Surgical hand rub and healthy skin are basic requirements to prevent surgical site infections. Nevertheless, there is little knowledge about the current practice of skin protection and/or skin care products (SP/SC) using among surgeons as well as a lack of data pertaining to the influence of SP/SC on the antimicrobial efficacy of surgical hand rub.A 10 weeks-survey among German surgeons as well as an experimental crossover study involving 26 participants were conducted. The immediate and sustainable efficacy (IE/SE) of surgical hand rub and participants’ hand moisture were measured after an 8-day usage of SP/SC, as well as the influence on micro-perforations on surgical gloves.The questionnaire was available to 16,000 German surgeons. Thereof, 1,771 surgeons accessed the questionnaire, representing a total participation rate of 11%. As 19% (n = 338) of questionnaires were incomplete, a total of 1,433 completed questionnaires were available for further analysis. More than 75% of the participants stated not to use any SP/SC, yet, almost 50% suffered from skin irritation or discomfort. Only 5% used SP/SC at the beginning of their shift. 10% refused to use SP/SC because of concerns that SP/SC may reduce the antimicrobial efficacy of surgical hand rub.After usage of SP/SC over 8-days, skin moisture was significantly higher (P < 0.001), whereas no significant influence on the antimicrobial efficacy of surgical hand rub was observed . Micro-perforations were detected in 8/52 surgical gloves (15%), with no statistical significant difference between SP/SC users  and non-users .Following the results of this largest questionnaire base survey among German surgeons on skin care, there is a need to educate and inform surgeons on the correct application and the concept of SP/SC strategies. In the present study, the combination of selected SP/SC products and one alcohol-based hand rub formulation did not show a negative interaction with surgical hand rub or surgical glove perforation. However, it is advisable to ascertain the compatibility of SP/SC products with the used hand disinfectant prior to purchase. The skin of hands is exposed to a number of physical and chemical substances during hand washing, routine hand disinfection and wearing of gloves, which may reduce the natural protective mechanisms of the skin-5. HealtIn a previously published prospective questionnaire based survey it was dTo evaluate the usage of SP/SC by surgical staff in the daily clinical routine a questionnaire containing nine short questions was designed. Three questions aimed at the person: (1) gender, (2) age, (3) and profession . The following 6 questions addressed SP/SC practices and possible skin irritations. Specifically the following was asked:(4) Is the difference between SP and SC known to you?(5) Do you start at the beginning of your shift with SP cream, SC cream, or none of both?(6) How many times daily do you use SP/SC: never, 1-2 times, 3-4 times, >4 times, other (how often?)(7) Do you use SP/SC : before every surgical hand disinfection, after hand washing/after operation, 1x in the morning or evening, irregularly after hand washing or surgical hand disinfection, when hands feel rough and dry, only if I have spare time, or not at all?(8) If you do not use any SP/SC, please indicate why : time wasting overhead, stress, uncomfortable feeling of the hands after application of SP/SC, unpleasant smell of SP/SC, no SP/SC are available at the workplace, doubt regarding the efficacy of surgical hand disinfection, doubt regarding the efficacy of SP/SC?(9) Do you suffer from skin irritation : not any skin irritations, pruritus of the hands, reddening/rubor of the hands, rough and/or dry feeling of the hands, contact dermatitis, finger nail fissures or splittering, other reason.The Professional Board of German Surgeons (PBGS) sent the digitally created questionnaire via email to all surgical departments in Germany to reach all of the 16,000 registered surgeons. Replying the answers was possible through the website of the PBGS. Only questionnaires returned within 10 weeks after submission were included into the further analysis.Additionally to the questionnaire-based survey, a prospective experimental study involving healthy adult participants was conducted. Inclusion and exclusion criteria, randomization, SP/SC, and the parameters to identify benefits or negative influences in the treatment group were defined in a written study protocol approved by the ethics committee of the University of Greifswald according to the Helsinki Declaration (ethic committee votum no. BB18/12). Written informed consent for participation in the study was obtained from all participants.Twenty-six participants without any visible or diagnosed skin irritations were randomly assigned to one of two study arms, consisting of 13 participants each. Group A started 8 days before the experimental day (ED) 1 and used SP cream  and SC products  three times daily. The participants were instructed to assure the compliance with the recommended order in which the products should be used. The simultaneous usage of other skin products was not allowed. Participants in group A used SP cream one hour before surgical hand rub.Group B did not use any SP/SC products. At ED 1, the efficacy of surgical hand rub using an alcohol-based hand rub  was determined for all participants in both study arms.According to the crossover design, the following day group B started to apply SP/SC three times daily for eight days, while group A had to wait for a minimum of 8 days before the cross-over experiment without SC/SP products was performed. This measure allowed diminishing of the previous SC/SP product application. At ED 2, the efficacy of surgical hand rub again was determined for all participants in both study arms . These measurements resulted in relative values ranging from 0 to 120. The corneometer values were interpreted as follows: < 30 very dry skin; 30-40 dry skin; and > 40 well moisture skin.In order to standardize surgical hand rub each volunteer received 5 ml of alcohol-based hand rub into both dry palms and rubbed them sufficiently over 90 seconds. First, the forearms were rubbed for 5 seconds. During the next 80 seconds the hands were disinfected following to the European Norm EN 12791 for testing surgical hand disinfection. To measAdditionally, the frequency of surgical glove micro-perforation was measured following to the European Norm EN 455-1, includist and 3rd quartile, if not indicated otherwise. Fisher’s exact test was applied for categorical variables. A Wilcoxon rank-sum test or Kruskal-Wallis test, as indicated, was used for quantitative data. A statistically significant difference was assumed when P was less than or equal to 5% (P ≤ 0.05).Statistical analysis and plots were performed using Prism 5 . Data were presented as median with 1The questionnaire was available to all 16,000 surgeons currently listed with the PBGS in Germany. Thereof, 1,771 surgeons accessed the questionnaire and submitted their replies. Hence, the total participation rate was 11%, which represents a large proportion of German surgeons. As 19% (n = 338) of questionnaires were incomplete, a total of 1,433 completed questionnaires were available for further analysis.The majority of respondents were practicing surgeons . More than three quarters of participants were male , and most of them were 41-50 years old . 38% (n = 537) of respondents stated having regularly dry and rough feeling of the hands, 14% (n = 196) stated having broken finger nails or fissures, 12% (n = 178) pruritus, and 10% (n = 145) rubor of the hands. Half of the respondents  stated not to suffer from any skin irritation.More than half of the respondents  stated to know the differences between SP and SC products. However, at the beginning of the day 78%  do not apply SP/CP at all, 14% (n = 197) used SC products, and 5% (n = 75) SP cream. During the complete working shift, 47% (n = 681) never use SP/SC routinely, 40% (n = 571) once to twice daily, and 9% (n = 132) three or more times. Mostly, SP/SC are only used when the hands feel rough and dry , at the beginning or at the end of the shift , and randomly during the day , respectively.SP/CP is not used for several reasons: 27.6% (n = 396) disliked the hand feeling or smell, 23.9% (n = 343) indicated stress at their working places as the main reason and even 10.2% (n = 146) had concerns that SP/SC may impair the efficacy of surgical hand rub.In both study arms, the measured skin moisture was significantly higher after SP/SC , Table 10) were 2.8 ± 1.49 (IE) and 1.57 ± 2.4 (SE), respectively. After application of SP/SC during 8 consecutive days, the bacterial reduction factors (log10) were 1.98 ± 1.83 (IE) and 1.84 ± 1.41 (SE), respectively. The application of SP/SC product had no significant influence on the efficacy of hand disinfection . Detailed results are summarized in Table Without using any SP/SC products, the immediate (IE) and sustained (SE) bacterial reduction factors  of which 6 occurred in participants not using SP/SC products during 8 consecutive days before surgical hand rub, and 2 in participants using SP/SC products. Although trend-wise the frequency of micro-glove perforation was higher in participants without usage of SP/SC products, the difference in micro-perforation within the SP/SC group  and non-SP/SC group  was statistically not significant .To our knowledge, this survey is the largest ever performed on practices of skin care or skin protection practices among surgeons. However, one of the limitations of the results may be that particularly surgeons with personal interest in hand hygiene or those with chronic or intermitted skin disorders may have responded. This may have introduced a participation bias, distorting results towards higher knowledge on SP/SC application or higher proportions in reported skin affections. Indeed, about half of the respondent stated not having any form of skin irritation, and more than half stated to know the difference between SP and SC products. Even if a participation bias may be present in the collected data, the fact that chief criteria such as self-reported knowledge and skin condition are distributed evenly among a large proportion of German surgeons allows drawing meaningful conclusions.While it