gcts in korea . between 2005 and 2012 , 654 cases of newly diagnosed primary malignant cns gcts were registered in the kccr . the incidence of cns gcts in korea was more than two times higher than that in japan and the united states . furthermore , the incidence of pediatric cns gcts in korea ( 0.434 per 100,000 ) was similar to the incidence of cns gcts in kumamoto prefecture ( 0.45 per 100,000 ) . kumamoto and korea may also share a similar genetic background because of their geographical proximity . the survival rate of pure germinoma is known to be very high , with the 10-year overall survival rate attaining 90% . for nongerminomatous gct , the 10-year overall survival rates were reported to be 30%-80% ; however , cns gcts showed better prognosis among pediatric patients . matsutani et al . reported that the 10-year survival rates for pure germinoma and mature teratoma were both over 90% . even though we did not report 10-year survival rates because of our short follow - up period , the survival outcomes observed in this study suggest that cns gcts are curable . the 5-year observed survival rate for all patients with cns gcts was 91.2% , with no differences observed according to sex , age group , or primary tumor site . however , patients with germinoma showed a greater 5-year survival rate ( 95.3% ) than those with nongerminomatous gcts ( 77.6% ) and malignant teratomas ( 76.5% ) . specifically , the kccr does not record cancer risk factors or specific treatment - related factors , making it difficult to determine specific prognostic factors for cns gct . nevertheless , the kccr data encompasses over 97% of the population of korea , and includes up - to - date information with longer follow - up periods than the data sources used in previous studies . in conclusion , our nationwide population - based study revealed that the incidence of cns gcts in korea is significantly higher than the reported incidence for the overall population of the united states , but is comparable to the rate reported for americans of asian / pacific islander backgrounds .

purposemalignant central nervous system ( cns ) germ cell tumors ( gcts ) , although rare , are thought to occur more frequently among asians . however , a recent population - based study revealed no differences in gct incidence between asians and caucasians . therefore , this study was conducted to determine the incidence and survival rates of cns gcts using the national cancer incidence database , and to compare these rates to those in the united states and japan.materials and methodswe extracted cns gct patients diagnosed between 2005 and 2012 from the korea central cancer registry database . age - standardized rates ( asrs ) , annual percentage change , and the male - female incidence rate ratios ( irrs ) were calculated . to estimate the survival rate , we used data for patients diagnosed between 2005 and 2010 and followed their cases until december 31 , 2013.resultsthe asr for cns gct between 2005 and 2012 was 0.179 per 100,000 ( 95% confidence interval , 0.166 to 0.193 ) , with an overall male - to - female ( m : f ) irr of 2.95:1 . however , when stratified by site , the m : f irr was 13.62:1 for tumors of the pineal region and 1.87:1 for those located in nonpineal regions . the most frequent histologic type was germinoma ( 76.0% ) , and the most frequent location was the suprasellar region ( 48.5% ) . the 5-year survival rate of germinoma patients was 95.3%.conclusionthe incidence rate of cns gcts in korea during 2005 - 2012 was 0.179 per 100,000 , which was similar to that of the asian / pacific islander subpopulation in the united states . moreover , the cns gct survival rate in korea was similar to rates in japan and the united states .

You are an expert at summarizing long articles. Proceed to summarize the following text: heatstroke is characterized by hyperpyrexia , multiorgan damage and dysfunction , and predominant central nervous system dysfunction ( such as delirium , convulsion , or coma ) [ 13 ] . the full spectrum of the signs and symptoms occurring during heatstroke in humans can be mimicked by the rodent heatstroke model . when mice were subjected to acute heat stress , the stress response indicators such as mortality , hypothermia , and multiple organ apoptosis , were observed [ 5 , 6 ] . other line of evidence has accumulated to show that testosterone increases the susceptibility toward a wide variety of infectious diseases including human sepsis , shock , and severe injury . in addition , depletion of testosterone by castration prior to soft - tissue trauma results in better maintained immune and myocardial function in male mice [ 10 , 11 ] . flutamide , an androgen receptor antagonist , has been shown to restore the depressed cell - mediated immunity , and cardiac and hepatic function following soft - tissue trauma and hemorrhagic shock . it has also been promoted that testosterone plays a role in the regulation of heat balance in male rats . this raises the possibility that testosterone depletion by castration may protect male mice from heatstroke - induced multiple organ damage and lethality . to deal with the hypothesis , the effects of surgical castration with or without testosterone replacement on the heatstroke - induced thermoregulatory deficits ( in particular , the hypothalamic neuronal damage and apoptosis and hypothermia ) , multiple organs dysfunction or damage and lethality were assessed in mice [ 5 , 6 ] . all the experiments were carried out in accordance with the ethical guidelines laid down by the committee for the purpose of control and supervision of experiments on animals , chi mei medical center ( tainan , taiwan ) . icr inbred male mice , 8 weeks old , were given food and water ad libitum and acclimatized to room temperature at 24c , relative humidity ( rh ) of 50 8% , and a 12 h dark / light cycle for 1 week before the start of the experiment at least . animals were exposed to heat stress treatment ( 41.2c , rh-5055% , 1 h ) in an environment - controlled chamber . the time at which mice were removed from the environmental chamber was called 0 hour . the heat - stressed mice were returned to the normal room temperature ( 25c ) after the end of the heat exposure . mice that survived on day 4 of heat treatment were considered survivors , and the data were used for analysis of the results . core temperatures were measured every 5 minutes with a copper constantan thermocouple inserted into the rectum and connected to a thermometer ( hr1300 , yokogawa , tokyo , japan ) . heatstroke resembles sepsis in many aspects [ 15 , 16 ] . like many sepsis studies , we use death as an endpoint in conscious mice in this study fourteen days before the experiment , briefly , after the initiation of general anesthesia with ketamine and xylazine ( 8.7 and 1.3 mg/100 g bw , i m ) and application of 75% alcohol to disinfect the scrotum , a small midline incision was made and the testes were exteriorized . the spermatic vessels were tied with 4.0 silk sutures , and the testes were removed . the incision was then closed with 4.0 silk sutures . in sham - operated mice , the skin of the scrotum was incised to draw out and back the testes and closed with sutures only . an interval of 14 days after castration was chosen for subcutaneously implanting testosterone or heat stress experiments because previous studies have demonstrated the absence of any detectable plasma testosterone levels at this interval . for testosterone replacement study , the castrated groups were subcutaneously implanted with testosterone 2 weeks after the castration . briefly , after the initiation of general anesthesia with ketamine and xylazine ( 8.7 and 1.3 mg/100 g bw , i m ) , a small incision was made in the skin of the back , a pellet of testosterone ( 0.5 mg / pellet , 21-day release ; innovative research ) was subcutaneously implanted . for the other sham - implanted animals , the skin of the back was incised and then closed with 3.0 silk suture only . four major groups of animals were designated for the experiment . in the normothermic control ( nc ) groups , the animals were exposed to room temperature ( 26c ) throughout the entire experiments . the sham - operated heatstroke ( soh ) mice , the castrated , vehicle - treated heatstroke ( cvh ) mice , and the castrated , testosterone - treated heatstroke ( cth ) mice were treated with heat regimen of 41.2c for 1 h. before the start of experiments , their core temperature was within the normal body temperature range of 37.0 ~ 37.6 . peripheral blood samples were harvested from urethane - anesthetized mice ( 1.4 g / kg bw , ip ) by heart puncture via a syringe containing 3.8% sodium citrate ( 9 : 1 vol / vol ) . plasma concentration of testosterone was measured by enzyme immunoassay ( eia ) as described in the instructions provided by manufacturer 's kits ( cayman chemical usa , catalog no.582701 ) , which presents 6 pg / ml of sensitivity , and 100% of specificity . the heat - treated mice were sacrificed at heat off 2.5 h under the heat stress model . perfusion and prefixed procedure with the pbs and 10% formaldehyde were performed after the general anesthesia with urethane ( 1.4 g / kg bw , ip ) . the brain , liver , spleen , and kidney were excised and postfixed in a solution containing 30% sucrose and 10% formaldehyde for at least 24 hours . after fixation , the organs were embedded separately in tissue tek oct embedding medium ( miles ) . snap frozen samples were cryostat sectioned ( 8 m thick ) and placed on slides coated with poly - l - lysine for tunel assays . tunel staining was done using a bd apoalert dna fragmentation assay kit ( bd biosciences - clontech ) , according to detailed protocol provided by manufacture . in brief , tissue slides were pretreated with 20 g / ml proteinase k solution for 5 minutes and were incubated with the reaction mixture containing terminal deoxynucleotidyl transferase ( tdt ) and fluorescein - conjugated deoxyuridine triphosphate ( dutp ) for 1 hour at 37c . afterwards , sections were washed with pbs , their nuclei were costained with 4,6-diamidino-2-phenylindole ( dapi ) using dapi - containing vectashieldr mounting medium ( vector laboratories , burlingame , ca ) , and subsequently analyzed using olympus e800 fluorescent microscope equipped with olympus coolpix 995 digital camera ( both from olympus , japan ) . apoptosis induction efficacy was calculated as percentage of fluorescein - positive to dapi - stained nuclei . at the end of experiment , the brain was removed , fixed in 10% neutral buffered formalin , and embedded in paraffin blocks . serial ( 5 m ) sections through the hypothalamus were stained with hematoxylin and eosin for microscopic evaluation . the extent of hypothalamic neuronal damage was scored on a scale of 03 , modified from the grading system of pulsinelli et al . , in which 0 is normal 1 indicates that approximately 30% of the neurons were damaged , 2 indicates that approximately 60% of the neurons were damaged , and 3 indicates that approximately 100% of the neurons are damaged . degenerative damage was considered to have occurred in any neurons showing pyknosis of the nucleus and cell shrinkage . all values , except those on table 3 , are expressed as the mean sem and were analyzed by one - way analysis of variance followed by the fisher 's least significance test as a post hoc test for multiple comparisons among means . for the data in table 3 , the wilcoxon tests convert the scores or values of a variable to ranks , require calculation of the sum of the ranks , and provide critical values for the sum necessary to test the null hypothesis at a given level of significance . these data are presented as the median , followed by first and third quartiles . wbh treatment was used to induce heatstroke and thermoregulatory deficit ( e.g. , hypothermia ) in mice as described in section 2 . both figures 1 and 2 indicate that 1 h of wbh resulted in 33% mortality and hypothermia ( ~27c core temperature ) monitored at 4 h of wbh in soh mice . however , in cvh mice , the values of both percentage of survival and core temperature were significantly reached to new levels of 87% and 34.5c , respectively . when the cth groups were exposed to the same heat treatment , the values of both percentage of survival and core temperature table 1 summarizes the plasma levels of testosterone for different groups of mice monitored at 4 h of wbh in soh , cvh , and cth groups or the equivalent time in nc group . as compared to those of nc or soh groups , the cvh mice displayed significantly lower levels of plasma testosterone ( 4 2 pg / ml versus 403 91 or 525 115 pg / ml ) . however , cth mice showed significantly higher levels of plasma testosterone ( 260 24 pg / ml versus 4 2 pg / ml ) as compared to those of cvh ( table 1 ) . as summarized in table 2 , the numbers of tunel - positive cells in the hypothalamus evaluated at 2.5 h postwbh were 0 , 344 107 , 70 17 , and 312 95 per hypothalamic section , respectively , for nc ( n = 7 ) , soh mice ( n = 7 ) , cvh ( n = 7 ) , and cth ( n = 7 ) . photomicrographs of tunel - positive cells in the hypothalamus of an nc , a soh mouse , a cvh mouse , and a cth mouse were shown in figures 3(a)to 3(d ) . as compared to those of nc group , soh mice had higher numbers of tunel - positive cells in their hypothalami ( figure 3(b ) ) . the heat - induced increased numbers of hypothalamic tunel - positive cells could be significantly reduced by castration ( figure 3(c ) ) . however , the beneficial effects of castration were significantly reversed by testosterone replacement ( figure 3(d ) ) . table 3 summarizes the effects of heat exposure on the neuronal damage scores of the hypothalamus from nc mice , soh mice , cvh mice , or cth mice . the scores for hypothalamic neuronal damage in soh mice significantly ( p < .05 ) exceeded those of the respective nc mice . however , the hypothalamic neuronal damage scores in cvh mice were significantly ( p < .05 ) lower than those of soh mice . furthermore , it was found that the hypothalamic neuronal damage score in cth mice were significantly ( p < .05 ) higher than those of cvh mice . two and half hours after termination of heat stress , soh mice exhibited cell shrinkage and pyknosis of the nucleus in the hypothalamus ( figure 4(b ) ) . the heatstroke - induced neuronal damage in the hypothalamus was markedly less in cvh mice ( figure 4(c ) ) or cth mice ( figure 4(d ) ) . both tunel and he stainings revealed that apoptosis , cell shrinkage and pyknosis that occurred in the hypothalamus of a soh ( figure 5(b ) ) mouse could be reduced by castration as shown in a cvh mouse ( figure 5(c ) ) , which could be reversed by testosterone replacement in a cth mouse ( figure 5(d ) ) . tunel assays of splenocytes , hepatocytes , and kidney cells were