Introduction. Little research has been conducted looking at the effects of osteopathic manipulative treatment (OMT) on preterm infants. Aim of the Study. This study hypothesized that osteopathic care is effective in reducing length of hospital stay and that early OMT produces the most pronounced benefit, compared to moderately early and late OMT. A secondary outcome was to estimate hospital cost savings by the use of OMT. Methods. 110 newborns ranging from 32- to 37-week gestation were randomized to receive either OMT or usual pediatric care. Early, moderately early, and late OMT were defined as <4, <9, and <14 days from birth, respectively. Result. Hospital stay was shorter in infants receiving late OMT  than controls. Subgroup analysis of infants receiving early and moderately early OMT resulted in shorter LOS . Costs analysis showed that OMT significantly produced a net saving of €740  per newborn per LOS. Conclusions. This study shows evidence that the sooner OMT is provided, the shorter their hospital stay is. There is also a positive association of OMT with overall reduction in cost of care. Preterm birth, defined by the American Academy of Pediatrics and the World Health Organization as birth, that occurs in or before the end of the 37th week of pregnancy , 2 repreModerate preterm (MP) and late preterm (LP) infants have been loosely classified by current literature –6, as coAlthough length of stay (LOS) for MP and LP infants is much less than that for extremely preterm infants, the impact in terms of hospital stays is similar because of the large volume of these two groups , 12.Preterm birth has been also associated with a negative socioeconomic impact. Mean hospital costs associated with LOS are approximately between US$1,000 for a term infant and US$40,000 for an infant born either moderately or late preterm .Noninvasive treatment aimed at reducing LOS of preterm infants and cost of neonatal care could well prove an appealing option worth investigating.Very little research has been conducted looking at the effects of osteopathic manipulative treatment (OMT) on preterm infants –16. In tHowever, the application of OMT in preterm infants remains uncertain and a more rigorous study design is warranted.The objective of the present randomized controlled trial (RCT) was to investigate the effectiveness of OMT in reducing hospital stay and related costs in MP and LP infants.Osteopathic medicine is a form of drug-free noninvasive manual medicine. It relies on manual contact for diagnosis and treatment. Osteopathic practitioners use a wide variety of therapeutic manual techniques  to improIn the osteopathic literature, somatic dysfunction is defined as “impaired or altered function of the somatic (body framework) system: skeletal, arthrodial and myofascial structures and their related vascular, lymphatic and neural elements” .Two essential components of osteopathic health care are the structural evaluation of the patient for somatic dysfunction diagnosis and an array of manipulative techniques for treatment .The aim of a structural examination is to locate the somatic dysfunction. In infants, the structural exam is usually performed with the patient lying down. Diagnostic criteria for somatic dysfunction are focused on tissue texture abnormalities and tone. Areas of asymmetry and misalignment of bony landmarks are evaluated. The quality of motion, its balance, and organization are noted.In treating preterm infants during the very first days of life, osteopaths use several manual techniques , 22, in This study hypothesized that osteopathic care is effective in reducing the length of hospital stay in a population of MP and LP infants and that early OMT produces the most pronounced benefit (primary outcome). Secondary outcome was to estimate the potential savings, in terms of hospital costs related to LOS, by the use of OMT.MP and LP infants entering the NICU of Macerata Public Hospital from October 2010 to July 2012 were assessed for eligibility. All subjects met the following criteria: infant born at Macerata Public Hospital with a gestational age between 32 and 37 weeks, preterm infant free of medical complications and with written informed consent from parents or legal guardians. Exclusion criteria, applied at study entry and to any portion of the infant's hospital course, included the following: gestational age <32 or >37 weeks, first OMT provided after 14 days from birth; genetic/congenital disorders; cardiovascular abnormalities; proven or suspected necrotized enterocolitis with or without gastrointestinal perforation; proven or suspected abdominal obstruction; pre/postsurgery patients; pneumoperitoneum; newborns from an HIV seropositive or drug addicted mother; infants transferred to or from another unit or hospital; early postnatal discharge .NCT01784835).The trial was approved by the Ethics Committee of Macerata Public Hospital (number 22/int./CEI/27239) and was registered at ClinicalTrials.gov  and 2 osteopaths performed the structural evaluation and the treatment (group B).In order to provide blinding and avoid possible confounding, osteopaths from groups A and B were allowed to enter the NICU two days per week and during different hours.None of the osteopathic practitioners in either group were involved in the study design, data entry, or statistical analysis.Newborns allocated to the study group received standard pediatric care plus two osteopathic treatments per week, for the whole