is difficult to state that surgeons reporting having knowledge on SP and SC, the opposite may certainly be assumed. In fact, some 40% of the responding surgical staff did not know the difference between SP and SC products. This may result in incorrect usage. Furthermore, among the 57% of the respondents stating to be familiar with SP/SC products, only 5% used SP cream in the morning, as recommended by the manufacturers. Consequently, training and educational programs still seem to be necessary to explain the importance of SP products among surgical professionals,10. ThisOne factor, which may inhibit the primary usage of SP products, is their smell, as 35% of respondents disliked the smell and the feeling on hands after SP product usage. Improved SP formulations may increase the primary usage of SP products before skin irritations may develop. Most likely, easily absorbing, odorless, and perfume-free products should be preferred.Some 10% of respondents stated that they have concerns that previous use of SP/SC products may negatively affect the efficacy of surgical hand rub. Indeed, this view sometimes is also shared in hand hygiene or surgical site infection prevention sessions during surgical conferences. While infrequently discussed, there is little data to support or reject this view. Therefore, we conducted an experimental crossover study among practicing surgeons. For the intervention arm, we chose highly absorbing, odorless, and perfume-free SP/SC products to exclude possible influences of added ingredients. Furthermore, a SC cream with a low urea concentration was selected in order to increase skin permeability and to aThe results of this study did not show any significant differences for the efficacy of surgical hand disinfection, regardless of usage of SP/SC products. These results are in line with a previous study investigating the possible influence of SP cream on hand disinfection among nurses in medical and surgical intensive care. HoweverOur study clearly demonstrated that after regular use of SP/SC products over a period of one week, skin moisture significantly increased. However, based on the corneometry measurements the skin of hands still was "dry" and did not reach a well moisture condition, which is indicated by corneometry measurements above 40 points. Furthermore, this relative improvement was reached only without regular surgical hand preparation, including hand washing with liquid soap, which may further dehydrate the skin of,27. In tAn interesting side finding of our experimental study was that a higher proportion of micro-perforations was detected in participants that did not use SP/SC products prior to surgical hand disinfection. Although the difference in micro-perforation between those using SP/SC products (7.7%) 8 days prior to glove wear and those, which did not use SP/SC products (23.1%) was statistically not different – which may be the result of a possible beta error due to small observation numbers – an overall glove micro-perforation rate of 15% may seem to be surprising. The observed grove perforation rate in our present study was almost 15x times higher than what may have been expected at rest conditions. As our One factor remaining as possible explanation for the difference in glove perforation is the improved skin condition of participants during wearing of gloves. Indeed, although not statistically different, the glove perforation rate in participants which had used SP/SC products one week prior to the surgical hand disinfection and wear of gloves over a 3-hour period at rest was 7.7%, while in participants without use of SP/SC products, the perforation rate was 23.1%. Since concurrently with the usage of SP/SC products the moisture condition of the skin of hands significantly improved, it may be speculated that dry hands and cracks in skin may lead to increased micro-perforation of surgical gloves, even at rest. Although our study yields data that may support this view, this study was not designed to study in detail the correlation of dry skin and glove perforation rates. However, this aspect may warrant further studies in the operation theatre.Following the results of the largest questionnaire base survey among German surgeons on skin care, there is a need to educate and inform surgeons on the correct application and the concept of SP/SC strategies. Any doubts raised by surgeons regarding the possibility of interaction of SP/SC products with the efficacy of surgical hand disinfection should be taken seriously. In the present study, the combination of selected SP/SC products and one alcohol-based hand rub formulation did not show a negative interaction. However, it is advisable to ascertain the compatibility of SP/SC products with the used hand disinfectant prior to purchase.APIC: Association of Professionals in Infection Control and Epidemiology; AQL: Acceptable quality level for surgical gloves (GAMMEX AQL: 0.065); cfu: Colony-forming unit; ED: Experimental day; IE: Immediate efficacy of surgical hand rub; PBGS: Professional Board of German Surgeons; SC: Skin care; SE: Sustainable efficacy surgical hand rub; SP: Skin protection.This study was financed through the routine research grant of the Institute for Hygiene and Environmental Medicine, University Medicine Greifswald, Germany. The authors have no competing interests to report. A Kramer and O Assadian have partly received travel compensation and speakers honoraria from Bode Chemie GmbH in the past. O Assadian is member of the Medical Scientific Advisory Board of Hutchinson santé, France.JC Harnoss, A Kramer, and CD Heidecke planned and designed the experimental study. JC Harnoss, A Kramer, CD Heidecke, and J Ansorg planned and designed the questionnaire. JC Harnoss, A Kramer, and L Brune supervised and coordinated data collection. JC Harnoss, A Kramer, and O Assadian performed the statistical analysis. All authors have participated in analysis and interpretation of data, drafting and revising the manuscript, and have read and approved to the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/14/315/prepub


Bordetella pertussis is an important human respiratory pathogen. Here, we describe a loop-mediated isothermal amplification (LAMP) method for the rapid detection of B. pertussis in clinical samples based on a visual test. The LAMP assay detected the BP485 target sequence within 60 min with a detection limit of 1.3 pg/μl, a 10-fold increase in sensitivity compared with conventional PCR. All 31 non-pertussis respiratory pathogens tested were negative for LAMP detection, indicating the high specificity of the primers for B. pertussis. To evaluate the application of the LAMP assay to clinical diagnosis, of 105 sputum and nasopharyngeal samples collected from the patients with suspected respiratory infections in China, a total of 12 B. pertussis isolates were identified from 33 positive samples detected by LAMP-based surveillance targeting BP485. Strikingly, a 4.5 months old baby and her mother were found to be infected with B. pertussis at the same time. All isolates belonged to different B. pertussis multilocus sequence typing groups with different alleles of the virulence-related genes including four alleles of ptxA, six of prn, four of tcfA, two of fim2, and three of fim3. The diversity of B. pertussis carrying toxin genes in clinical strains indicates a rapid and continuing evolution of B. pertussis. This combined with its high prevalence will make it difficult to control. In conclusion, we have developed a visual detection LAMP assay, which could be a useful tool for rapid B. pertussis detection, especially in situations where resources are poor and in point-of-care tests. Bordetella pertussis, a Gram-negative bacterium first reported in 1906  is a simple and cost-effective nucleic acid amplification method, which can be applied to rapidly detect ertussis –17. Prevsequence , 19. Howcificity . In 2008ly IS481 . Our stuB. pertussis vaccine strains were tested, including strain 18530, which originated from United States, strain P3s10, which has been used to produce Pw vaccines since the early 1960s, and strain CS, which has been used to produce Pa vaccines since 1995. Paired sputum and nasopharyngeal swabs were collected from 105 hospitalized patients using rayon-tipped swabs  between the spring of 2010 and spring of 2014. The patients  came from rural areas of China and had been treated for coughs and pneumonia for more than 7 days. Ten pairs of sputum samples and nasopharyngeal swabs from healthy people were also collected as controls. One swab or sputum sample was immediately placed in Regan-Lowe transport medium for culture and the other was stored at −70°C in an empty sterile tube for bacterial nucleic acid isolation.Thirty-four bacterial strains were used for specificity analysis, which are listed in Table Bordetella pertussis strains were cultured on Bordet–Gengou agar supplemented with 15% defibrinated sheep blood for 4–5 days at 37°C. Species identification was carried out using the Phoenix Automated Microbiology System (BD Diagnostic Systems) and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. Genomic DNA was extracted from all samples using TIANamp Bacteria DNA Kit . The sequences of 16S ribosomal DNA (rDNA) and BP485 were validated by PCR-based sequencing and showed 100% identity with those previously reported.adk, fumC, glyA, tyrB, icd, pepA, and pgm were detected by PCR. The allele number for each gene was assigned on the basis of the information in the B. pertussis MLST databaseprn, ptxA, tcfA, fim2, and fim3) by PCR as previously reported (Seven housekeeper genes including reported .The sequence of BP485 (Accession number: CP002695.1) was downloaded from NCBI GenBank database and further analyzed by Primer Explorer Version 4Bst DNA polymerase, 2 μl template for real-time turbidimeter, and another 1 μl calcein/Mn2+ solution for visual detection. Primers were used at a concentration of 40 pmol for FIP and BIP, 20 pmol for LB and LF, and 5 pmol for F3 and B3. The reaction mix was overlaid with a sealing agent mainly comprised wax to prevent cross contamination of samples by aerosol. During the amplification, the protectant melted and became liquid without disturbing the reaction, avoiding volatilization of amplified products after reaction, and the