done 2.5 h after the termination of heat stress for different groups of mice . the numbers of tunel - positive cells of spleen , and kidney from svh mice were significantly higher than those of nc mice ( table 2 ) . as compared to soh mice , cvh mice had significantly lower numbers of tunel - positive cells in multiple organs ( table 2 ) . in addition , the cth mice showed significantly higher numbers of tunel - positive in all these 3 organs as compared to those of cvh mice . photomicrographs showing examples of tunel - positive cells of spleen and kidney for different groups of mice were depicted in both figures 6 and 7 , respectively . it has been demonstrated that plasma levels of estradiol are related to heat tolerance in anesthetized rats . for example , the heat tolerance of estrus female rats was superior to the heat tolerance of ovariectomized or leuprolide - treated female rats . induction of high levels of plasma estradiol caused by intravenous delivery of a high dose ( 1 ml / kg ) of premarin in estrus female , ovariectomized , or leuprolide - treated female rats conferred protection after heatstroke occurrence , as reflected by prolonged survival time . evidence has also been provided to suggest that premarin can act via estrogen receptors to rescue the unanesthetized , unrestrained mice from heatstroke - induced lethality . in the present study , we have further evidence to promote that testosterone depletion by castration is able to protect the unanesthetized , unrestrained mice from heatstroke - induced lethality . it appears that low testosterone and/or high estradiol are able to protect mice from heatstroke - induced lethality . the contention is consistent with several clinical and experimental studies which demonstrate that gender dimorphism in immune and organ responsiveness and in the susceptibility and morbidity from shock , trauma , and sepsis . in view of these findings , clinically relevant therapeutic strategies should be performed using estrogen or premarin , and/or the androgen receptor antagonist , flutamide in heatstroke victims since heatstroke resembles sepsis in many aspects [ 15 , 16 ] . testosterone produced by leydig cells of the testes is the major androgen in the circulation of men and adult males of most mammalian species . androgen may proceed to amplify the action of testosterone through its conversion to dihydroxatone or its aromatization to estradiol . this raises the possibility that the increased levels of both dihydrosterone and estradiol may be induced following castration - induced testosterone depletion in the current model . however , our findings reveal that castration does not affect the plasma levels of both dihydrosterone and estradiol in our mice and indicate that low testosterone , rather than high estradiol , is the main cause for the beneficial effect of castration in preventing heat - induced lethality ( the data are not shown here ) . our previous results have shown that mice display increased production of cellular ischemia ( e.g. , glutamate and lactate - to - pyruvate ratio ) and injury ( e.g. , glycerol ) markers in the hypothalamus following heatstroke . the current findings further show that both apoptosis ( as indicated by tunel staining ) and neuronal damage ( as indicated by both cell shrinkage and pyknosis by h and e staining ) in the hypothalamus occur during heatstroke . apparently , the hypothermia that occurred after heatstroke in mice [ 5 , 6 ] may have resulted from neuronal apoptosis and degeneration in the hypothalamus . the heat - induced thermoregulatory deficits as well as neuronal degeneration and apoptosis in the hypothalamus can be significantly prevented by testosterone depletion caused by surgical castration ( as shown in the present results ) . furthermore , the beneficial effects of testosterone in preventing neuronal damage and apoptosis in the hypothalamus and thermoregulatory deficit ( e.g. , hypothermia occurs during room temperature exposure ) can be reversed after testosterone replacement . in addition to ischemic damage to the hypothalamus , severe heat causes apoptosis of spleen and renal cells , which can be ameliorated by testosterone depletion . as mentioned in the introduction section , multiorgan dysfunctions ensued from severe heatstroke include cardiac depression , cerebral ischemia and neuronal damage , systemic inflammation , hepatic and renal failure , systemic inflammation , and hypercoagulable state . the increased proinflammatory cytokine release by kupffer cells normally observed in intact inflammatory male mice following trauma - hemorrhage can be prevented by castration [ 12 , 21 , 22 ] . castration of male rats 2 weeks prior to the onset of trauma - hemorrhage prevented the depression of myocardial function . flutamide ( an androgen receptor antagonist ) has also been shown to prevent the depression of cardiovascular responses following trauma and severe blood loss in male rats . in addition , evidence has accumulated to indicate that testosterone is able to enhance both platelet aggregation [ 23 , 24 ] and vasoconstriction [ 25 , 26 ] . these observations prompted us to think that testosterone depletion may improve heat tolerance during heatstroke by reducing multiple organ dysfunction . in summary , the current results demonstrate that testosterone depletion by castration may rescue mice from heat - induced multiple organ damage and lethality . in order to transfer those effects into clinical usage , studies mimicking castration by the use of an androgen receptor antagonist such as flutamide should be conducted following the onset of heatstroke in future studies .

when the vehicle - treated , sham - operated mice underwent heat stress , the fraction survival and core temperature at + 4 h of body heating were found to be 5 of 15 and 34.4c 0.3c , respectively . castration 2 weeks before the start of heat stress decreased the plasma levels of testosterone almost to zero , protected the mice from heat - induced death ( fraction survival , 13/15 ) and reduced the hypothermia ( core temperature , 37.3c ) . the beneficial effects of castration in ameliorating lethality and hypothermia can be significantly reduced by testosterone replacement . heat - induced apoptosis , as indicated by terminal deoxynucleotidyl- transferase- mediatedudp - biotin nick end - labeling staining , were significantly prevented by castration . in addition , heat - induced neuronal damage , as indicated by cell shrinkage and pyknosis of nucleus , to the hypothalamus was also castration - prevented . again , the beneficial effects of castration in reducing neuronal damage to the hypothalamus as well as apoptosis in multiple organs during heatstroke , were significantly reversed by testosterone replacement . the data indicate that testosterone depletion by castration may protect mice from heatstroke - induced multiple organ damage and lethality .

You are an expert at summarizing long articles. Proceed to summarize the following text: motor and cognitive impairments in stroke patients dramatically reduce their independence in activities of daily living ( adl ) . in particular , the physical symptoms of stroke have a greater effect on the patients independence than the cognitive component1 . therefore , understanding the relationship between motor function and adl is important to design efficient rehabilitation programs aimed at improving adl performance . this ability to perform adl is influenced by motor functions of the upper and lower limbs2 , 3 and the trunk4,5,6 . likhi et al.7 reported that adl performance in stroke patients correlated more closely with the impairment level of the trunk than that of the upper limb , whereas lower limb impairment showed no correlation with adl . however , fong et al.8 reported that lower limb impairment correlated more closely with adl than upper limb impairment . in contrast , ezure et al.9 reported that the upper limb , lower limb , and trunk functions were significantly correlated with adl . multiple linear regression analysis revealed that trunk function exhibited a stronger relationship with adl than the affected side function . therefore , the impact of limb and trunk function impairment on adl in stroke patients remains highly controversial . this is consistent with the well - known strong association between motor functions of the affected upper and lower limbs . for instance , a correlation analysis between the affected upper limb function and adl must be conducted in the absence of the effect of the affected lower limb function on adl . to the best of our knowledge , no study has conducted partial correlation analyses between limb or trunk function impairment and adl in stroke patients . therefore , the present study aimed to investigate the independent influence of the affected upper and lower limb , trunk , and unaffected side function on adl using partial correlation analysis . the study cohort included 77 stroke patients ( 53 males and 24 females ) who were admitted to the northern fukushima medical center between october 2010 and november 2013 . they fulfilled the following inclusion criteria : first stroke ; unilateral supratentorial hemispheric lesion ; absence of marked cognitive deterioration [ 5 cognitive items of the functional independence measure ( fim)11 , described below ] ; and unilateral spatial neglect based on the stroke impairment assessment set12 ( sias ; described below ) . the mean patient age was 68.5 years , and the mean time from stroke onset was 84.8 days . subject characteristics are listed in table 1table 1.stroke-related characteristics of study subjectsmeansdrangeage , years68.512.73693time post - stroke , days84.837.437236males , % 69.2right - sided hemiparesis , % 48.8affected upper limb function ( 010)6.43.0010affected lower limb function ( 015)11.73.8115trunk function ( 06)5.31.006unaffected side function ( 06)5.30.926barthel index ( 0100)86.817.75100motor item of fim ( 1391)73.316.02291fim : functional independence measure . the study protocol was approved by the institutional ethics review board of northern fukushima medical center ( fukushima , japan ) . fim : functional independence measure we compiled data on motor function , trunk function , and unaffected side function from the sias , barthel index ( bi)13 , and fim evaluations . the sias test ( 05 ) items evaluate motor function of the affected limb ( knee - mouth , finger function , hip flexion , knee extension , and foot - pat tests ) , the trunk ( abdominal muscle strength and verticality ) , and the unaffected side ( strength of knee extension and grip strength ) . details on the method , reliability , and validity of sias have been reported elsewhere12 , 14,15,16 . in addition , the independence index of adl was determined using the bi and motor items of the fim scoring system . in the present study , the affected upper limb function was calculated from the total score of the knee - mouth and finger function tests . lower limb function was calculated from the total score of the hip flexion , knee extension , and foot - pat tests . furthermore , trunk function was calculated from the total score of the abdominal muscle strength and verticality tests , and the unaffected side function was calculated from the total score of grip strength and knee extension strength tests . we used simple correlation and partial correlation analyses to remove the effect of age and other motor function parameters ( affected upper limb , lower limb , trunk , and unaffected side function ) , and estimated the independent effect of the affected upper limb , lower limb , trunk , and unaffected side functions on bi or fim . all correlations were investigated using spearman s rank correlation analysis with spss version 22.0 for windows ; p values < 0.05 were considered statistically significant . it was observed that half of the patients ( 48.8% ) had right - sided hemiparesis , with mild to moderate impairment of the upper and lower limbs . simple and partial correlation analyses were conducted between the parameters of motor function ( affected upper limb , lower limb , trunk , and unaffected side function ) and adl ( bi or fim scores ) ( table 2table 2.simple and partial correlation analyses between motor functions and indexes of activities of daily living ( fim and bi ) in stroke patientssimple correlation ( n=77)partial correlation ( n=77)fimbifimbiaffected upper limb function0.31**0.34**0.020.07affected lower limb function0.51**0.51**0.48**0.42**trunk function0.37**0.33**0.150.13unaffected side function0.38**0.34**0.32**0.27*values are spearman s rank coefficients ; * * p0.01 . fim : functional independence measure ; bi : barthel index ) . moreover , simple correlation analyses revealed significant positive correlations for all comparisons . partial correlation analyses generated remarkably different data when the effect of age and other body part functions on adl were excluded . significant positive correlations were found between the affected lower limb or unaffected side function and bi or fim . in contrast , there was no significant correlation between the affected upper limb or trunk function and bi or fim . this discrepancy is explained by the strong functional interactions between the affected upper limb and lower limb functions and between the trunk and unaffected side functions ( table 3table 3.simple correlation analyses between motor functions in stroke patientsaffected u / l functionaffected l / l functiontrunk functionunaffected side functionaffected u / l function0.68**0.010.08affected l / l function0.68**0.140.03trunk function0.010.140.39**unaffected side function0.080.030.39**values are spearman s rank coefficients ; * * p0.01 . fim : functional independence measure ; bi : barthel index ; u / l : upper limb ; l / l : lower limb ) . fim : functional independence measure ; bi : barthel index values are spearman s rank coefficients ; * * p0.01 . fim : functional independence measure ; bi : barthel index ; u / l : upper limb ; l / the present study provides insightful information on the relationship between motor function and adl in stroke patients . the ongoing debate on motor functions affecting adl was resolved by designing partial correlation analysis protocols considering the possible interactions between body parts . simple correlation analysis suggested that the affected upper limb , lower limb , unaffected limbs , and trunk influence adl performance . in contrast , partial correlation analysis , excluding age and the influence of other body parts , revealed the absence of correlation between the affected upper limb or trunk function and adl in stroke patients . this discrepancy was explained by the strong interactions between the affected upper and lower limb functions and between trunk and unaffected side functions . this new