hospitalization period.OMT included the application of a selected range of manipulative techniques , dependiEach OMT session lasted 20 minutes and was not based on a predetermined protocol and the treatment was not standardized. Data on structural examinations and OMT techniques are not reported as this was not the focus of this study.Preterm infants in the control group received standard pediatric care plus two osteopathic structural evaluations per week. The structural evaluations were performed according to the same schedule as the study group and lasted 10 minutes. Once completed, osteopaths from group A remained standing in front of the incubators or open cribs for an additional 10 minutes so that the total time spent with each infant in both the control and treatment groups was equal, to further assist in blinding the ancillary NICU staff.Subjects were randomly allocated to study or control group by an information technology consultant. A permuted-block randomization with an allocation ratio of 1 : 1 was performed using the R software as computer random generator .NICU staff were blinded to outcome measurements and patient group assignment.Data was collected using EBOM-GCCN software . NursingMaternal data was also obtained and included reported pregnancy complications, single versus multiple gestation, fetal presentation, type of delivery, premature rupture of membranes, and abruption of the placenta.Neonatal data collected included gender, gestational age, infants small for gestational age, birth weight, neonatal complications , and diagnosis-related group (DRG).Sample size calculation used multiple regression method. An effect size of 0.3 was applied and a total number of predictors equal to 4 were considered. Defining a statistical power of 0.90 and an alpha level equal to 0.05, a sample size of 52 subjects per group was computed. To allow for attrition, the sample size was increased to 55 subjects per group.The assessment of normality was performed using Shapiro's test.Statistical analyses were based on intention-to-treat model. Missing data was handled using last observation carried forward imputation technique. The baseline characteristics of the population were analyzed using descriptive statistics. Univariate statistical tests were used to compare the study and control groups at baseline.A generalized linear model was performed to study the independent effect of OMT on LOS, taking into account the following confounders: gender, gestational age, birth weight, DRG-386 (prematurity with respiratory distress syndrome), DRG-387 (prematurity with major complications), and DRG-388 (prematurity without major complications) .A subgroup analysis was performed to address the relationship between the timing of the first OMT and LOS.early OMT as <4 days from birth;moderately early OMT as <9 days from birth;late OMT as <14 days from birth.Depending on when the first OMT was provided, three different time frames were established as follows:The use of three different time frames resulted from the osteopathic care schedule. Osteopathic care was provided 2 days per week on Mondays and Thursdays.The statistical program used for data analyses was R (version 2.15.0) .A multivariate analysis was performed to study the average hospitalization costs among infants of study and control groups. Cost data was extracted from 2011 administrative databases of the Regional Office of the Ministry of Health (ROMH) of Marche, where the NICU of the present RCT is located. More specifically, the Ministry of Health, besides its central offices, is divided into regional offices distributed throughout Italy. In relation to their individual skill sets, each ROMH carries out activities of control and offers services to the population. Then, the Istituto Superiore di Sanità  estimates a precise amount of reimbursement for each DRG and hospitals receive funds according to patients DRG.In this trial, DRG and reimbursements considered were DRG-386, prematurity with respiratory distress syndrome , DRG-387, prematurity with major complications , and DRG-388, prematurity without major complications  .For this study, the cost of each OMT was theoretically set at 20,00€ , taking Ordinary least squares regression was used to investigate the effects of OMT on hospitalization costs after adjusting for gender, gestational age, LOS, and birth weight.Cost estimates were adjusted for inflation to 2012 euros using the Medical Component of the Consumer Price Index.As shown in N = 110 were selected for the final sample and randomized 1 : 1 to study group (N = 55) and control group (N = 55).After the application of exclusion criteria, None of the subjects dropped out up during the trial and no adverse events were recorded.W = 0.95, P = 0.65) and birth weight  resulted in a Gaussian distribution.The assessment of normality for gestational age (P = 0.03).As shown in P < 0.05) (The mean LOS was 15.6 ± 7.4 for the study group and 17.1 ± 6.3 for the control group ( < 0.05) .The first multivariate linear model was run to test the independent effect of factors associated with LOS.P < 0.01), as well as one-week increases in gestational age reduced LOS . Results also showed that both DRG-387 and -386 significantly increased hospitalization by almost 4 days .As shown in A subgroup analysis was performed to investigate the relationship among early OMT, moderately early OMT, and hospital stay.Using the time frame of 9 days (moderately early OMT), the