protectant solidified as the temperature in the tubes decreased (Patent: ZL201210371448.5 in China).Loop-mediated isothermal amplification assays were carried out using the Loopamp DNA Amplification kit . Briefly, the LAMP amplification system in a final volume of 25 μl contained 12.5 μl reaction mixture, 1 μl 2+) in the reaction buffer form a white magnesium pyrophosphate precipitate , 1 μM BP-113F3 and BP-113B3 primers, and 2 μl of DNA template in a final volume of 25 μl. PCR was performed using the following cycling conditions: initial PCR activation, 95°C for 5 min; amplification, 40 cycles of 95°C for 30 s, 55°C for 30 s, and 72°C for 30 s; final extension, 72°C for 7 min. PCR products were visualized on a 1% agarose gel stained with ethidium bromide. Images were documented with a Gel Doc EQ imaging system (Bio-Rad).B. pertussis by a LAMP assay for the first time. Five different primer sets were initially tested, four of which resulted in successful amplification as shown in Figure BP485 was targeted for detection of Reaction temperatures from 60 to 67°C were compared for optimal amplification. Amplification efficiency was highest at 64°C Figure  and was B. pertussis, genomic DNA was extracted from B. pertussis ATCC18530, B. pertussis ATCC58003, B. pertussis ATCC53894, and 31 other pathogenic respiratory bacteria and tested using real-time turbidity or visual detection of color change as readouts. Both methods of analysis positively identified the B. pertussis isolates. All other strains, including the blank control, tested negative, indicating that the LAMP assay was specific to B. pertussis  were tested. The results were shown in Figure To compare the detection limit of LAMP using either real-time turbidity measurements or color change with traditional PCR, 10-fold serial dilutions of genomic DNA extracted from B. pertussis was successfully cultured from 12 samples, all of which had been positively identified by LAMP. The healthy control samples all tested negative in each of the assays.A total of 105 clinical sputum samples and nasopharyngeal swabs were collected for LAMP-based surveillance of BP485 from patients with suspected respiratory infections in China during 2010–2014. Ten pairs of sputum samples and nasopharyngeal swabs from healthy people were collected as controls. All clinical samples were analyzed by LAMP and PCR simultaneously. As shown in Table B. pertussis isolates confirmed conservation with the nucleotide sequences of reported genes. Multilocus sequence typing (MLST) analysis of B. pertussis showed that five of the seven housekeeping genes belonged to a single genotype, similar to reported global genotypes. However, the adk and tyrB housekeeping genes had two different genotypes belonging to type 1 and type 3, respectively.The sequence analysis of the BP485 gene from the ptxA, prn, tcfA, fim2, and fim3 were analyzed. All isolates had virulence-related genes belonging to different genotypes with all four ptxA alleles, six prn alleles, four tcfA alleles, two fim2 alleles (fim2-1 and fim2-2), and three fim3 alleles  present across the samples. Our data show that B. pertussis is widespread in respiratory infections, and the diverse genotypic features indicate on-going evolution.To further characterize the virulence-related genes of the 12 isolated strains, the alleles of B. pertussis, and can cause severe disease, particularly in infants. Although vaccines are widely used in most countries, the morbidity of pertussis is rising, even in developed countries with high vaccination coverage. Remarkably, many adolescents and adults become infected despite having been vaccinated as infants as a result of waning antibody titers, which can result in further transmission to children. Unfortunately, conventional wisdom holds that pertussis is a pediatric disease, leading to substantial under-diagnosis in adolescents and adults. Pertussis is highly infectious, and therefore rapid and simple methods to aid diagnosis would be advantageous in controlling disease spread.Pertussis, also known as whooping cough, is an acute respiratory infectious disease caused by B. pertussis, e.g., culture, serological assays, and, most commonly, PCR-based methods. These approaches are either time-consuming or costly and frequently require skilled technicians and precision instruments. They are therefore not suitable for situations where resources are limited and fast results are required such as for point-of-care assessments. Since its introduction in 2000, a nucleic amplification method known as LAMP (B. pertussis by color change.Several diagnostic techniques have been established for detecting  as LAMP  has been as LAMP , 28. A n481, have been used to diagnose pertussis, we chose BP485, which, unlike IS481, is able to distinguish B. pertussis from B. bronchiseptica and B. parapertussis (B. pertussis strains and 31 homologous species by both real-time turbidimeter and visual color change methods. All B. pertussis strains tested positive and all 31 non-pertussis respiratory tract pathogens, including B. bronchiseptica and B. parapertussis, tested negative. These results demonstrated that LAMP targeting BP485 had a high specificity for the detection of B. pertussis and that using turbidity or color change as readouts gave comparable results. The sensitivity of LAMP to detect BP485 was compared with traditional PCR using 10-fold serial dilution of genomic DNA extracted from B. pertussis. The detection limit of the LAMP assay used here was 1.3 pg/μl, 10-fold higher than conventional PCR, in agreement with previous reports. Furthermore, LAMP can be completed in one hour using a simple thermostat, whereas a PCR run takes approximately 3 h and requires a relatively complicated thermal cycler. LAMP is therefore a more rapid and simple technique making it better suited to field use.Although many target genes, such as ISertussis . SpecifiTwo readouts were used for the LAMP assay to detect amplification products, real-time turbidity and visual observation of color change. Detection by color change was as sensitive and specific as real-time turbidity measurements. As this color change is visible to the naked eye, it would further simplify the assay. It is worth noting that the use of a wax sealant over the reaction mixture was essential to minimize cross contamination by aerosol, which frequently resulted in false positives.B. pertussis was prevalent in the community with over 30% of samples testing positive. The cases included a 35-year-old female patient from rural China who was admitted for treatment in the city hospital after suffering with cough and pneumonia for 14 days. Her baby had contracted whooping cough from her as a result of close contact. This was an example of increasing numbers of “adult to child” transmissions, which may be a major factor in the rising incidence of pertussis.Application of the assay to samples taken from hospital admissions of cough and pneumonia indicated that B. pertussis allows for positive samples to be identified by the naked eye immediately after amplification is completed. The visual method is as sensitive and specific as real-time turbidity measurements and is more sensitive than PCR. It is a rapid, simple, and low-cost method to diagnose B. pertussis, making it particularly useful for point-of-care testing where time and resources are limited.In conclusion, the visual LAMP assay developed here for detecting JY and SZ helped conceive project and designed experiments. WL, YX, and HL performed and wrote the manuscript. XZ, LL, YZ, MZ, XW, XW, and SH designed and executed experiments. DD and LH helped to edit the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Current publicly reported data do not focus on variation in national results or annual changes.The Centers for Medicare & Medicaid Services publicly reports risk-standardized mortality rates (RSMRs) within 30-days of admission and, in 2013, risk-standardized Describe U.S. hospital performance on AMI, HF, and pneumonia mortality and updated readmission measures to provide perspective on national performance variation.To identify recent changes and variation in national hospital-level mortality and readmission for AMI, HF, and pneumonia, we performed cross-sectional panel analyses of national hospital performance on publicly reported measures.Fee-for-service Medicare and Veterans Health Administration beneficiaries, 65 years or older, hospitalized with principal discharge diagnoses of AMI, HF, or pneumonia between July 2009 and June 2012. RSMRs/RSRRs were calculated using hierarchical logistic models risk-adjusted for age, sex, comorbidities, and patients’ clustering among hospitals.Median (range) RSMRs for AMI, HF, and pneumonia were 15.1% (9.4–21.0%), 11.3% (6.4–17.9%), and 11.4% (6.5–24.5%), respectively. Median (range) RSRRs for AMI, HF, and pneumonia were 18.2% (14.4–24.3%), 22.9% (17.1–30.7%), and 17.5% (13.6–24.0%), respectively. Median RSMRs declined for AMI  and remained similar for HF  and pneumonia . Median hospital-level RSRRs declined: AMI , HF , and pneumonia .We report the first national unplanned readmission results demonstrating declining rates for all three conditions between 2009–2012. Simultaneously, AMI mortality continued to decline, pneumonia mortality was stable, and HF mortality experienced a small increase.The online version of this article (doi:10.1007/s11606-014-2862-5) contains supplementary material, which is available to authorized users. The Centers for Medicare & Medicaid Services (CMS) began reporting hospital-specific 30-day risk-standardized mortality rates (RSMRs) for patients hospitalized with acute myocardial infarction (AMI) and heart failure (HF) in June 2007, and for patients hospitalized with pneumonia in 2008 through the Hospital Inpatient Quality Reporting (IQR) Program . In 2009, CMS also began reporting hospital-specific 30-day risk-standardized readmission rates (RSRRs) for all three conditions.Hospital Compare website.Patients and other stakeholders can compare individual hospitals’ performance on these six quality measures on CMS’s Hospital Compare.We aim to describe the performance of U.S. hospitals on mortality and readmission measures following hospitalizations for AMI, HF, and pneumonia. Specifically, we summarize the national distribution of