information on motion dynamics in stroke patients should lead to the development of more efficient rehabilitation programs . this study demonstrates that adl performance in stroke subjects is hindered more by the affected lower limb than by the unaffected side . previous studies reported that balance2 , gait17 , 18 , and stair19 performance are affected by lower limb function . thrane et al.20 reported that the affected lower limb function is associated with self - care dependency . further , the present study also indicates that the affected lower limb function plays an important role in adl . we established a considerable relationship between the unaffected side function and adl , based on the strength of the quadriceps muscle of the lower limb and the grip strength . it has been reported that the strength of quadriceps muscle influences sit - to - stand21 and transfer22 activities in stroke subjects . colebatch et al.24 indicated that the strength of muscles ipsilateral to the lesion was reduced in hemiplegic patients compared with healthy subjects . therefore , rehabilitation programs aiming to improve adl should target the muscle strength on the unaffected side . the lack of correlation between the affected upper limb function and adl may be explained by the fact that most activities can be performed with the unaffected upper limb . further , previous studies mentioned that the upper limb function is required to reach a certain threshold before performance actually starts to increase25 , and improvement in the functional limitations of the upper limb does not necessarily lead to a full recovery of adl function26 . therefore , there may be a non - linear relationship between the affected upper limb function and adl . thrane et al.20 reported no significant relationship between the affected upper limb impairments and adl using lower limb function as covariate , as in our study . thus , the impact of upper limb function impairments on everyday activities may be lower than expected27 . the close relationship between trunk function and adl has been reported by previous studies4,5,6,7 , 9 . however , to the best of our knowledge , this is the first study to identify the independent effect of trunk function on adl using partial correlation analysis . in addition , our results suggest that the impact of trunk function on adl is lower than expected . however , the average score of trunk function in our patients was very high , suggesting that a relationship between trunk function and adl could have been missed due to the ceiling effect . therefore , this result should be carefully interpreted . first , simple and partial correlation analyses can only detect linear relationships between two variables . . the correlations between each motor function and adl may differ depending on the adl independence level .

[ purpose ] this study aimed to clarify the independent impact of the affected upper and lower limb , trunk , and unaffected side motor functions on activities of daily living in stroke patients using partial correlation analysis . [ subjects and methods ] this retrospective study included 77 stroke patients . motor functions were assessed using the stroke impairment assessment set , and the activities of daily living performance was assessed using the barthel index or functional independence measure . further , simple and partial correlation analyses were conducted between each motor function and activities of daily living parameter . [ results ] simple correlation analysis identified significant positive correlations for each pair . in contrast , partial correlation analysis only identified significant positive correlations between the affected lower limb or unaffected side functions and the barthel index or functional independence measure . this discrepancy between the two tests was explained by the significant interaction between the affected upper and lower limb functions and between the trunk and unaffected side functions . [ conclusion ] the present study identified the affected lower limb and unaffected side motor functions as the major determinants of activities of daily living performance in stroke patients . these findings suggest that rehabilitation programs can be improved by targeting these areas .

You are an expert at summarizing long articles. Proceed to summarize the following text: many children 's intakes of nonmilk extrinsic sugars ( nmess ) and saturated fatty acids ( sfa ) fail to meet dietary targets for these nutrients . diets high in nmes and sfa are likely to contribute to the continued high prevalence of obesity and overweight amongst children . the scottish government has taken several steps to try to improve children 's diets , including interventions in the school setting . the schools ( health promotion and nutrition ) scotland act , passed in 2007 , sets out nutritional standards for school meals and prohibits the sale of foods high in sugar in primary and secondary schools ( e.g. , confectionery and sweetened soft drinks ) and limits the sale of foods high in fat ( e.g. , fried foods and most snacks ) . once the act was implemented across all schools in scotland , attention turned to some of the other factors which could be influencing school - aged children 's diets . one suggestion was to address children 's purchasing of food and drinks high in fat and/or sugar in outlets found in the vicinity of schools . such outlets are referred to in scotland 's obesity route map action plan as being beyond the school gate . evidence suggests that the presence and geographical density of food outlets ( this includes restaurants and stores ) influences the diet of local people , including children and adolescents , thereby contributing to the so - called obesogenic environment [ 4 , 5 ] , though whether that influence is positive or negative , in terms of impacting on rates of obesity and diet quality , is uncertain [ 6 , 7 ] . it is clear , however , that the local food environment is associated with socioeconomic inequalities in diet , obesity , and health , though the evidence is mixed regarding an association between deprivation and the prevalence of fast food outlets [ 8 , 9 ] . there is little evidence in scotland of the extent to which children access food and drink in outlets beyond the school gate , though one study involving older children ( aged 1416 years ) at three schools in scotland reported that over half of young people left the school grounds every day to purchase food and that factors associated with personal liberty ( e.g. , being treated as an adult at local stores and a desire to make a personal choice about where to eat ) influenced decisions to purchase food beyond the school gate . another study found that some children wanted to escape the school environment at lunchtime . in england , an in - depth study of two secondary schools found that food bought in shops close to schools contributed 23% to children 's energy intakes , a quarter of which came from total sugars ( 15% from nmes ) . of the children given permission by schools to leave the grounds at lunchtime , at least 97% purchased food outside school . many schools in the uk do not allow children to leave the school grounds during the school day , particularly younger children , which could act as a barrier to purchases beyond the school gate , at least for those who obey the rules . however , many secondary school canteens are not big enough to seat all their students and canteens are often reported by young people to be noisy , unpleasant , and offering a poor choice of food [ 79 ] ; therefore , such factors can act as pushes for children to seek food and drink elsewhere , regardless of the rules about leaving the school grounds . children can also purchase food and drink on the way to or from school ( and during break times and free periods ) ; therefore , lunchtime is not the only opportunity for purchases to be made . as there are reported to be an average of 24 food outlets around secondary schools in one large city in scotland , there is certainly opportunity for local outlets to attract young consumers with price promotions and a fast service , both of which are thought to be important factors within the local food environment . the limited evidence from within the uk and scotland more specifically and the recent policy spotlight on food and drink purchasing beyond the school gate informed the decision to develop a new survey module on food purchasing behaviour , as part of the 2010 survey of diet among children in scotland . this was the first attempt to obtain data from a representative sample of children in scotland about their food and drink purchasing habits beyond the school gate and was therefore an important first step towards considering whether such purchases influence dietary intakes of nmes and sfa . the overall aim of the food purchasing module ( fpm ) was to assess the food and drink purchasing habits outside of school on school days among primary ( aged 811 years ) and secondary ( aged 1116 years ) school children living in scotland . the specific objectives were the following.to assess the opportunities for children to purchase food and drink outside of school.to estimate the proportion of children purchasing food and drink outside of school.to identify the types of foods and drinks children are purchasing outside of school . to explore some of the factors that influence whether children go outside of school to purchase food or drink.the aim of this paper is to describe the development of the food purchasing module ( fpm ) . to assess the opportunities for children to purchase food and drink outside of school . to estimate the proportion of children purchasing food and drink outside of school . to identify the types of foods and drinks children are purchasing outside of school . to explore some of the factors that influence the fpm was designed to be administered as part of the 2010 survey of diet among children in scotland . the dietary survey aimed to monitor dietary trends of children in scotland and was similar to the design of the earlier 2006 survey of sugar intake among children in scotland , which entailed parents and children completing a food frequency questionnaire ( ffq ) before taking part in a face - to - face computer assisted personal interview ( capi ) with an interviewer . several decisions had to be made about the design of the new fpm , including whether to include all school - aged children in the sample , how to deliver the fpm to children alongside the dietary survey , which time points around the school day to ask children about , and how best to design questions which would address the study 's objectives . whilst the main dietary survey included children aged 316 years , the fpm was concerned with food and drink purchased by children for themselves during the school day ; therefore , children aged 3 - 4 years were automatically excluded as they had not yet reached school age . it was felt that most children aged 57 years would be unlikely to purchase food for themselves therefore they were also excluded . it was considered that some children may not wish to discuss their food and drink purchasing behaviours in front of their parents ; therefore , some questions were designed to be delivered through a self - completion paper questionnaire ( scq ) and other less sensitive questions would be delivered through the capi of the main dietary survey . the capi was designed so that parents of primary school children ( aged 811 years ) would answer the questions , with some input from the child , whilst secondary school children aged 1116 years would complete the capi themselves with input from their parent(s ) as needed . the authors considered that children are likely to display different behaviours with regard to food and drinks purchased at different points during the school day ; therefore , questions were designed to assess purchasing behaviour at four time points : ( i ) on the way to school , ( ii ) at break time and during free periods , ( iii ) lunchtime , and ( iv ) after leaving school . whilst the rules about secondary school children leaving school during break and lunchtime are variable across schools in scotland , it was felt that very few primary school children would be allowed to leave school during break or lunchtime ; therefore , children aged 811 years were asked questions about food purchasing on the way to / from school only . the survey concentrated on all 4 time points for secondary school children aged 1116 years . in order to address the fpm objectives , it was important to consider and define what constituted opportunities for purchasing food and drink on the way to / from school and it was agreed that this meant the child walking or cycling past places selling food or drinks . it was felt that going past places selling food or drinks in a car , bus , taxi , or other vehicles did not represent an opportunity for children to purchase anything , without requesting the adult driving the vehicle to stop . at break time / free periods and lunchtime , the opportunity to purchase food or drinks was defined as the child being able to get to places outside of school that sell food or drinks . opportunities to purchase were based on parents ' and children 's perceptions of the type of places they considered accessible and whether they perceived that these outlets sell food or drinks . the fpm made it clear that we were interested in food and drinks children purchased themselves ; this was designed to exclude purchases made for them by adults or other children . it is worth noting that the fpm was concerned with the purchasing of food and drinks ; therefore , this might not relate to consumption as we can not determine if the food and drinks purchased were actually consumed . when deciding which factors to explore in relation to reasons for children purchasing food and drinks outside of school , we drew on the authors ' expertise and other relevant research and literature [ 1012 , 14 ] . the factors asked about in relation to buying food / drink on the way to / from school included purchasing food because of hunger / thirst , copying friends , not having anything to eat / drink from / at home , and wanting food / drink to eat later . in relation to leaving school at break / free periods or lunchtime questions were asked about wanting a break from school , preferring the food sold outside school , and exercising choice about where to purchase food . questions were also asked about why children did not leave school at break and lunchtime including , not having enough money , having nowhere to go , not being hungry / thirsty , taking food / drink to school from home , not having time to purchase anything , and preferring to purchase food / drink at school . whilst the questions exploring the reasons