initial sample was reduced to 91 subjects. Among them, 43 were in the study group and 47 were controls.P < 0.01).At baseline, the two groups were well matched for neonatal and maternal characteristics . At the P < 0.001); gestational age , DRG-387 , DRG-386 ; birth weight .A second linear regression model was run to study the independent effect of moderately early OMT (<9 days from birth) on hospital stay . ResultsP < 0.001).In looking at those subjects receiving early OMT (<4 days), the sample was further reduced to 55 subjects, 26 in the study group and 29 controls. At baseline, study and control groups were balanced with regard to neonatal and maternal characteristics . At discP < 0.001); gestational age ; gender ; birth weight ; DRG-387 ; DRG-386 .A third linear regression model was performed to measure the independent effect of early OMT (<4 days from birth) on hospitalization . The folP = 0.68), the use of OMT produced a net saving of approximately 175,00€  per newborn per LOS, providing an overall cost reduction of almost 10.000€ .As far as cost analysis is concerned, in the present study OMT represented a cost-saving procedure. Although results from univariate statistical analysis showed that mean costs for study group and controls did not vary significantly  per newborn. Results also confirmed cost increases according to DRG-387 , DRG-386 , and OMT time frame .The ordinary least square regression took into account several potential confounders listed as follows: gender, gestational age, birth weight, LOS, OMT time frame, OMT, DRG-388, DRG-387, and DRG-386. Results were expressed in terms of mean cost savings between each confounder and DRG-388 was set as the reference category. As shown in The present study was designed to yield accurate quantitative data on the effectiveness of OMT in preterm infants, especially those born either moderately or later preterm.The major findings in this population-based study of length of hospital stay in MP and LP infants were that OMT is effective in reducing LOS and the sooner treatment was received the sooner infants were discharged from hospital.P < 0.01). Subgroup analysis of infants under early (before day 4) and moderately early OMT (before day 9) showed a linear correlation between LOS and time frame of first OMT. It was found that early OMT was associated with the shortest LOS  and moderately early OMT produced a reduced hospital stay of 3 days .In detail, a mean reduction of 2 days was found to be statistically significant in infants receiving late OMT (within 14 days from birth) compared with controls , but this difference is smaller in the group of infants who received early OMT  and might be related to the different characteristics of the samples under study. On the other hand, data by Pizzolorusso et al. [Although OMT has been barely studied in the care of premature infants –16 our fFinally, the potential economic benefits of the use of OMT in NICU were investigated. In the present study, OMT produced a cost saving per infant of €740,00, in contrast with €3000,00 per infant found by Cerritelli et al. . ResultsPossible explanations to the positive effects of OMT in the reduction of hospital stay are difficult to outline although several mechanisms are proposed.Feeding difficulty in preterm infants is a major cause of delayed discharge .In 2011, Lund described a case of hospitalized premature twins with nipple-feeding dysfunction. After the application of OMT, nipple-feeding performance improved to full oral feeding, suggesting the positive effect of OMT in the coordination of suck and swallowing.In the same year, Pizzolorusso et al. investigated the effects of OMT in 350 premature infants. The data suggested that patients from the study group experienced fewer gastrointestinal symptoms such as vomiting, regurgitation, and gastric residuals.In MP and LP infants, the autonomic nervous system undergoes significant maturation between 31 and 38 weeks of gestation, represented by decreases in heart rate and increases in heart rate variability (HRV) . In lighIn 2007 Meltzer and Standley  developeGiven the evidence that the skin surface of neonates ≤32 weeks GA have higher levels of proinflammatory cytokines than full term infants , the autOne of the limitations of this study is that it was conducted in only one NICU located in Central Italy. Potential differences in practice may exist in other institutions, influencing generalizability of our findings.Furthermore, discharge plan for study and control groups only took into account the health of the child and followed the proposed guidelines of the AAP . ParentaFinally, cost estimates were based on a theoretical approach based on mathematical computation of hospital net savings, rather than the real hospital stay.The present RCT shows evidence that osteopathic care in NICU offers advantages in the reduction of hospital stay.The approach taken, focusing on the impact of different time frames  of first OMT, is rather novel and well thought out for substantiating the results.Our findings may be of interest and use to researchers, stakeholders, and policy-makers planning to evaluate the impact of osteopathic care in national health care systems, particularly those wishing to incorporate within a decision analytic framework the economic impact of MP and LP birth and the cost-effectiveness of treatment strategies.RCTs based on multicentric design are warranted before any firm conclusions can be drawn.