variation in hospital performance on the publicly reported outcomes measures based on the most current data (July 2009 to June 2012) and quantify annual changes within the 3-year period reported on The cohort for the six measures consists of hospitalizations for all Medicare fee-for-service (FFS) and VA beneficiaries aged 65 years and older, discharged from non-federal or VA acute care hospitals and having a principal discharge diagnosis of AMI, HF, or pneumonia. Medicare FFS beneficiaries are included if they have been enrolled in Medicare for the 12 months before and including the date of the index admission to ensure a full year of data for risk adjustment. The index hospitalization is the admission being measured for the outcome and identified based on patients’ principal discharge diagnosis. Discharges included in the publicly reported measures in 2013 occurred during July 2009 through June 2012. Additional details on measure methodology are provided in the The data sources are CMS administrative (claims and enrollment) data and VA administrative data. Index hospitalizations and readmissions are identified from inpatient claims. Dates of death were ascertained from the CMS enrollment database and VA records. To identify patient risk factors, the measures use inpatient and outpatient claims from the year prior to the index admission and secondary diagnosis codes from the index admission. The The mortality measures assess death from any cause, within 30 days of admission for the index hospitalization. The mortality outcome is attributed to the initial admitting hospital, regardless of subsequent transfers.The readmission measures assess unplanned re-hospitalization to any acute care facility for any cause within 30 days of discharge from the index hospitalization. Readmissions to observation status or non-acute units such as rehabilitation are not included. Readmission is attributed to the hospital that ultimately discharges a patient to a non-acute care setting . Planned readmissions, such as hospitalizations reflecting readmissions for elective chemotherapy or scheduled procedures, are not considered outcome events in these measures and are defined using a publicly vetted approach that is delineated in the supplemental Details of the risk models used are provided in the To describe national hospital variation in publicly reported RSMRs/RSRRs, we evaluated their corresponding descriptive statistics, such as mean, standard deviation, median, and ranges. Hospitals were further characterized as “better” (“worse”) than the national rate if their risk-standardized rate was lower (higher) than the national rate and 95% confidence intervals did not include the national rate; if the hospital’s 95% confidence intervals included the national rate, the hospital was characterized as “no different than” the national rate.To report annual changes in outcomes, a 1-year (July 1 through June 30) RSMR or RSRR was calculated for each hospital, condition, and measure for July 2009 through June 2012. For patients with multiple eligible admissions within a 1-year period, we selected a single index admission for inclusion in the mortality analyses. We calculated the median hospital rate and inter-quartile range at each time point for each measure. We used a generalized estimating equation (GEE) model to test whether the mean annual RSMR/RSRR changed significantly over the three year reporting period. We used annual hospital RSMRs/RSRRs as dependent variables and the three 12-month time periods as independent variables, and accounted for the correlation among the same hospitals over time. We also conducted pairwise comparisons of mean RSRRs or RSMRs between different time periods.We calculated the number of hospitals changing performance categories and absolute differences in hospital-level risk-standardized rates between the 2012 (prior year) and 2013 (current) public reporting periods. We report these changes as “improved” , “no change”, or “worsened” .All analyses were done with SAS version 9.2 . We created figures with R (version 2.11.1).The measures include data from more than 4,500 hospitals. Over the 3-year period, we included 511,404 admissions in the AMI mortality measure cohort, 1,042,203 for HF mortality, and 1,037,583 for pneumonia mortality . During the same period, the median and mean annual hospital-level 30-day RSMR for HF increased by an absolute 0.2%  and decreased for pneumonia by an absolute 0.2% .The annual hospital-level 30-day RSMRs revealed a decline of 0.8% in the median Table  and meanp < 0.001, Table There has been a statistically and clinically significant decrease in the annual mean RSRRs for all three measures  at least three absolute percentage points lower than those for poor performing hospitals (90th percentile) for five of six measures; the AMI readmission measure demonstrates 2.4 absolute percentage points between top and bottom deciles. Documentation of this variation provides evidence of continued room for improvement in care quality. The publicly reported measures are designed to benchmark an individual hospital against how an average hospital performs when caring for a similar case-mix. The goal of public reporting is not to reduce mortality or readmission to zero, but rather to bring as many hospitals as possible to the performance standards set by the nation’s highest performing hospitals.The measures continue to demonstrate wide performance variation, with outcome rates for high performing hospitals  percentage point within the last 3 years of available data, compared to year-to-year changes in annual median RSRRs ≤ 0.3 absolute percentage points between 2007 and 2010.Although cross-sectional and including only the 3-year current measurement period, these data are the first indication that measure-specific readmission rates are declining and support evidence published by Gerhardt, et. al in 2013 that all-condition readmission rates are declining.One concern expressed by critics of examining hospital readmissions as a measure of hospital quality is that focus on readmissions will divert attention from other important quality improvement efforts and/or result in unintended consequences.There are several limitations to consider in interpreting these results. First, administrative claims carry less face validity for adequate case-mix adjustment compared to clinical data. The risk models used in these measures have been validated against and demonstrate similar performance assessments to models based on medical record data.Examination of 2009–2012 data reveals variation in the quality of care provided to patients with AMI, HF, and pneumonia. Our study summarizes unplanned readmission rates nationally and signals potential early declines in readmission rates. The 2013 publicly reported measures update suggests payment incentive programs may be influencing hospital readmission performance without a concomitant increase in mortality, at least for AMI and pneumonia patients, and supports the need for simultaneously measuring mortality and readmission to encourage better quality across all aspects of care and monitor for unintended consequences.ESM 1(DOCX 382 kb)Below is the link to the electronic supplementary material.


Fibroblast growth factor 23 (FGF23) regulates mineral homeostasis. In developed renal dysfunction, FGF23 levels increase to maintain the phosphate excretion capacity. However, in diabetic patients with early-stage renal impairment, the FGF23 elevation is not very sensitive. We hypothesized that urinary phosphate (U-P)/serum FGF23 ratio would theoretically be an index that reflects the number of nephrons (nephron index). In this study, we determined whether the nephron index would be associated with renal function and vascular diseases in diabetic patients.In total, 142 patients with diabetes mellitus were enrolled. The nephron index was calculated using the following formula: U-P (mg/day)/ serum FGF23 (pg/ml).2, respectively. Thirty patients had a medical history of macroangiopathy. The Nephron index was significantly decreased in subjects with macroangiopathy compared with those without macroangiopathy. A multivariate analysis of risk factors for macroangiopathy revealed that duration of diabetes, eGFR, and nephron index were significantly associated with a higher frequency of arteriosclerotic disease.The mean age was 63 ± 11 years and eGFR levels were 79.5 ± 25.4 ml/min/1.73 mThese findings suggest that a decrease in nephron index reflects early-stage renal impairment and is an independent risk factor of macroangiopathy in diabetic patients. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that plays a central role in the metabolic regulation of phosphate (P) and vitamin D–3. FGF23Diabetes mellitus can cause CKD and is a risk factor for atherosclerosis and cardiovascular mortality. Although diabetic patients in early stages of CKD (stages 1 and 2) are reported to have lower FGF23 than nondiabetic patients matched for sex, age, and estimated glomerular filtration rate (eGFR), FGF23 mIn this report, we propose the ratio of U-P excretion (mg/day) to FGF23 as an index that theoretically represents the number of nephrons (nephron index), 14. ProIf the Nephron index indeed reflects the functional nephron number, it will start decreasing in early stage CKD and potentially be useful for following up the progression, evaluating the risk for complications, and making a decision when to start the treatment in preemptive medicine. In the present retrospective, cross-sectional study, we determined whether the nephron index would be associated with renal function and vascular diseases in diabetic patients.The present study enrolled 142 subjects with type 2 diabetes mellitus. The cohort had a mean age of 63.0 years and included 73 men and 69 women. The subjects had been hospitalized at Jichi Medical University Saitama Medical Center to control their plasma glucose levels and complicated disorders. Blood samples after overnight fasting and daily total urine samples were collected from the subjects. Based on the KDIGO 2012 CKD guideline, the patients were classified into three groups according to eGFR degrees as follows: normal or high , mildly decreased , and mildly to moderately decreased . Subjects categorized as G4  were excluded from the present