for purchasing / not purchasing food and drinks are not exhaustive , they provide baseline information from a representative sample for the first time and can be developed further in future surveys . the main study received ethics approval from the nat cen social research ethics committee ; the cognitive testing phase received ethics approval from the university of aberdeen 's college ethics review board . as this was a new survey module , cognitive testing was carried out to check if children understood the wording and routing of the questions and could navigate the self - completion questionnaire . seventeen interviews were conducted with primary and secondary school children , and five interviews were conducted with parents who had primary school - aged children . during the cognitive interviews , children and parents were asked to describe what they were thinking as they tried to navigate the scq or answer the capi questions . observations were recorded about the way each child or parent worked their way through the module questions ( e.g. , whether they read the instructions for each section ) . children completed the scq without help from the interviewer , to replicate the main stage of the survey , and , similarly , the capi was administered exactly as it would be administered in the main phase of the survey . the interviewer also probed participants about their understanding of some of the terms used in the questions , to determine if children and parents understood them in the way intended . the cognitive interviews highlighted that primary and secondary school children found navigating their way through the scq problematic and that primary school children struggled to complete the scq . however , there were few problems with the interview - based ( capi ) questions as they were originally designed . nearly all the primary school children had problems navigating through the scq and could not follow the routing of the questions ( e.g. , being asked to go to question 6 if they gave a negative response to an earlier question ) ; this caused the majority of their problems with the scq . some of the youngest children were not able to read words in some of the questions or did not know what the words meant . some did not understand the instructions at the start of the questionnaire while others did not read the instructions at all . questions asking about the type of food or drinks purchased outside of school created a lot of confusion among the primary school children as they were unsure what food this related to in their day . children 's interpretation of some of the terms used to describe foods was probed and in general their understanding was good . the term packets of snacks ( which referred to savoury snacks ) was interpreted by most children to mean sweet snacks . most children were familiar with the terms diet and non - diet drinks but the majority of secondary school children did not read the instructions at the start of the questionnaire and went straight to the first question . most of them had some problems navigating through the questionnaire following the routing of the questions . most of them did not read or follow the go to instructions . all secondary school children appeared comfortable completing this type of self - completion questionnaire , perhaps because they are regularly asked to complete this style of questionnaire at school . children in this age group understood the meaning of the food and drinks as intended . as with the primary school children though , packets of snacks tended to be interpreted as sweet foods . it was apparent that examples were required to illustrate some of the types of foods . following the cognitive interviewing , some changes were made to the wording of the questions , but the main changes were made to the delivery of the fpm . it was decided that the problems that primary school children had completing the scq meant it would work better if all questions were incorporated into the computer - assisted personal interview ( capi ) . some routing problems were also observed with the secondary school children , mainly due to children not reading or not following the instructions . to try and limit this problem , some of the questions were incorporated into the capi which meant the interviewer could then score out some questions in the scq , based on the capi answers given , to prevent children mistakenly answering some questions in the scq . for example , if children said they never bought food at lunchtime , the interviewer could score out the questions relating to purchases made at lunchtime in the scq . the routing instructions that remained in the scq were highlighted more clearly in the final version of the questionnaire . the questions included in the final capi and scq are outlined in table 1 for younger and older children . the main dietary survey aimed to achieve a representative sample of 1500 children aged 316 years . it was designed to be representative of children living in scotland in terms of sex , ethnicity , urban - rural distribution , and age distribution . in the main dietary survey , 1906 further details about sampling are available in the published reports [ 13 , 16 ] . fieldwork for the fpm was conducted between june and november 2010 . when interviews were conducted during the school holidays , parents and children all eligible primary school children from the dietary survey completed the fpm ( n = 564 ) . of the eligible secondary school children ( n = 653 ) , 615 ( 94% ) completed the scq questionnaire . there were no significant differences in response rates to the scq by sex or levels of socioeconomic deprivation . despite making changes based on the findings from the cognitive testing phase , there were several errors in the scq data because of navigation and routing problems . when such errors occurred , children were excluded from the analysis as it was impossible to know which responses were correct . for example , if a respondent answered that they did not purchase food or drinks on the way home from school but then answered the questions about the type of food and drinks purchased at that time point , they were deemed as not purchasing food and drinks on the way home from school and were excluded from the analysis of food and drink purchasing at this time point . decisions about such navigation and routing errors had implications for the numbers available for the subsequent analysis , as indicated by figure 1 . this is the first time a survey has been developed on food purchasing behaviour beyond the school gate using a nationally representative sample of children in scotland . the results from this survey provide an overview of the food and drink purchasing habits of school children in scotland and an insight into the issue of school children purchasing food and drinks high in fat and/or sugar on the way to and from school and in the vicinity of the school grounds at break times and lunchtime . designing a module on a new topic presents several challenges . as the overall prevalence of food and drink purchasing outside of school was unknown at the time the study was designed , it was not possible to estimate in advance what size of sample would be required to provide sufficient numbers of children making purchases who could be asked detailed follow - up questions . as a consequence , a limitation of the results from the new module was the available sample size for exploring differences between subgroups ( e.g. , by age or deprivation quintile ) and for exploring the influences on children 's purchasing behaviour . the fpm data can now provide an estimate of the sample size required to ask more detailed follow - up questions and make comparisons between subgroups in future surveys . importantly , developing the fpm and reporting on the process of this development provides much needed information about children as survey respondents . it is crucial that children are given the opportunity to report on their own lives as information provided by proxy , from their parents , for example , does not usually result in data that is as accurate . the combined use of the capi and scq data collection methods for secondary school children sometimes led to inconsistencies between the answers given in each mode , which meant that not all of the data could be used in the analysis . some of these inconsistencies may have resulted from children choosing not to accurately disclose their purchasing habits in the presence of a parent or guardian during the capi ; only 46% of secondary school children reported in the scq that they sometimes or always told their parents what foods or drinks they purchased at lunchtime , perhaps indicating that a significant proportion did not routinely discuss their food choices with parents and therefore might not be comfortable in doing so . inconsistencies between the capi and scq may also have stemmed from a social desirability effect ( e.g. , wanting to answer all the questions to please the interviewer or their parents ) as well as some children getting confused by the scq routing instructions . the decision about which questions to include in the capi was largely driven by a judgment about which were the least potentially sensitive topics . in many cases , it was also driven by the complex routing of questions ; capi methods are preferable to self - completion methods in such cases , as routing errors are eliminated in capi as the computer programme automatically routes respondents to the next appropriate question , based on their previous responses . complex questions can be difficult to answer for any respondent , not just children , and it was appropriate to ask children themselves about their own purchasing behaviours , rather than their parents , although this was not achieved to the same extent with regard to primary school children who were not given the option of a scq following the lessons learnt during the cognitive testing phase . given that interviewers asked the parents or guardians of children under 12 questions in the capi , rather than asking the child directly , this may have also influenced the accuracy of the data collected . despite these limitations , the survey provides timely and unique information about this important topic and has generated some useful methodological insights for future studies . for example , a computer - assisted self - completion interview ( casi ) in which the children read questions on screen and input their own answers ( as opposed to the capi which is interviewer administered ) would be an alternative to the paper - based self - completion questionnaire and would help avoid future errors due to confusion with routing and overcome the issue of answering sensitive questions in front of parents or guardians . casi methods were not appropriate for this study because it would have added to the interview length ( the paper - based scq was completed by the children while the adult continued with the capi ) . whilst casi methods are ideal for older children , an audio - casi could also be developed for use with younger children or those with literacy problems . this would involve children listening to questions via headphones ( rather than reading text on screen ) and inputting their answers directly onto a computer or tablet . the survey format provided an appropriate method for exploring this topic , but a number of questions were raised which warrant further investigation . using qualitative methodologies to explore food and drink purchasing beyond the school gate would facilitate an in depth understanding of some of the factors influencing children 's purchasing behaviour . such an approach would help uncover and explain the complexity of children 's food and drink purchasing practices including exploring possible contradictions in their behaviour . the reasons children gave for leaving the school grounds at lunchtime and for purchasing / not purchasing food and drink were based on the list of reasons developed by the research team , which drew on their expertise and also on the relevant literature in this area . qualitative work would allow children to voice their own reasons for purchasing food and drinks . the fpm module recorded the types of outlet which were most often used by children during the school day , but the survey could not explore in - depth why some outlets were used and not others , despite opportunities to purchase at a range of outlets . qualitative research would help answer these questions and facilitate further exploration of the way that food and drink purchasing beyond the school gate might be contributing to children 's intakes of nmes and sfas . assessing the availability and purchasing of energy dense foods by children from outlets in the vicinity of schools , termed beyond the school gate , is an important policy goal in scotland and has relevance to other countries where obesity is a problem . a number of methodological issues were raised during the development of the survey module , including that younger children experience problems using a self - completion questionnaire and that older children do not always successfully navigate a scq . the need to respect children 's rights not to disclose their food and drink purchasing habits in front of parents is an important consideration and should inform the way that future surveys are developed . the fpm can be developed further , alongside qualitative research to look in more depth at the issues covered by the survey .

many children eat a diet which supplies a higher than recommended amount of nonmilk extrinsic sugars and saturated fatty acids . the school setting is often targeted for nutrition intervention as many children consume food at school . in scotland , attempts have been made to improve the nutritional content of food in schools and attention has now turned to food and drink available beyond the school gate . this paper describes the development of a module on food and drink purchasing behaviour . the food purchasing module was designed to collect data , for the first time , from a representative sample of children aged 816 years about food and drinks purchased on the way to / from school , during break time / free periods , and at lunchtime , from outlets around schools . cognitive testing of the module highlighted that younger children find self - completion questionnaires problematic . older children have fewer problems with self - completion questionnaires but many do not follow question routing , which has implications for the delivery of future surveys . development of this survey module adds much needed evidence about effectively involving children in surveys . further research exploring food and drinks purchased beyond the school gate is needed to continue to improve the nutritional quality of children 's diets .