study. Thirty subjects had a history of treatment for macroangiopathy . Overall, 76 subjects had hypertension, 72 subjects had dyslipidemia, and 45 were smokers. None of the patients were administering vitamin D or calcium carbonate. The duration of the diabetes mellitus was estimated by the patients’ medical records. The occurrence of diabetic retinopathy was confirmed by an ophthalmologist.Blood samples were collected into tubes and centrifuged at 3,000 rpm at 4°C for 15 min. The supernatants were decanted and frozen at −80°C until assayed.Serum levels of HbA1c, Ca, P, 25OH vitD, FGF23, and intact PTH were determined. Serum FGF23 was measured by enzyme-linked immunosorbent assay (ELISA) using intact FGF23 ELISA kits . The intra- and inter-assay coefficients of variation were <4.0% and 4%, respectively. Serum 25OH vitD was measured by ELISA using 25OH vitD ELISA kits . The intra- and inter-assay coefficients of variation were both <7.0%. Serum FGF23 and serum 25OH vitD were measured in duplicate. Other variables were measured at a central laboratory section of the Jichi Medical University Saitama Medical Center. Renal function was determined by the eGFR, assessed by the Modification of Diet in Renal Disease equation revised for the Japanese population by the Japanese Society of Nephrology:2) = 194 × serum creatinine (mg/dl)−1.094 × age−0.287 × 0.739 [eGFR . The nepThe study was approved by the Ethics Committee at Jichi Medical University Saitama Medical Center (No. 14–60) and performed in compliance with the Declaration of Helsinki. We obtained written consent from participants.t test or Mann—Whitney U test, as appropriate. Categorical variables were compared by Fisher’s exact test. The post-hoc analyses was performed as needed (Holm test for serum FGF23 and Nephron index). Pearson’s correlation coefficient analysis was used for linear correlations between eGFR and serum P, intact PTH, FGF23, and Nephron index. Multivariate logistic regression analysis was conducted after univariate analysis. The variables were selected based on the comparison between with or without macroangiopathy. Namely, statistically significant variables were selected.Data are expressed as mean ± standard deviation, and skewed variables are described as median with interquartile range. Clinical characteristics were compared among the three groups using one-way ANOVA or Kruskal-Wallis test. Two groups were compared by Student’s These variables were divided into two groups based on their averages in multivariate analysis. When a parameter revealed skewed distribution, the variable was transformed logarithmic parameters before analysis in correlation coefficient analysis and regression analysis. There was no missing data in each variable.p < 0.05 was considered significant.All analyses were performed with EZR , a graphical user interface for R  and a modified version of the R commander (ver. 1.6–3) that was designed to add statistical functions frequently used in biostatistics. p < 0.0n = 40; G2: n = 70; G3: n = 32), the prevalence of hypertension, age, and duration of diabetes mellitus was significantly greater at the highest CKD stage class. There were no differences in serum calcium (Ca), P, and 25-hydroxyvitamin D3 (25OH vitD) levels. In contrast, serum FGF23 increased, and the nephron index decreased in association with the progression of CKD stage. A post-hoc analysis (Holm test) showed significant alterations in both FGF23 and nephron index initially at stage G2  and Ln FGF23  and a positive correlation of eGFR with Ln nephron index , but not with serum P , as shown in n = 30) and without (n = 112) macroangiopathy. The age and duration of diabetes mellitus were significantly higher in subjects with macroangiopathy. eGFR was significantly decreased in subjects with macroangiopathy compared with those without macroangiopathy. Regarding mineral metabolic parameters, U-P excretion and nephron index were significantly lower, whereas FGF23 was higher in subjects with macroangiopathy. There were no differences in serum Ca, P, intact PTH, and 25OH vitD levels. To determine the independent variables associated with the absence or presence of macroangiopathy, we performed a multiple logistic model analysis, shown in The clinical characteristics of the study participants are shown in stage G2 . There wWhen CKD progresses to stages 4 and 5, hyperphosphatemia induces phenotypic changes, transforming vascular smooth muscle cells into osteoblast-like cells, thus contributing to calcification of blood vessels. Elevation of serum FGF23 is associated with cardiovascular calcification and mortality in end-stage kidney disease–19. In tet al. have revealed that higher serum FGF23 levels are more strongly associated with mortality and cardiovascular events when accompanied by lower FEp in a population with relatively mild CKD (mean eGFR 71 ml/min/1.73 m2)[et al. have reported that a high serum FGF23 level was a significant predictor of poor prognosis in subjects with CKD stage 3–4, but FEp did not modify the relationship between FGF23 and clinical outcome[et al. showed that a low FEp/FGF23 ratio was associated with the severity of abdominal aortic calcification in patients with CKD stages 3–4 independent of age, gender, and presence carotid plaque[2, serum FGF23 was not an independent factor for macroangiopathy. Nakano et al. have shown that the serum FGF23 level in CKD stages 1 and 2 in diabetic patients is lower than that in nondiabetic patients due to dysfunction or decreased density of osteocytes and that diabetes mellitus affects vitamin D metabolism[Several studies have reported a relationship between FEp and serum FGF23 levels in mild-to-moderate CKD stages. Dominguez /1.73 m2). Beck etl outcome. These sl outcome. Recentlid plaque. Our pilid plaque, abnormaid plaque. In contetabolism. Indeed,etabolism. The resThere are limitations in our study. First, we could not determine whether the nephron index serves as an independent predictor of macroangiopathy in nondiabetic patients, such as in patients with CKD with primary glomerulonephritis, nephrosclerosis, and other kidney diseases. Second, we did not assess bone measures, including bone mineral density and medical history of bone fracture. It is known that patients with diabetes have abnormalities in bone metabolism (low bone formation) and an increased risk of hip and vertebral fractures–28. The The present study demonstrates that the nephron index, which theoretically reflects the number of functional nephrons, is significantly decreased in early-stage CKD in diabetic patients. Furthermore, the number of nephrons is an independent risk factor for macroangiopathy. Further studies are needed to establish the nephron index as one of the earliest biomarkers of CKD.


To propose an alternative and practical model to conceptualize clinical patterns of concomitant intermittent strabismus, heterophoria, and convergence and accommodation anomalies.Despite identical ratios, there can be a disparity- or blur-biased “style” in three hypothetical scenarios: normal; high ratio of accommodative convergence to accommodation (AC/A) and low ratio of convergence accommodation to convergence (CA/C); low AC/A and high CA/C. We calculated disparity bias indices (DBI) to reflect these biases and provide early objective data from small illustrative clinical groups that fit these styles.P = 0.001). Accommodative esotropia (n = 3) showed less disparity-bias (DBI 0.03). In the high AC/A–low CA/C scenario, early presbyopia (n = 22) showed mean DBI of 0.17 , compared to DBI of −0.31 in convergence excess esotropia (n=8). In the low AC/A–high CA/C scenario near exotropia (n = 17) showed mean DBI of 0.27. DBI ranged between 1.25 and −1.67.Normal adults (n = 56) and children (n = 24) showed disparity bias (adult DBI 0.43 , child DBI 0.20 ; Establishing disparity or blur bias adds to AC/A and CA/C ratios to explain clinical patterns. Excessive bias or inflexibility in near-cue use increases risk of clinical problems. Asymptomatic binocular vision requires integration of angles of deviation, refractive error, and accommodation and convergence to images moving in depth. Atypical accommodative convergence to accommodation (AC/A) ratios characterize a few but not all diagnoses. Complex theoretical models have been developed to explain binocular control, involving feedback loops from accommodation and vergence in combination with tonic and phasic inputsOur research has focused on naturalistic vergence and accommodation to the main cues available in any stimulus moving in depth; blur disparity and proximity ; and the relative weighting between cues.Δ at 1m, whereas a large adult with a 70 mm IPD will converge 7Δ but both will converge 1 MA to fix bifoveally. They are also a useful because MA can be plotted on the same scale as diopters. 3 D of accommodation accompanies 3 MA of convergence, leading to response gains of 1.0 and an AC/A ratio of 1 MA to 1 D (6Δ to 1 D in an adult with an IPD of 60 mm).AC/A ratios (convergence change driven by a change in blur) are commonly used to explain many characteristics of strabismus, but clinicians may be unaware of significant limitations of clinically measured ratios. For example , 3.0 D of blur is often assumed to drive 3.0 D of accommodation , and so the change in angle per diopter is calculated by dividing by 3—a stimulus  AC/A ratio. In stimulus AC/A ratio  will be higher in example 1 because they converge more. The response ratios (convergence change in relation to accommodation response and the measure that most vision scientists consider the “true” ratio) may be very different. In example 1 the divisor is 2.4 D, but in example 2 it is only 0.6 D; therefore, both stimulus ratios are lower than the response ratios, but much lower for example 2. Response ratios rarely correlate with stimulus ratios.Δ to 1 D in an adult), despite very different responses to the change in blur. Example 1 responds well to blur; example 2 does not. Both stimulus and response ratios are missing detail about how we use blur as a cue.However, perfect accommodation rarely happens and underaccommodation to blur is common. The rarely considered CA/C ratio describes accommodation associated with convergence driven by disparity (rather than vergence to blur above) and is similarly problematical.The two ratios are inversely,In this study we predicted how different biases toward blur and disparity, in combination with anatomical factors, such as position of rest and refractive error, would result in specific diagnoses and treatment responses. We queried our database to determine whether specific diagnoses fitted the model predictions.Our dataset was collected from a wide range of normal controls and patients in the course of other published and unpublished studies. Ethics approval was obtained from University of Reading and Berkshire NHS Ethics committees. All subjects provided written informed consent. The clinical details of the different study participants are provided elsewhere.jaapos.org). Simultaneous, objective, vergence position and accommodation were calculated from eye position and refraction data collected by a PlusoptiX S04 PowerRefII photorefractor . We calculated convergence angle in MAs and accommodation in D at each fixation distance after correcting for IPD, angle lambda , and spectacle magnification. We then calculated response gain in relation to demand across the different distances. Different target manipulations allowed us to assess responses to blur, disparity, and proximity separately as the target moved in space. By allowing binocular viewing or by remotely occluding one eye we could present or eliminate disparity. By presenting a detailed clown cartoon or a Gabor patch target we could present or minimize blur cues,Laboratory data were collected using a remote haploscopic photorefractor to present images moving in depth between distances of 0.33 m to 2 m, described in detail elsewherebdp; blur [b], disparity [d], and proximal [p]) target ; a blur-only (b) target ; disparity only (d) target .Our discussion concentrates on the three targets most pertinent to our argument: (1) a naturalistic all-cue (b condition (convergence gain/accommodation gain) and response CA/C ratios using accommodation gain/convergence gain in the d condition.We calculated response AC/A ratios using the gains in the b target, and those to the d target, then subtracted the b target gains from the d target gains to form a disparity bias index (DBI). If blur and disparity responses are equal, the DBI is zero; a larger positive number indicates a stronger disparity bias, whereas a smaller or negative number indicates more blur bias.As we argue that the ratios are insufficient, we also needed a measure of bias toward better responses to disparity or blur, independent of the AC/A and CA/C ratios. We averaged vergence and accommodation gains ([accommodation gain + vergence gain]/2) to the •“Normal/classical” AC/A and CA/C A,B: blur•High AC/A and low CA/C C,D: verg•Low AC/A and high CA/C E,F: accoWe present six hypothetical patterns:(bdp) cue show that overall responses stay within normal limits, but responses to blur and disparity within this stimulus can be very different. We then present real examples drawn from our laboratory dataset . See The AC/A and CA/C ratios are identical in each pair, but with different blur and disparity biases. The upper tables under the pairs of charts show the responses used to calculate AC/A and CA/C ratios as well as the disparity bias index (DBI). The lower tables show how changing blur or disparity has different effects on the angle of deviation and/or the accommodation depending on the pattern. Responses to the naturalistic bdp) condition, with perfect vergence and slight accommodation lag for near . Both have identical and normal response AC/A and CA/C ratios, but pattern A's normal responses are stronger to disparity than blur, whereas pattern B's responses to blur and disparity are more equal.Patterns A and B show classical normal responses in the naturalistic (P = 0.001). See Δ to 1 D in both groups). The weaker response to blur explains why spectacles rarely change heterophoria much in nonstrabismic individuals. Disparity is the main drive, so changing blur makes little difference if disparity remains available. However, researchers who use naive participants , consistently find that disruption of binocularity causes a significant drop in accommodation as well as major inaccuracies of convergence that occur in strabismus.30Most normal people are disparity-biased, with more bias in adults (adult (n = 56) DBI 0.43 vs child (n = 24) DBI 0.20, t (78) = 3.52; Δ greater than distance while still retaining control with spectacles). These 10 fell between this group and Pattern D below, with a DBI of 0.01 and AC/A ratio of 1.7 MA to 1 D. The vergence and accommodation of pattern A are more disrupted by occlusion or suppression disrupting disparity cues but less disrupted by lenses or developing refractive error changing blur. Pattern B is more affected by blur change but less disrupted by disparity change. Because the AC/A and CA/C ratios are normal, blur change drives more accommodation than convergence and disparity change drives more convergence than accommodation.As additional lenses or change in refractive error rarely change angles of deviation in nonstrabismic children and adults, our hypothesis was that disparity bias is normal, whereas accommodative strabismus, where lenses change angles of deviation, would show blur-biased pattern B. As predicted, classic accommodative esotropias  followed pattern B , with a There are also disparity-biased vs blur-biased alternatives possible for the high AC/A and low CA/C (convergence exceeds accommodation) and the low AC/A and high CA/C (accommodation exceeds convergence) scenarios, each pair with similar ratios (patterns C and D).Disparity-biased pattern C shows a higher DBI. Despite the high AC/A ratio, blur stimuli should not lead to overconvergence because blur is a weak cue; underaccommodation occurs, but overconvergence does not. The vergence response to disparity (low CA/C ratio) might not drive sufficient accommodation in the case of orthophoria where there is normal convergence demand, but in exophoria, the additional convergence required to overcome the deviation would not result in overaccommodation. The weak accommodation of early presbyopia A by neceP = 0.008). See bdp responses in the figure show hypoaccommodation, suggesting that some try to control their deviation, but at the expense of clear near vision.In blur-biased pattern D the high AC/A ratio causes excessive convergence in response to blur; individuals with this pattern are at risk of convergence excess accommodative esotropia. As predicted, high AC/A ratio convergence excess esotropias (n = 8) fit pattern D, with a negative DBI of −0.31, significantly lower than normal children .Patterns E and F in overaccommodation.Δ larger near angle) and were in fact recruited as normal controls (P = 0.028) than normal and accommodated more than the normal adults while responding to the d target (2.98 D vs 2.45 D (t [71] = 3.34); P = 0.001). We predict clearer differences in clinical populations.Disparity-driven pattern E subjects do not accommodate well to increasing blur targets, and do even less convergence, leading to near exophoria. Poor blur response might be found in straight-eyed hyperopic ametropic amblyopia. Reducing disparity cues by dissociation, prisms or surgery, however, significantly reduces accommodation, while the need to control a large exodeviation, for example, might result in controls . They haPattern F responds to blur. Although the high CA/C ratio means that accommodation exceeds convergence, the weakness of disparity-driven responses does not result in over-accommodation. We predict that hyperopic children who manage to accommodate over their refractive error without becoming strabismic would fit this group. Our dataset did not include any individuals in pattern F. Our patient participants were drawn from a hospital population, referred for poor visual acuity, so this “silent” group of hyperopic children with good vision is difficult to detect because they pass screening. We predict that subjects with the combination of convergence insufficiency but good accommodation will fit into this group.We readily accept other theoretical models based on complex feedback loops, engineering-type modeling, AC/A and CA/C cross-links, and slow tonic versus rapid step adaptive mechanisms,We suggest clinicians should first consider which aspect of the visual stimulus is mainly used to compute target depth. Is the subject a “disparity person” or a “blur person”? Next, determine whether accommodation and convergence are strongly linked in the individual, assessing changes induced by lenses, prisms, or dissociation, whether the individual accommodates more than converges, or vice versa. AC/A and CA/C ratios help, but are only informative if an individual's blur or disparity bias is also known. How much, or whether, “ratios” matter depends on “style,” basic angle, and refraction. We can then understand etiology and clinical characteristics and predict response to treatment.Although there are many individual differences in cue use within asymptomatic normal individuals, inflexibility and excessive bias appear to characterize clinical groups and predict treatment responses. Time or orthoptic exercises may alter biases, for example, teaching a blur-biased accommodative esotropic patient to pay closer attention to single vision while accepting some blur.Disparity people, the majority, maintain binocularity by motor fusion and are less concerned with the effect on accommodation. Lenses change angles little, but they may dissociate more on occlusion. If, as is usual, most of their accommodation is also driven by disparity, then dissociation, prisms or surgery will not only change the angle, but also influence accommodation.If most people are disparity-driven, why do we not see more accommodative problems? Imprecise accommodation may be normal. Binocular accommodation is better than monocular, monocular accommodation is rarely required, and blur is often tolerated. Our large dataset suggests that hypoaccommodation is common. We found underaccommodation of >1.0 D at 33 cm in 22% of normal adults, 12% of normal children, 22% of hyperopic subjects with glasses, and 100% of hyperopic subjects without glasses.Blur people will be more sensitive to changes in clarity and accommodate accordingly. These seem rare among the general