You are an expert at summarizing long articles. Proceed to summarize the following text: a 4yearold , female spayed beagle was referred for a history of gait abnormalities ( present since birth ) , intermittent urinary incontinence , and generalized seizures which were present since 2 years of age and had been treated by administration of phenobarbital . the dog appeared to walk on the digits ( tiptoes ) with all 4 limbs in rigid extension during ambulation ( fig 1a ) . physical examination revealed a broad skull with wideset eyes ( fig 1a ) , characteristic ridge within the ear cartilage ( fig 1b ) , brachydactyly of the outer toes , pronounced skeletal muscle definition , mild bilateral carpal valgus deformity , decreased to absent range of motion in joints of all 4 limbs , and a grade ii / vi intermittent left basilar systolic murmur . no other abnormalities apart from the gait and tail abnormalities were detected on neurologic examination , although flexor withdrawal reflexes were difficult to evaluate due to decreased range of motion . image of case 1 illustrating the tiptoe posture and characteristic facial features ( a ) , and folded ear ( b ) . cbc revealed panleukopenia ( 2.99 10/l , reference range 617 10/l ) , mature neutropenia ( 2.24 10/l , reference range 312 10/l ) , lymphopenia ( 0.54 10/l , reference range 15 10/l ) , and eosinopenia ( 0.03 10/l , reference range 0.11.25 10/l ) . a repeat cbc performed 2 weeks later and after gradual discontinuation of phenobarbital revealed resolution of the pancytopenia . the thoracic radiographs revealed a vertebral heart score of 12.25 ( reference range 8.710.7)1 with no cardiopulmonary changes noted . the ecg revealed a sinus arrhythmia with a mean electrical axis of + 30 and one of the criteria for left ventricular enlargement ( r > 1.0 in lead i ) . the echocardiogram revealed turbulent flow across both the left and right ventricular outflow tracts , but no valvular changes , wall thickening , or chamber dilatation were identified . csf analysis showed that nucleated cell counts and protein concentration were within reference range , with vacuolated mononuclear cells suggestive of lipid / myelin phagocytosis . electromyography ( emg ) of the palmar and plantar interossei , flexor carpi ulnaris , extensor carpi radialis , biceps , triceps , supraspinatus , infraspinatus , lateral gastrocnemius , medial gastrocnemius , cranial tibialis , biceps femoris , vastus lateralis , semimembranosus , semitendinosus , and tail muscles revealed mildly increased insertional activity in several muscle groups ( palmar and plantar interossei , flexor carpi ulnaris , semimembranosus , semitendinosus , and tail ) , but no spontaneous activity was identified . due to the sporadic nature of the findings and lack of consistent nerve distribution patterns , the increased insertional activity was most likely not clinically relevant . biopsies were obtained from the cranial tibial muscle and either flashfrozen in isopentane precooled in liquid nitrogen or fixed in 10% neutralbuffered formalin and paraffinembedded . no abnormalities were identified that would suggest a congenital myopathy or muscular dystrophy . compared to an agematched control , no expansion of endomysial or perimysial connective tissues was found , and localization of these proteins was appropriate , based on cryosections incubated with monoclonal or polyclonal antibodies against collagen vi and laminin 2 ( gifts from eva engvall ) ; and fibrillin1 ( polyclonal antibody 9543 ) , fibrillin2 ( polygonal antibody 868 ) , and fibrillin3 ( monoclonal antibody 689 , gifts from lynn sakai ) . stainings also included antibodies against dystrophin ( dys1 ) , utrophin ( ncldrp2 ) , and developmental myosin heavy chain ( dmhc ) ( all from novocastra laboratories ; leica biosystems inc , buffalo grove , il ) , and sarcoglycan ( gift from eva engvall ) . results of tests for organic acid and amino acid analysis ( biochemical genetics laboratory , university of california san diego , lajolla , ca ) , carbohydrate screening , and a mucopolysaccharide spot test ( penngen laboratory , university of pennsylvania , philadelphia , pa ) in urine were negative . an 11weekold , male beagle puppy was referred for difficulty righting and stiff gait . the pup was among a litter of 6 , 2 of which died at 1 day of age . of the remaining 4 puppies ( 2 males and 2 females ) , this was the only affected puppy . the breeders did not notice any abnormalities until the puppy was 9 weeks of age , at which time he began having trouble righting himself and appeared stiff . the stiffness was progressive with concurrent development of characteristic facial features , including broad skull and wideset eyes . the disposition of the affected pup was purportedly very placid compared to unaffected littermates . on physical examination , the puppy had thick skin , a broad muzzle , and wideset eyes diagnostic examinations included electrophysiologic evaluation ( emg , mncv of the tibial nerve , repetitive nerve stimulation , and brainstem auditoryevoked potentials ( baep ) ) , all of which were within reference ranges . on postmortem examination of case 2 , lesions were consistent with widespread accumulation of collagen . skin was diffusely thickened with extensive fibrosis of the hypodermis and adhesion to underlying layers . collagen and connective tissue surrounding kidney , adrenal glands , lymph node capsule , small intestine , esophagus , testes , trachea , pinnae , stomach , urinary bladder , heart , and dura was dense . staining with picrosirius red showed birefringent red / green fibers characteristic of collagen in vessel walls and interstitium of organs . the epimysium surrounding some entire muscles was excessive and comprised of dense collagen ( not shown ) , and in some cases , it was restrictive ; however , perimysial and endomysial connective tissue between muscle fascicles and individual myofibers , respectively , appeared normal ( fig 2 ) . muscle bundles contained almost no fat ( appropriate for age ) , and the epimysial connective tissue was a dense seam of tissue containing blood vessels . ligaments and , to a lesser extent , tendons diffusely contained an increase in tenocyte nuclei , and there were small foci of mineralized mucinous matrix ( sections with ligamentum nuchae were especially affected ) . nerve fibers in the sciatic nerve were surrounded by visible , but not excessive , endoneurium . several focal areas of replacement of cortical bone with fibrous tissue were present in the digit ( p2 ) , rib , and ulna . a region of the central cartilage of the pinnae was thickened in a vertical line ( similar to fig 1b ) . abnormalities were not detected in other organs , including the brain and peripheral pulmonary airways . immunofluorescence staining of muscle cryosections from a beagle dog with musladinlueke syndrome ( case 2 ) and agematched but not breedmatched control muscle . staining was performed for localization of laminin 2 , the rod domain of dystrophin , utrophin , sarcoglycan , collagen vi , fibrillins , and developmental myosin heavy chain . the endomysial ( surrounding individual muscle fibers ) and perimysial connective tissue layers ( surrounding muscle fascicles ) did not differ from control muscle . regenerating fibers were not observed with the antibody against developmental myosin heavy chain . in the figure , fibrillin 9543 binds to fibrillin 1 , fibrillin 868 binds to fibrillin 2 , and fibrillin 689 binds to fibrillins 1 , 2 , and 3 . both cases were homozygous for a founder mutation in the adamtsl2 gene on cfa 9 , indicative of musladinlueke syndrome , as previously reported.2 further characterization of fibroblasts was performed to evaluate the functional effects of musladinlueke syndrome on tissues . skin samples were minced and plated , allowing cells to adhere to tissue culture plates ( mls 1 , 2 ; control 1 , 2 ) , or tissue was further enzymatically dissociated ( controls 3 , 4 , 5 ) using 0.1% collagenase ( cls4 , worthington biochemical corporation ) and 0.05% elastase ( worthington biochemical corporation ) . as mls fibroblasts grew slower than fibroblasts from control dogs , they were plated at higher density to ensure that control and mls fibroblasts reached confluency at the same time . after reaching confluency , cells were cultured for another 2 days in 10% fbs to allow matrix synthesis and were incubated for 2 days in serumfree media . subsequently , their conditioned medium was used to assess tgf secretion , and cellular smoothmuscle actin ( sma ) expression was assessed by immunofluorescence . the total tgf in medium was measured by elisa ( promega ) in triplicate , and the tgf reading was conducted immediately after obtaining primary cell lines . high tgf levels were detected in media from the mls fibroblasts ( case 2 ) , whereas no free tgf was detected in the wildtype sample ( control dog 1 ( ctl1 ) ) ( fig 3a ) . dermal fibroblasts from case 2 and from 4 control adult dogs of unknown genetic background ( ctl1 , ctl3 , ctl4 , ctl5 ) were stained with antialpha sma antibody ( clone 1a4 , sigma 2547 ; diluted 1/400 ) and analyzed by flow cytometry . fibroblasts from case 1 and control dog 2 ( ctl2 ) were not included in the flow cytometry analysis due to a lack of sufficient cells . whereas fibroblasts from 3 of the control dogs ( ctl1 , ctl3 , ctl5 ) expressed only low levels of sma , and fibroblasts from control dog 4 showed both low and high expressing populations , mls fibroblasts ( case 2 ) showed uniformly high sma expression approaching that of smoothmuscle cells ( smc ) ( fig 3b ) . sma expression was also assessed by immunofluorescence staining3 and confirmed high sma expression in mls fibroblasts ( case 2 ) ( fig 3c ) . in addition , by immunofluorescence , mls fibroblasts from case 1 were also found to express high levels of sma ( fig 3d ) . to test contractility , 3 10 skin fibroblasts from case 2 and 5 control dogs ( ctl1 through ctl5 ) were seeded into collagen gels , and each sample was assayed in triplicate for the extent of contraction , as previously described.3 mls fibroblasts showed significantly enhanced contractility ( fig 4a , b ) . to assess whether there was a correlation between sma expression and contractility , wholemount sma staining of contracted collagen gels was performed , which also showed strong sma staining in the mls cells ( fig 4c ) . skin fibroblasts from mls dogs ( mls 1 , case 1 ; mls 2 , case 2 ) exhibit characteristics of myofibroblasts . mls fibroblasts secrete high levels of tgf ( a ) and express the myofibroblast marker smoothmuscle actin determined by ( b ) flow cytometry and ( c , d ) immunofluorescence ( sma , green nuclei ; dapi , blue nuclei ) . mls cells contract collagen gels more efficiently than fibroblasts from control dogs ( mls 2 , case 2 ) . shown are representative images of gels after contraction ( a ) , and the percentage of the original surface area after contraction ( mean sem of 3 independent experiments ) ( b ) . the significance of the difference between the mls and control samples was determined with a student 's ttest ( tails 2 , type 1 ) , and the p values were found to be < .05 ( * ) , < .01 ( * * ) and < .0003 ( * * * ) . the difference between mls and ctl 4 was not significant . sma fluorescence of cells in contracted collagen gels ( nuclei are stained blue using dapi ) shows comparable cell density but stronger sma staining and extended morphology of mls cells ( c ) . a variety of mutations affecting different regions of the adamtsl2 gene ( including the p.r221c substitution identified in mls ) in humans leads to a severe connective tissue disorder , autosomalrecessive geleophysic dysplasia ( gd ) type 1.4 , 5 adamtsl2 interacts with the microfibrilforming extracellular matrix ( ecm ) glycoproteins fibrillin1 and fibrillin2 , as well as with latent tgf binding protein 1 ( ltbp1).4 , 6 , 7 dominant gd is caused by mutations affecting fbn1,6 and a fibrillin1 defect in mice ( tight skin ( tsk ) ) also results in severe fibrosis.2 , 8 tight skin , however , has not been observed in adamtsl2/ mice , which die at birth with severe bronchial occlusion . this and additional differences among gd , mls , and mouse adamtsl2 knockouts are discussed.7 , 9 , 10 because of the established role of fibrillin microfibrils and ltbp1 in sequestering and maintaining the latency of tgfs , it is thought that the ecm defects arising from the absence of adamtsl2 lead to tgf dysregulation . excess tgf activity is thought to lead to fibroblastmyofibroblast transition.10 , 11 a potential link to altered tgf signaling is also strengthened by finding ltbp3 mutations in gd.12 gd type 1 is a progressive disorder in which affected individuals have a short stature , brachydactyly , thick skin , restricted joint mobility , and a happy face due to characteristic facial features.5 , 13 , 14 , 15 , 16 the name geleophysic dysplasia comes from the greek words geleos , meaning other findings in individuals with gd can include hepatomegaly , tracheal stenosis , pseudomuscular hypertrophy ( due to excessive collagen ) , and cardiac disease characterized by thickening of mitral , pulmonary , and aortic valves.5 , 13 , 14 , 15 , 16 the cardiac and tracheal abnormalities of gd lead to death in 33% of affected individuals before the age of 5.14 the beagles described in this report exhibited a similar array of features ( table 1 ) , including brachydactyly of the outer digits , broad facial features including wideset eyes , a characteristic ear fold , fibrosis of the joints , and a pleasant disposition . some owners report that the skin is tight , which was not apparent in these cases . cardiac disease has been inconsistently reported in association with mls.17 seizures have also been reported in other affected beagles with this disease , which is consistent with case 1 , but no underlying etiology has been identified in the literature.2 , 17 in contrast to humans with gd in which the disease progresses rapidly , beagles with mls appear to stabilize at about 1 year of age and have a normal life span unless other congenital defects are present.17 clinical features of adamtsl2 mutations reported in dogs , humans , and mice mice with adamtsl2 deletion die shortly after birth . the anomalies were not seen in newborn mutant mice , but may possibly appear with maturity . conditional deletion of adamtsl2 in limbs leads to shorter limb bones and brachydactyly ( hubmacher d , apte , s.s . , unpublished data ) . of interest , the endomysial and perimysial connective tissue layers of muscle appeared to be preserved , whereas the epimysial layer surrounding the entire muscle was thickened . it is not clear whether collagen types differ between different connective tissue layers in muscle . although a duplicate screen of collagen vi , fibrillins , and laminin2 was not performed on skin as they were on muscle , extensive fibrosis ( ie , accumulation of collagen ) was documented on routine postmortem examination in case 2.2 in the adamtsl2 knockout mouse , the bronchial epithelial cells appear to be most severely affected , with muscle generally preserved or only mildly affected.7 this species difference could arise from the inability of affected mice to survive past birth , which could mask a progressive muscle or skin disorder , or to differences in the fibrillin repertoire of these species , because humans and dogs have 3 fibrillins , but mice only have 2 fibrillins.18 adamtsl2 is thought to selectively influence assembly of fibrillin1 , and fibrillin2 , or both through direct binding , and analysis of adamtsl2/ mice demonstrated an excess of fibrillin2 microfibrils in the bronchii.7 , 10 the variable phenotypic manifestation in different tissues could also depend on different fibrillin1/fibrillin2 ratios in specific tissues , and the degree to which other adamts proteins may be able to compensate,6 , 10 which then determine the effect of the adamtsl2 mutation.7 in this context , little is presently known about adamts proteins and fibrillins in canine tissues and during canine development . investigating this could be a complex undertaking , because in mice , for example , adamtsl2 mrna shows a dynamic expression pattern and was detected in developing skeletal muscle , as well as liver , bronchial and arterial smooth muscle , skin , nucleus pulposus of the intervertebral disk , perichondrium , pancreas , and spinal cord.7 , 19 analysis of dermal fibroblasts from mls dogs was necessarily limited and should be considered preliminary because of the lack of sufficient number of cells and of strain and appropriate agematched controls . nevertheless , the findings are consistent with previous work demonstrating the increase in soluble tgf and strongly suggesting myofibroblastic transition of the mls fibroblasts , represented by strong sma expression , and enhanced contractility within collagen gels.4 , 20 in summary , the present study expands on the clinical understanding of mls , provides additional tissue analysis , and limited cell analysis which supports a potential profibrotic effect of the mls mutation and a physiological antifibrotic role for adamtsl2 in some tissues such as muscle and skin . the clinical work was performed at the purdue university veterinary teaching hospital and the university of missouri veterinary medical teaching hospital . laboratory studies were performed at the cleveland clinic lerner research institute and the comparative neuromuscular laboratory , school of medicine , university of california san diego . the work was supported in part by nih awards ar53890 ( to sa ) and t32hl00791408 to hb ( training program in vascular biology and pathology , principal investigator , edward plow ) . a synopsis of the clinical findings in the dogs described in this study was previously published in a manuscript identifying the genetic basis of musladinlueke syndrome ( bader et al . this manuscript here presents a complete clinical description of the cases as well as previously unpublished laboratory research using tissue and cells from the cases .

musladinlueke syndrome ( mls ) , previously termed chinese beagle syndrome , is an autosomalrecessive connective tissue disorder characterized by extensive fibrosis of the skin and joints that was first identified in beagles in the 1970s . recent research identified a founder mutation ( c.660c > t ; p.r221c ) in the adamtsl2 gene in beagles with mls . here , we report the detailed clinical phenotype and laboratory findings in 2 beagles affected with mls . we discuss these findings in relation to the human disorder geleophysic dysplasia ( gd ) , which also arises from recessive adamtsl2 mutations , and recent findings in adamtsl2deficient mice .

You are an expert at summarizing long articles. Proceed to summarize the following text: consistent with the iom aim to improve health care effectiveness , an explicit goal of the pcmh is the attainment of optimal , patient - centered outcomes.2 the development of clinical outcomes measures relevant to primary care practice has been the focus of numerous recent efforts aimed at practice certification , public reporting , and pay for performance programs.4,5 over time , the reliability and precision of measures has improved , for example , by replacing single evidence - based process measures with measures of adherence to guidelines that incorporate multiple processes , e.g. , from proportion of 2-year - olds with an mmr vaccine to proportion of 5-year - olds with all recommended immunizations . nonetheless , clinical performance metrics for primary care remain limited in scope compared to , for example , the set of 146 quality of care indicators used by the national health service of the uk.6 the pcmh was built on a foundation of research on the effectiveness of primary care ; a comprehensive set of outcome measures would ideally include a variety of types of health conditions , including mental health conditions , and measurement of patient - experienced health improvement and outcomes.7 there are several challenges to measuring pcmh effectiveness . coordinated implementation of clinical information technology in us medical practices could substantially improve data collection for outcomes studies . in addition , some practice - level measures , such as cervical cancer screening and use of asthma controller medications , can be collected through paid claims and supplemented with laboratory or pharmacy data . the use of these data would be facilitated by the development of large multipayer administrative databases that aggregate data across public and private payers.8 the national quality forum is developing a set of national voluntary consensus standards for ambulatory care using clinically enriched administrative data.9 another challenge is that some outcomes , such as mortality rates or new events such as stroke or renal failure , may be too far removed temporally from the primary care process for them to be attributed to a particular practice . this can be addressed by measuring intermediate outcomes , such as blood pressure control , or evidence - based processes such as treatment intensification for high - risk patients in poor control of cvd risk - factors.10 a fourth challenge , the lack of power in individual practice panels to detect differences in major primary care sensitive health system events such as hospitalizations , emergency department visits , or re - hospitalization for patients recently discharged , can be met by examining these outcomes at the level of health system or community . patient - centeredness is a cornerstone of the pcmh.1 an explicit goal is to assure that patients get the indicated care when and where they need and want it in a culturally and linguistically appropriate manner.2 additional emphasis is placed on the robust partnership between physicians , patients , and the patient s family , with active participation by patients and families in health care decision - making and quality improvement activities within the practice.2 expanded access provides patients with alternate means of interacting with the medical practice , such as by phone , e - mail , or through interactive websites.2 measuring patient - centeredness as a pcmh outcome requires patient surveys that directly assess the extent to which patients needs , wants , and desires are met , their concerns are addressed , and they feel adequately engaged and able to provide input into both their personal health care decisions and the practice organization . the quality of the patient - physician relationship , particularly patient - physician trust , is an important part of the patient experience.1113 although the consumer assessment of healthcare providers and systems ( cahps ) clinician and group survey is a standardized survey that has been widely adopted to measure patient experience , it does not capture adequately all aspects of patient - centeredness . other measurement tools include the ambulatory care experiences survey ( aces ) , the primary care assessment survey ( pcas ) , ambulatory health literary , the patient assessment of chronic illness care ( pacic ) , the patient assessment of culturally competent care , and the patient outcomes survey.1418 a recent systematic review discusses the large number of patient experience measures used in europe.19 further work is needed to understand how well these existing tools can be adapted to measure patient - centeredness in the context of the pcmh and the optimal way to administer such surveys on a recurring basis . there are questions of when people should be surveyed ( at a fixed point in time or after a visit ) , who should be surveyed ( all patients , heavy users , ages ) , who should administer the survey ( the physician practice or an external source ) , and how many are needed . implementation of the pcmh , by focusing on increasing quality , coordination , and integration of care in addition to enhanced access , should result in fewer waits and delays , improving the timeliness of care in accordance with the iom aims . in recent years innovative scheduling systems such as advanced access have led to the development of practice - level metrics of timeliness , including demand and capacity , panel size , third next available appointment , future open capacity , and continuity of care.20,21 other measures may be equally important , including time to phone triage ( time left on hold and time until called back ) and cycle times ( time from showing up to leaving the office visit ) . as patient care interactions shift to interactive websites and e - mail , measures of time to response for these types of interactions are also needed . waits and delays in receipt of indicated care could also be measured , for example , time to receipt of colon cancer screening after patient s 50th birthday , time to patient receipt of test results , and time to medication adjustment ( e.g. , for patients with hyperlipidemia ) . although some of these measures might be available using claims databases , most would require new data collection from practices or patients.22 to the extent that the pcmh is able to meet its goals of integrating and coordinating care with specialists and other aspects of the health care system , other wait times should also decrease . declines might be seen , for example , in time to follow - up after emergency department visit or hospitalization , time to receipt of discharge summary by the primary care physician , time to physical therapy appointment , social services evaluation , or home health visit . there are several well - established hospital initiatives to decrease wait times and delays for receipt of interventions that could substantially alter the course of illness ( e.g. , door - to - balloon time for heart attack patients requiring angioplasty ) . in the outpatient arena such measures do not exist and would be much more complicated to measure . for example , time to first antibiotic dose after a positive chest x - ray for community - acquired pneumonia includes the time for a radiologist ( who is often located at an independent facility ) , to track down the appropriate provider with the x - ray results , the time for the provider to notify the patient of the results and prescribe the antibiotic , the time for the pharmacist to fill the prescription , and the time for the patient to receive the medication . while these measurements might be possible in a large integrated health system , measurement in the more fragmented setting of small community - based primary care practices and independent laboratories and radiology practices is much more challenging . the pcmh model requires increased investment in primary care practices through payment reforms.2 meanwhile , long - term cost savings may accrue to the health care system ( not necessarily the primary care practice ) through , for example , decreased redundancies , decreased overuse of inappropriate services , decreased medical errors , decreased ed visits and hospitalizations , decreased rehospitalizations for patients recently discharged , prevention of costly complications , and appropriate use of palliative care at the end of life . a broader range of other potential efficiencies should also be considered . if team - based care is expanded , an appropriate shift in certain tasks from physicians to other team members or automated systems may result . if access is enhanced by phone and e - mail , in - person visits for routine questions might decrease . as wait times in the medical practice decline , patients should miss less time from work or school . as patients with chronic and complex conditions develop continuous relationships with personal physicians , the relative proportion of contacts with the personal physician should rise and the number of redundant tests should decline . as care becomes more coordinated and integrated , wait times for specialty consultation should decrease and the proportion of patient contacts during which the patient s medical records are unavailable to the treating provider should decline . provided a recent thorough review of available measures of health care efficiency.23 they argue that although health care efficiency is of considerable interest to payers and purchasers in particular , the concept has not been well - defined and that , in contrast to most quality measures , there is little convergence around a consensus set of efficiency measures . existing measures have been subjected to few rigorous evaluations to evaluate reliability , validity , and sensitivity to methods used . almost all of