population but do appear in our clinical caseload. Even a normal, but especially a high, amount of vergence associated with the response to blur, risks accommodative esotropia in hyperopia as we know. If less vergence is associated with this accommodation (low AC/A), hyperopes may be able to respond to blur without over-converging—an advantage in uncorrected hyperopia, but a disadvantage for the clinician hoping to change an angle with spectacles. Blur-driven people's sensitivity to disparity may be low, so changing an angle with prisms, dissociation or surgery will have less effect on their accommodation but weaker fusion might mean that binocularity is more easily lost. Are these also the people who notice small changes of refractive prescription, be slow to settle into new glasses and insist on them being clean?Our examples are only illustrative and not comprehensive, but some more predictions from this model are summarized in Further laboratory and clinical research is necessary to test these speculations, but in the meantime it is probably clinically important to test clarity of a near target to threshold, to ask about image clarity at every swap of an occluder during a prism cover test and to measure accommodation objectively.or disparity to drive responses, and to be able accommodate and converge more independently (“positive and negative relative fusion”) to compensate for “style” biases. Our naturalistic paradigm repeatedly finds that responses are variable, accommodation and vergence do not always co-vary, and “ratios” are rarely fixed or repeatable, so perhaps the two systems are, and need to be, less closely linked than we assume.Remaining symptom free may depend on being able to use both blur


P < 0.01), and immunohistochemistry with Neurofilament 200 indicated more myelinated afferents existed in MTrSs (P < 0.01). Spontaneous electrical activity (SEA) recordings at MTrSs showed that specific block of myelinated afferents in sciatic nerve with tetrodotoxin (TTX) led to significantly decreased SEA (P < 0.05). Behavioral assessment showed that mechanical pain thresholds (MPTs) of MTrSs were lower than those of non-MTrSs (P < 0.01). Block of myelinated afferents by intramuscular TTX injection increased MPTs of MTrSs significantly (P < 0.01), while MPTs of non-MTrSs first decreased (P < 0.05) and then increased (P > 0.05). 30 min after the injection, MPTs at MTrSs were significantly lower than those of non-MTrSs (P < 0.01). Therefore, we concluded that proliferated myelinated afferents existed at MTrSs, which were closely related to pathology of SEA and mechanical hyperalgesia of MTrSs.Myofascial trigger points (MTrPs) are common causes for chronic pain. Myelinated afferents were considered to be related with muscular pain, and our clinical researches indicated they might participate in the pathology of MTrPs. Here, we applied myofascial trigger spots  of rats to further investigate role of myelinated afferents. Modified pyridine-silver staining revealed more nerve endings at MTrSs than non-MTrSs ( Myofascial trigger points (MTrPs), which are critical for Myofascial Pain Syndrome, are hyperirritable nodules of spot tenderness in muscle taut bands  . When stμV) and a low frequency but high amplitude intermittent activity (100~700 μV) [SEA is the combination of endplate noise and endplate spikes with action potential , 4. It c~700 μV) . Local p~700 μV) . Accordi~700 μV) , 6, 7. T~700 μV) .Myelinated afferents were considered to mediate electrically induced muscle pain . ClinicaHowever, current proofs were almost clinical ones and were more subjective other than objective. And some further investigations, especially invasive tests, were hardly to be applied to human beings. In order to get a more definitive conclusion about the role of myelinated afferents in peripheral changes of MTrPs with more objective and morphological proofs, we designed this animal study. Modified pyridine-silver staining method and immunohistochemistry with Neurofilament 200  were fiFifty-four adult male Wistar rats (specific pathogen free (SPF) level, weight about 300~400 g) bought from Shandong University Lab Animal Center  were used in the study. All the rats were fed with food and water ad libitum in the animal house (26°C) with 12 : 12 hours of reversed light : dark cycle. This study was approved by Shandong University Animal Use Committee. Considering some gender differences, such as concentration of estrogen , may affRats were lightly anesthetized with most of the spinal reflexes reversed and immobilized in prone position. Fur and skin covering the biceps femoris were shaved and cleared. As myofibers of taut band were stiffer than the surrounding tissues, an experienced investigator could identify the taut band (diameter of 2~3 mm) by palpating the biceps femoris. Next, squeezing the muscle along the taut band was done until an LTR existed. An LTR is brisk contraction of a group of muscle fibers in a taut band when MTrSs were stimulated. According to our experience and the current literature, usually only one most sensitive spot in the taut band can induce LTR , and thiA hollow-needle electrode  was used as an active needle electrode inserted into MTrS region while the control needle electrode was inserted into the normal tissue, and the ground electrode was placed in the tail.μV) and a low frequency but high amplitude intermittent activity (100~700 μV) [The active needle electrode was advanced about 1 mm per step until there was SEA (a high frequency but low amplitude persistent background current <50 0 μV and ~700 μV) , 6, 18. μV/division, and the sweep speed was 100 ms/division.Settings of the EMG unit were as follows: the high frequency filter was 1000 Hz, while the low frequency filter was 100 Hz, the amplitude for recording was 20 3, 0.1 mL, and distilled water, 5 mL) for 24 hours. Then the tissue blocks were immersed in 10 mL of absolute ethyl alcohol containing 0.1 mL of ammonia solution for another 24 hours and were washed with distilled water for 30 min. After that, the blocks were stained in 2% AgNO3 for 3 days away from light (25°C) and were put into 10 mL of 5% formic acid containing 0.4 mg of pyrogallol for 6–24 hours [μm by a rotary microtome (Leica), collected, and made into paraffin sections [Twenty rats were used in this section, and the MTrS/non-MTrS tissues in biceps femoris were localized and removed. 10 MTrSs and 11 non-MTrSs were used for modified pyridine-silver staining to show the nerve endings in these tissues. All the tissues were fixed in a freshly prepared fixative . After that, dewaxing and antigen retrieval were carried out. After that, routine immunohistochemistry with NF 200 was carried out. NF 200 antibody was diluted to a proper concentration  with phosphate-buffered saline (PBS). Peroxidase histochemistry was carried out with diaminobenzidine (DAB). Then the NF 200 positive myelinated afferents were stained brown.12 MTrSs and 8 non-MTrSs were used for the immunochemistry with NF 200 (CST) to show myelinated afferents specifically . The tisIn this section, for both modified pyridine-silver staining and immunochemistry, longitudinal sections were used to show location and morphology of stained fibers, while 100 nonoverlapping transverse views for MTrSs/non-MTrSs, respectively, were analyzed to get the mean number of stained fibers with light microscope equipped with a digital camera (Olympus). In order to limit the error, all measurements were performed by the same investigator.2 1 mM, glucose 10 mM, CaCl2 2 mM, and Tris 5 mM, and had been adjusted to pH 7.4 with HCl.24 rats with MTrSs were randomly divided into TTX/isotonic saline group. After MTrS was located in the biceps femoris, a diagonal incision was made at the midpoint of ischial tuberosity and knee of the same side with MTrS. The skin, subcutaneous tissue, and fascia were dissected in sequence, and gluteus maximus was blunt dissected to expose sciatic nerve. The skin and fascia around the incision were lifted to make a bath, and artificial cerebrospinal fluid (ACSF) was used to immerse the nerve. ACSF was made up of NaCl 150 mM, KCl 5 mM, MgClμM, Aladdin) was added into the bath to block myelinated afferents selectively [2 [For rats in TTX group, TTX solution , and this model was confirmed to be an effective one to test the muscular sensitivity of lightly anaesthetized rats, and the results could been treated as “objective” ones –27. TherIn this section, 10 rats were used. An electronic von Frey (VF) analgesiometer with a hard tip was used to stimulate the skin above the MTrSs, until ipsilateral hind-limb NWR existed. The minimum stimulus intensity that just evoked the NMR was mechanical pain threshold (MPT) which can represent the mechanical sensitivity of MTrSs/non-MTrSs , 25.