the purported efficiency measures reviewed would be classified as cost of care measures , not true efficiency measures.23 to evaluate the pcmh , it will be important to include both cost and non - cost measures of efficiency and to include the perspective of the patient as well as the providers . health care safety has been identified as one of the most urgent of the six aims in the iom framework and is a core principle of the pcmh.2 to date , measures of safety in ambulatory care have been limited to prescribing errors and medication safety , two areas where the pmch could be expected to have an impact.24,25 beyond this , the iom has described the knowledge of the kind and magnitude of errors and the development of safety systems in ambulatory care settings , as rudimentary.26 much work remains to be done to develop safety measures for ambulatory care and , further , to determine the potential impact of the pcmh on safety.27 disparities in health and health care are well - documented.28 as the pcmh model is more widely adopted , it will be important to consider its potential impact on health care equity . to the extent possible , data on personal characteristics , such as gender , race , ethnicity , and socioeconomic status , should be collected to allow for stratified analysis on all of the other outcome measures so that disparities can be measured and documented over time . although it is critical to measure the impact of the pcmh at the level of the practice , for several reasons it is also important to measure the impact on the population level as the pcmh moves beyond demonstration projects to be more widely adopted . first , some outcomes are difficult to assess at the level of the practice due to insufficient sample size or challenges attributing an outcome to a single practice when a patient may see multiple providers.2931 other outcomes ( e.g. , reductions in sexually transmitted diseases ) are simply easier to measure at the population level because of available public health data . as the pcmh becomes the standard model of primary care in a community , there may be changes in practice patterns across the continuum of care that can only be assessed by measurement at the community level ( e.g. , reduction in risk behaviors or increase in the proportion of the population with an identified primary care provider ) . finally , the pcmh model explicitly calls for providers to work together in the community context and across individual practice boundaries . for example , appropriately arranging care with other qualified professionals and coordinating and integrating care across all elements of the complex health care system and the patient s community.2 population effects can be assessed at the level of the community , state , region , or country . logically , it makes sense to focus on the community , as that is where one would expect to first see the effects of the pcmh on population health . also , studying the population impact of the pcmh at the community level offers the best opportunity for understanding the processes by which the pcmh can impact population health . for example , community level outcomes can be correlated with the degree of adoption of the model within the community both longitudinally within the same community and cross - sectionally among communities . community level impacts are also meaningful to employers who draw their workforce from the community . traditional boundaries such as the metropolitan statistical area may be too large for assessing the impact of the pcmh on communities and do not include rural communities . political boundaries such as towns , cities or counties may not correspond to actual communities as defined by use of primary care . hospital service areas may be an appropriate definition of a community in areas where most primary care patients use a single hospital . another approach to identifying geographically defined communities is through the use of claims data to define an area within which most people obtain most of their primary care.32 a second challenge is to measure the extent of adoption of the pcmh within a community and track it over time . counting the proportion of primary care practices in a community that meet an agreed - upon definition of a pcmh would provide a simple but incomplete measure . because the pcmh is multifaceted , it would be more informative to measure the degree to which practices , and practice networks , adopt key components of the pcmh and to aggregate these measures over the community they serve . this approach would also allow for the study of the adoption threshold at which pcmh has measurable community level impacts . a third fundamental challenge is choosing community - based measures that are therefore likely to be sensitive to adoption of the pcmh . a substantial body of literature exists demonstrating a link between the level of primary care in an area and a variety of health outcomes including lower rates of cause - specific and total adult mortality,3335 infant mortality , low birth weight,36 lower health care costs,37 better self - reported health,38 and reduced health disparities.39,40 it is hoped that the generalized adoption of the pcmh model , by improving the quality of community primary care , will improve many of the same outcomes . three broad categories of community level outcomes that could be affected by dissemination of the pcmh model are : ( 1 ) enhanced preventive services leading to improved vaccination and screening , risk factor reduction , and disease prevention ; ( 2 ) better management of chronic diseases leading to lower rates of emergency visits and hospitalizations and less lost productivity due to fewer sick days ; ( 3 ) improved structures and processes resulting in increased access , efficiency , and equitability . examples of outcomes in each of these three broad areas are provided in table 2 . table 2framework and examples of available community - based measures relevant to assessing the impact of the pcmhgeneral areaspecific areaexamples of population measures potentially sensitive to the adoption of the pcmhsources of data or survey instrumentshealth promotion and disease preventionvaccination and screeningvaccination rates at time of entry into kindergarten;state and county health departments ; chis , cms , nispercent of adults > 65 vaccinated for pneumococcus;mammograms;pap smearsrisk behaviors and risk factorstobacco use;brfss ; chis , nhis ; yrbssalcohol and drug abuse;risky sexual behaviors;obesity;hypertensionpreventable conditionsincident of sexually transmitted infections ( stis);state and county public health departments ; nvssincidence of teenage pregnancies;violence related mortality;low birth weight neonates and infant mortalitychronic disease managementavoidable complicationsemergency visits and hospitalizations for primary care sensitive ( pcs ) conditions ( e.g. , diabetes , chronic lung disease and congestive heart failure);hcup , nhdsearly readmissions for pcs conditionsmortalitymortality from tobacco related diseases;nvssmortality post - strokeefficiency and accesscommunicationuse and sharing of electronic medical records by practices , hospitals and pharmaciesnone foundcoordination and continuity of care% of visits with pcp;cms , cts / cqi% of specialist visits preceded by a pcp visit;% of all visits to same pcp;% of patients discharge from hospitalization for pcs seen by pcp within 2 weekscostslost work days;cms ; cns ; cts / cqi , hcup , meps , marketscanprocedures;avoidable emergency visits and hospitalizationsaccess% with identified pcp;chis , cns , cts / cqi% with a primary care visit in past 12 months;number of prenatal visitsequitysurveys which collect data on race , ethnicity , language , income and/or educationbrfss , hcup , nduh , nis , nvss , yrbssacronyms for measures ( sources):brfss = behavioral risk factor surveillance system ( nchs , cdc)chis = california health interview survey ( state of california)cms = center for medicare and medicaid services administrative data ( hhs)cts / cqi = community tracking study household survey/ community quality indexhcup= healthcare cost and utilization project ( ahrq)meps = medical expenditure panel survey ( ahrq)nhis = national health interview survey ( cdc)nhds = national hospital discharge survey ( cdc)nis = national immunization survey ( nchs , cdc)nvss = national vital statistics system ( nchs , cdc)nsduh = national survey on drug use and health ( samhsa)yrbss = youth risk behavior surveillance system ( cdc)acronyms of sources : ahrq = agency for healthcare research and qualitycdc = center for disease controlhhs = us department of health and human servicesnchs = national center for health statisticssamhsa = substance abuse and mental health services administration framework and examples of available community - based measures relevant to assessing the impact of the pcmh acronyms for measures ( sources ) : brfss = behavioral risk factor surveillance system ( nchs , cdc ) chis = california health interview survey ( state of california ) cms = center for medicare and medicaid services administrative data ( hhs ) cts / cqi = community tracking study household survey/ community quality index hcup= healthcare cost and utilization project ( ahrq ) meps = medical expenditure panel survey ( ahrq ) nhis = national health interview survey ( cdc ) nhds = national hospital discharge survey ( cdc ) nis = national immunization survey ( nchs , cdc ) nvss = national vital statistics system ( nchs , cdc ) nsduh = national survey on drug use and health ( samhsa ) yrbss = youth risk behavior surveillance system ( cdc ) ahrq = agency for healthcare research and quality cdc = center for disease control hhs = us department of health and human services nchs = national center for health statistics samhsa = substance abuse and mental health services administration while this section has focused on the geographically defined ( population - based ) community , it should be acknowledged that measuring outcomes in large integrated health systems such as kaiser permanente41 or geisinger health system,42 and in accountable care organizations,43 may provide some of the same benefits as community level measures for assessing pcmh - related outcomes . while most practice - level measures can be applied to networks and health systems , additional measures related to integration , communication and shared information systems are inherently more important for networks and systems than for discrete practices . community for which outcomes related to the pcmh can potentially be measured via claims , employment data , and employee surveys . traditional boundaries such as the metropolitan statistical area may be too large for assessing the impact of the pcmh on communities and do not include rural communities . political boundaries such as towns , cities or counties may not correspond to actual communities as defined by use of primary care . hospital service areas may be an appropriate definition of a community in areas where most primary care patients use a single hospital . another approach to identifying geographically defined communities is through the use of claims data to define an area within which most people obtain most of their primary care.32 a second challenge is to measure the extent of adoption of the pcmh within a community and track it over time . counting the proportion of primary care practices in a community that meet an agreed - upon definition of a pcmh would provide a simple but incomplete measure . because the pcmh is multifaceted , it would be more informative to measure the degree to which practices , and practice networks , adopt key components of the pcmh and to aggregate these measures over the community they serve . this approach would also allow for the study of the adoption threshold at which pcmh has measurable community level impacts . a third fundamental challenge is choosing community - based measures that are therefore likely to be sensitive to adoption of the pcmh . a substantial body of literature exists demonstrating a link between the level of primary care in an area and a variety of health outcomes including lower rates of cause - specific and total adult mortality,3335 infant mortality , low birth weight,36 lower health care costs,37 better self - reported health,38 and reduced health disparities.39,40 it is hoped that the generalized adoption of the pcmh model , by improving the quality of community primary care , will improve many of the same outcomes . three broad categories of community level outcomes that could be affected by dissemination of the pcmh model are : ( 1 ) enhanced preventive services leading to improved vaccination and screening , risk factor reduction , and disease prevention ; ( 2 ) better management of chronic diseases leading to lower rates of emergency visits and hospitalizations and less lost productivity due to fewer sick days ; ( 3 ) improved structures and processes resulting in increased access , efficiency , and equitability . examples of outcomes in each of these three broad areas are provided in table 2 . table 2framework and examples of available community - based measures relevant to assessing the impact of the pcmhgeneral areaspecific areaexamples of population measures potentially sensitive to the adoption of the pcmhsources of data or survey instrumentshealth promotion and disease preventionvaccination and screeningvaccination rates at time of entry into kindergarten;state and county health departments ; chis , cms , nispercent of adults > 65 vaccinated for pneumococcus;mammograms;pap smearsrisk behaviors and risk factorstobacco use;brfss ; chis , nhis ; yrbssalcohol and drug abuse;risky sexual behaviors;obesity;hypertensionpreventable conditionsincident of sexually transmitted infections ( stis);state and county public health departments ; nvssincidence of teenage pregnancies;violence related mortality;low birth weight neonates and infant mortalitychronic disease managementavoidable complicationsemergency visits and hospitalizations for primary care sensitive ( pcs ) conditions ( e.g. , diabetes , chronic lung disease and congestive heart failure);hcup , nhdsearly readmissions for pcs conditionsmortalitymortality from tobacco related diseases;nvssmortality post - strokeefficiency and accesscommunicationuse