μM TTX was injected into MTrSs as well as non-MTrSs to block myelinated afferents [2 [After MTrS was located in biceps femoris muscle of rat, a non-MTrS, a non-taut band spot , was located in the contralateral biceps femoris muscle. First, MPTs of MTrSs and non-MTrSs were assessed, respectively. Then, 0.1 mL 1 fferents . And MPTrents [2 , small drents [2 , 18.t-test was used to analyze the differences of silver/NF 200 marked fibers between MTrS and non-MTrS tissues. And a two-way ANOVA followed with Student Newman-Keuls Test (SNK) was used to analyze the differences of MPTs at different time after the TTX injection between MTrS and non-MTrS. For all data, it was considered to be significant if P < 0.05.The “a priori” sample size estimations for the rats needed in three sections were made according to the results of our preliminary experiments and the sample size estimations formulae. And the minimum of rats needed in each section was shown as follows: four rats for MTrS/non-MTrS group in modified pyridine-silver staining/IHC with NF200 in Section 1; eleven rats for TTX/isotonic saline group in Section 2; and four rats for MTrS/non-MTrS group in behavioral assessment in Section 3. Considering there might be unexpected conditions, we used a few more rats in the formal experiments. Fisher's exact test was applied to analyze the incidence rate differences of the significant SEA changes between TTX and isotonic saline groups in Section 2. All data in Sections 1 and 3 were presented as mean ± SD and analyzed with SPSS 13.0 for Windows . And the results indicated that data of each variable fitted normal distribution. Student's P < 0.01)   than non-MTrSs (11.06 ± 1.543) (P = 0.0447).For Section 2, in the TTX group, 7 rats showed significantly decreased SEA, while the other 5 rats had decreased, but not significantly changed, SEA after TTX addition. In the isotonic saline group, 2 rats had significantly decreased SEA after the addition of isotonic saline and the rest of the rats just had no significant changes see . IncidenF = 12.141, P < 0.01; 15 min after the block: F = 96.128, P < 0.01; 30 min after the block: F = 6.913, P < 0.01).For Section 3, a two-way ANOVA revealed, 5, 15, and 30 min after the block, there were significant differences between MPTs of MTrSs and non-MTrSs, and there was significant interaction between these two factors . And MPTs at MTrSs increased significantly 5, 15, and 30 min after TTX injection . For non-MTrSs, MPTs decreased significantly 5 min after the injection , while 15 min/30 min after the TTX injection, MPTs increased when compared with those prior to the injection, but the differences were not significant . Thirty minutes after TTX injection, MPTs of MTrSs were significantly lower than those of non-MTrSs   see .This study further investigated the function of myelinated afferents in pathology of MTrSs. We found more nerve endings, especially more myelinated afferents, existed in MTrS regions than normal tissue. And specific block of myelinated afferents with TTX resulted in decreased SEA as well as higher MPTs of MTrSs. Thus, we concluded proliferated myelinated afferents were closely related with SEA and mechanical hyperalgesia of MTrSs.Modified pyridine-silver staining method was used to indicate sensory nerve endings in skeletal muscles, and these nerve endings were stained as dark brown or black . In thisThe reason for proliferated myelinated afferents was not clear yet. It was reported that, after nerve injury, membrane properties of myelinated afferents changed which induced sprout of axon endings . We thouIn order to investigate the function of myelinated afferents, we selected TTX to block them specifically , 22, 31.SEA is one of the characteristics of MTrSs. It is a combination of endplate noise and endplate spikes with action potential , 23, 33 As no criterion about SEA changes was generally recognized, in Section 2, we chose 50% decrease of amplitude or frequency of the high amplitude wave as a significant change . Any SEP < 0.05), there were still 5 rats that had decreased but not significantly changed SEA after applying TTX. We inferred the reasons might be as follows. Individual differences of rats, such as numbers of sodium channels on myelinated afferents, led to different sensitivity to TTX [And it was worth noticing that although incidence rates of SEA significant changes caused by TTX/isotonic saline were significantly different , which protects the subject from nociceptive damage. NWR is a spinal polysynaptic reflex, and it has been used to investigate pain processing as well as pain pathways at spinal levels . MoreoveBesides, 30 min after the injection, although the MPT of MTrS was obviously increased, it was still lower than that of non-MTrS. We inferred C fibers and sympathetic nerves were responsible for this. C fibers participated in the conduction of nociceptive stimuli, increased the sensitivity of MTrSs , 38–40, Although this study demonstrated myelinated afferents affected SEA and mechanical hyperalgesia of MTrSs, the mechanism was still mysterious. We hypothesized the reactions between myelinated afferents and sensitization  of MTrSs  were resThe mechanism of MTrSs is mysterious, and in this study, we found proliferated myelinated afferents modified SEA and mechanical hyperalgesia of MTrSs and proposed a hypothesis of the modulatory mechanism. More studies, such as investigating central sensitization with immunohistochemistry about the nociceptive related receptors in spinal cord, afferent nerve tracing to show their connections and conduction, were already in operation to reveal the exact mechanism.This study demonstrated that MTrSs contained more myelinated afferents than normal healthy tissues, which were associated with pathology of SEA and mechanical hyperalgesia of MTrSs. Nevertheless, how myelinated afferents affect SEA and mechanical hyperalgesia was still uncertain. We hypothesized myelinated afferents affected SEA and mechanical hyperalgesia of MTrSs through central and peripheral sensitization. More studies were already in operation to reveal the exact mechanism.


Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma (MM). A few reports have linked bortezomib exposure with the development of thrombotic microangiopathy (TMA). We describe a case of biopsy-proven renal thrombotic microangiopathy associated with the use of bortezomib in a 51-year-old man with IgG lambda MM. To our knowledge, this is the first biopsy-proven case. In addition, reexposure to bortezomib 18 months later was associated with recurrence of TMA. This supports a possible causal role of bortezomib. The exact mechanisms remain to be elucidated. Thrombotic microangiopathy (TMA) is a rare cause of renal disease in multiple myeloma (MM) patients. It is defined by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. Pathological features are arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall . TMA con2) thalidomide- (100 mg) dexamethasone (40 mg) (VTD) therapy for newly diagnosed IgG kappa, Durie-Salmon stage IIIa, and ISS high risk multiple myeloma (MM). He had been diagnosed with monoclonal gammopathy of undetermined significance (MGUS) during the investigation of ulcerating acral skin lesions 9 years previously. M-protein level at diagnosis of MGUS had been 4.36 g/L. Workup for autoimmunity and cryoglobulinemia had been negative and biopsy of the skin lesions had shown nonspecific findings. The extent of the skin lesions seemed to correlate with the M-protein level. For this reason the patient had been treated with rituximab (7 doses of 375 mg/m2) and therapeutic plasma exchange (TPE). Other medical history included hypertension and hypothyroidism. His medications were amlodipine 5 mg, aspirin 80 mg, levothyroxine 75 μg, and transdermal fentanyl 50 μg/h. The patient had been smoking cigarettes for 30 years. The patient had received no other nephrotoxic medication and was well hydrated. Blood pressure was 150/83 mmHg. The patient's acral ulcers, which had been relatively well controlled with biweekly TPE for the last 9 years, had worsened, with development of a livedoid rash and painful edema of hands and feet and multiple necrotising ulcers (see A 51 year-old Caucasian man was found to have acute kidney injury (AKI) three weeks after start of bortezomib- (1.3 g/mcers see .μL). Platelet count was 119,000/μL, Hb 7.5 g/dL with schistocyte excess on peripheral blood smear and haptoglobin < 0,1 g/L, indicative of microangiopathic hemolytic anemia. There was hypocomplementemia ; cryoglobulins were absent; Coombs test, hepatitis B en C serology, ANF, and ANCA were negative. ADAMTS-13 activity was mildly reduced (34%). Genetic screening for complement mutations was negative. Renal sonogram revealed normal size kidneys with increased reflectivity of renal parenchyma. Punch biopsy of the livedoid skin rash showed nonspecific changes. Renal biopsy showed 7 out of 36 obsolete glomeruli and 15% chronic tubulointerstitial damage. One glomerulus had a capillary thrombus, with intimal edema of the afferent arteriole. These findings are indicative of a renal TMA lesion  dexamethasone (40 mg). This therapy had to be stopped after 7 months due to pancytopenia, despite dose reduction. After 8 months of watchful waiting there was disease progression with both increase in serum paraprotein level and bone lesions on MRI. Based on the good initial hematological response to VTD, the patient was restarted on VD (bortezomib and dexamethasone). Note that, at that time, the possible link between TMA and bortezomib was not clear. Baseline creatinine before reexposure to bortezomib was 2.9 mg/dL. Other medications at that time included  nifedipine 120 mg, levothyroxine 75 μL). The patient was oliguric. He had excruciating pain in his extremities due to a flare up of the chronic ulcers. Because of fluid overload, acidemia, and hyperkalaemia, hemodialysis had to be started. TPE was again intensified to once every two days. After withdrawal of bortezomib, there was a gradual recovery. Proteinuria dropped again to 0.6 g/24 h.Four weeks later, after 3 doses of bortezomib, the patient presented with a severe hypertension (188/102 mmHg), marked increase in serum creatinine  associated with the use of bortezomib in a multiple myeloma (MM) patient. Bortezomib is a first-generation proteasome inhibitor used in the treatment of MM. TMA has not been reported as a drug-related adverse event in CREST  and SUMMCarfilzomib, a second-generation proteasome inhibitor, has been linked to TMA in MM patients as well. Sullivan et al.  presenteIn all these reports the temporal relationship between exposure to bortezomib or carfilzomib and occurrence of TMA, and the improvement after discontinuation point towards proteasome inhibition as a possible cause of TMA. Our case is unique in that we documented recurrence of renal TMA after reexposure to bortezomib 18 months after the initial episode. This further supports a causal role for proteasome inhibition in the pathogenesis of renal TMA in multiple myeloma patients.κB pathways [Drug-induced TMA can be caused by idiosyncratic (non-dose-related) immunologic reactions or by toxic (dose-related) effects . The forpathways –22. ThisHowever, causality is difficult to establish. Hematopoietic stem cell transplantation, a known cause of TMA, could have played a role in 4 of the above-mentioned reports , 12. AnoTreatment of drug-induced TMA is limited to drug avoidance and supportive care . Some auWe report a case of renal TMA in a MM patient who is treated with bortezomib. This is the sixth case of TMA associated with bortezomib exposure in the literature. To our knowledge, this is the first biopsy-proven case. In addition we show that reexposure to bortezomib caused recurrence of TMA 18 months later. The possible mechanisms remain to be elucidated.