and sharing of electronic medical records by practices , hospitals and pharmaciesnone foundcoordination and continuity of care% of visits with pcp;cms , cts / cqi% of specialist visits preceded by a pcp visit;% of all visits to same pcp;% of patients discharge from hospitalization for pcs seen by pcp within 2 weekscostslost work days;cms ; cns ; cts / cqi , hcup , meps , marketscanprocedures;avoidable emergency visits and hospitalizationsaccess% with identified pcp;chis , cns , cts / cqi% with a primary care visit in past 12 months;number of prenatal visitsequitysurveys which collect data on race , ethnicity , language , income and/or educationbrfss , hcup , nduh , nis , nvss , yrbssacronyms for measures ( sources):brfss = behavioral risk factor surveillance system ( nchs , cdc)chis = california health interview survey ( state of california)cms = center for medicare and medicaid services administrative data ( hhs)cts / cqi = community tracking study household survey/ community quality indexhcup= healthcare cost and utilization project ( ahrq)meps = medical expenditure panel survey ( ahrq)nhis = national health interview survey ( cdc)nhds = national hospital discharge survey ( cdc)nis = national immunization survey ( nchs , cdc)nvss = national vital statistics system ( nchs , cdc)nsduh = national survey on drug use and health ( samhsa)yrbss = youth risk behavior surveillance system ( cdc)acronyms of sources : ahrq = agency for healthcare research and qualitycdc = center for disease controlhhs = us department of health and human servicesnchs = national center for health statisticssamhsa = substance abuse and mental health services administration framework and examples of available community - based measures relevant to assessing the impact of the pcmh acronyms for measures ( sources ) : brfss = behavioral risk factor surveillance system ( nchs , cdc ) chis = california health interview survey ( state of california ) cms = center for medicare and medicaid services administrative data ( hhs ) cts / cqi = community tracking study household survey/ community quality index hcup= healthcare cost and utilization project ( ahrq ) meps = medical expenditure panel survey ( ahrq ) nhis = national health interview survey ( cdc ) nhds = national hospital discharge survey ( cdc ) nis = national immunization survey ( nchs , cdc ) nvss = national vital statistics system ( nchs , cdc ) nsduh = national survey on drug use and health ( samhsa ) yrbss = youth risk behavior surveillance system ( cdc ) ahrq = agency for healthcare research and quality cdc = center for disease control hhs = us department of health and human services nchs = national center for health statistics samhsa = substance abuse and mental health services administration while this section has focused on the geographically defined ( population - based ) community , it should be acknowledged that measuring outcomes in large integrated health systems such as kaiser permanente41 or geisinger health system,42 and in accountable care organizations,43 may provide some of the same benefits as community level measures for assessing pcmh - related outcomes . while most practice - level measures can be applied to networks and health systems , additional measures related to integration , communication and shared information systems are inherently more important for networks and systems than for discrete practices . employee groups of large employers are another type of non - population - based community for which outcomes related to the pcmh can potentially be measured via claims , employment data , and employee surveys . whenever implementing change , one must consider unintended consequences.4446 short - term unintended consequences may result from changing care processes and business models . these unintended consequences are important in light of early research demonstrating that practice transformation to the pcmh model may take several years.47 long - term unintended consequences of the pcmh may reflect problems with the pcmh model itself . for example , increased reliance on technologies to improve efficiency might ultimately result in less human interaction and lower patient satisfaction . increased attention on chronic care management might divert resources from delivering high quality care for acute illness . in an attempt to deliver all recommended preventive services to all patients to meet outcomes goals incentives to reduce overuse might result in withholding diagnostic procedures and treatments when they are indicated . because only a small proportion of activities can be measured , there is a danger that unmeasured activities will be neglected to the detriment of patients . in addition , several studies looking at unintended consequences of quality improvement efforts demonstrate a negative impact on disparities.48 one important unintended consequence to consider is overuse , or the provision of services to those not likely to benefit . this is especially important for a patient with multiple co - morbidities or near the end of life.49 the ncqa s back pain recognition program addresses overuse by recognizing use of best practices for the management of uncomplicated low back pain.50 the national priorities partnership , a collaborative of 28 major national organizations representing a broad range of stakeholders , has identified overuse as one of six national priorities and has identified several primary care - related areas of concentration , including inappropriate antibiotic use , routine use of laboratory panels ( e.g. , sma 20 ) , and routine preoperative chest x - rays.51 in addition to these potential unintended consequences , transformation of the delivery system to the pcmh model could result in increased stress and decreased work satisfaction for providers as roles change , new technologies are implemented , new workflow patterns are established , and new patient - provider relationships are formed . this could have a critical impact on the already limited supply of adult primary care physicians . the potential negative impacts of measurement and reporting burdens shouldered by practices must also be considered . the patient - centered medical home has gained considerable traction in the us and is an important component of federal health reform efforts . this paper presents an overview of issues important to the development of a long - term policy - relevant research agenda on pcmh outcomes . in addition to this discussion , we have included a set of exemplar research questions for a policy - relevant research agenda in this area ( see table 3 ) . table 3developing a long - term policy - relevant research agenda for pcmh outcomes : exemplar research questionsidentifying a core set of measures of pcmh outcomes what are the best measures of clinical effectiveness that are sensitive to the pcmh model ; measurable at the level of the practice or community ; and feasible to collect? which clinical processes are most closely related to health outcomes and therefore should be measured to determine effectiveness? what are the evidence - based measures of patient safety in the ambulatory care setting that are sensitive to the pcmh model? what are the best measures of patient - centeredness , above and beyond patient satisfaction or experience? what are the best measures of timeliness that can be measured at the level of the practice and community ? how is timeliness linked to health outcomes , patient experience , and efficiency? how is efficiency best defined and measured with regard to the pcmh? what is the best set of measures to determine that health care delivered under the pcmh model is equitable that is it does not differ in quality based on personal characteristics such as gender , ethnicity , geographic location , and socioeconomic status? what are other measures that should be considered in evaluating the outcomes of the pcmh that go beyond the iom framework , for example , measures of workforce supply or provider satisfaction? what is the impact of non visit - based care on the six iom aims? what are the best measures of unintended consequences of the pmch model that would allow for early recognition of problems with model specifications? how large a set of core outcome measures can reasonably be collected and which measures should be included as high - value , core measures? how does choice of pcmh outcomes measures depend on the perspective of purchasers , payers , communities , providers , or patients?identifying the level at which to measure how can the patients of a medical practice be identified for the purposes of measuring pcmh outcomes? to what extent do individual physicians need to be linked to particular practices for the purposes of measuring practice - level outcomes ? how can this best be accomplished? how can a population - based community be defined for the purposes of measuring pcmh outcomes? which outcomes measures are best assessed at the level of the practice and which are best measured at the level of the community? how can the extent of adoption of the pcmh model within a community be measured? what is the level of adoption of the pcmh model that is necessary to produce changes in community health outcomes?additional questions when measuring its relationship to health care outcomes , to what extent does the pcmh model function as an integrated whole , rather than simply as a collection of components such as team - based care , advanced access scheduling , and chronic disease registries? in what ways can evaluation efforts be affected by gaming of performance measures by practices and providers? what is the best method for case - mix adjustment and how is patient preference included in outcomes calculations? what are the sample size challenges faced when trying to measure practice - level pcmh outcomes in very small physician practices ? how are these challenges best addressed? how can appropriateness best be defined and measured to detect overuse of inappropriate or unnecessary interventions , as well as underuse of necessary treatments? do the outcomes measurement issues and priorities differ among the major categories of physician practices ( e.g. , large integrated delivery systems , solo physician practices , fqhcs ) or within different types of communities ( for example , chronically underserved communities)? how do concepts such as integration , continuity , patient - physician relationship , comprehensiveness , patient trust , and care transitions within and between care settings relate to the measurement of pcmh outcomes? what is the role of specialist and hospital practices in ensuring positive patient outcomes from the pcmh ( e.g. , timely communication , etc.) who will be responsible for collecting data , evaluating impacts , and tracking changes over time at the level of the practice and the community? what will be the intended or unintended connection between outcomes measurement and other efforts such as practice accreditation or certification , public reporting , and/or pay for performance ? to what extent can these ongoing measurement activities be harnessed to yield outcomes for evaluating the impact of the pcmh? what uses of outcome measures will be most effective in promoting high performing medical homes ( e.g. , practitioner feedback , public reporting , pay for performance ) ? developing a long - term policy - relevant research agenda for pcmh outcomes : exemplar research questions although the pcmh model should not be expected to solve every problem in the health care system , developing a research agenda for measuring outcomes of delivery system innovations such as the pcmh should be considered in the context of the larger effort to improve the us health care system , with the ultimate goal to improve population health . the commonwealth fund has convened the evaluators of current pcmh demonstration projects to define best measures for use in those projects ; additional leadership will be needed to determine the best set of pcmh outcomes indicators over the longer term . much can be learned from leaders in the field of ambulatory care measurement and reporting , including organizations such as the agency for healthcare research and quality , the commonwealth fund , the robert wood johnson foundation , the national quality forum , and the national priorities partnership . large organized health systems that have demonstrated leadership in both the implementation of the pcmh model and measurement of outcomes include , for example , the veterans administration , kaiser permanente , and geisinger health system . state agencies , health plans , and purchaser coalitions all have vested interests in the outcomes of the pcmh and have experience to offer in measuring these outcomes , as do practicing physicians and patients . multistakeholder involvement will be essential in developing a long - term policy - relevant research agenda for outcomes of the pcmh .

backgroundthe patient - centered medical home ( pcmh ) is a widely endorsed model of delivery system reform that emphasizes primary care . pilot demonstration projects are underway in many states , sponsored by medicare , medicaid , major health plans and multi - payer coalitions.methodsin this paper we consider the development of a long - term policy - relevant research agenda on outcomes of the pcmh . we provide an overview of potential measures of pcmh impact , identify measurement challenges and recommend areas for further study . although the pcmh should not be expected to solve every problem in the health care system , developing a research agenda for measuring outcomes of delivery system innovations such as the pcmh should be considered in the context of the larger effort to improve the us health care system , with the ultimate goal to improve population health.resultsas a framework for our discussion , we have chosen the institute of medicine s six specific aims for 21st century health care : ( 1 ) safe , ( 2 ) effective , ( 3 ) patient - centered , ( 4 ) timely , ( 5 ) efficient and ( 6 ) equitable . in addition , we include potential areas of pcmh outcomes that do not easily fall under this framework and consider unintended consequences.conclusionmulti-stakeholder involvement will be essential in developing a long - term policy - relevant research agenda for outcomes of the pcmh .