TMstent-graft system has been shown to be safe and effective in high-risksurgical patients with complex suprarenal and/or infrarenal abdominal aorticaneurysm anatomy. The wireformed M-shaped stent architecture and proximalsprings with anchoring pins theoretically permit optimal sealing in shorterand more angulated proximal aneurysm necks even under off-label conditions.Nonetheless, extremely difficult anatomical situations and inherent graftsystem-related limitations must be anticipated. Herein, we describe ourtechniques to overcome the capture of the tip sleeve within the suprarenalbare-stent anchoring pins, other endograft segments, and native vessels.Endovascular aortic aneurysm repair with the Endurant Previous randomised trials have confirmed the short and mid-term benefits ofendovascular abdominal aortic aneurysm repair versus open repair.The success of these new stent-graft devices results from better adaptation andimproved performances in challenging anatomies and better trackability of deliverysystems.TM  stent-graft device.TM tip sleeve within the suprarenal bare-stentanchoring pins or within other endograft and native vessel segments, in order toavoid emergency conversion to open repair and the potential for adverseoutcomes.A recent report highlighted the application of troubleshooting techniques to overcome‘pitfalls’ in some of the steps of EVAR with the EndurantThis stent-graft is a new fourth-generation device comprising a high-densitymultifilament polyester graft material of low porosity, externally supported by anelectropolished nitinol stent structure and loaded in a low-profile hydrophiliccoating delivery system. The seals of the European Union (EU) as well as Food andDrug Administration (FDA) approval for this device were received in July 2008 andDecember 2010, respectively.TM stent-graft is designed to enhance performance in AAApatients with straightforward (friendly) or challenging (hostile) anatomies. Itshigh flexibility and conformability enables the device to adapt to straight as wellas severely tortuous proximal aortic necks and challenging iliac artery anatomies.These stent-grafts have a sinusoidal M-shaped architecture with a small amplitudeproviding optimal sealing in short and angulated proximal aneurysm necks.Furthermore, the M-shaped proximal stent at the upper pole of the endograft bodyfacilitates enhanced wall apposition, minimising the risk of in-folding andproviding another 5 mm of sealing zone.The EndurantTM stent-graft relies on proximal active fixation,incorporating a suprarenal bare stent ring with anchoring pins of increasedflexibility, compared to earlier generation stentgrafts. Initially covered by thetip sleeve, the suprarenal stent with anchoring pins provides controlled release andsecure fixation. The radiopaque markers at the proximal and distal edges of thestentgraft as well as the flow divider and contralateral gate markers ensureaccurate positioning of the device. Apart from a more flexible main body, the limbstent and optimal stent spacing offer more distal longitudinal flexibility and aredesigned to prevent kinking and provide refined adaptation to tortuous iliacarteries.The EndurantFinally, the graft delivery system is reduced by approximately 3 French (Fr) sizesfrom the smallest prior endograft delivery system. It is available in outerdiameters from 18- to 20-Fr for the main body and from 14- to 16-Fr for theextensions. Bifurcated main body proximal diameters include sizes of 23, 25, 28, 32and 36 mm; limb diameters include sizes of 10, 13, 16, 20, 24 and 28 mm. Thediameter of the stent-graft is oversized by approximately 20% in relation to theouter aortic diameter at the proximal fixation zone and about 10% in the distallanding zones .TM system has resulted in an improvedversion. Endurant® II provides three additional advanced design features: (1) a35% extended hydrophilic coating allows the 28-mm-diameter bifurcated component tofit inside an 18-Fr outer diameter catheter ; (2) availability of two new contralateral limb lengths (156 and 199 mm)enables more configuration options and requires fewer total components; and (3)improved radiopacity of the distal end of the bifurcated component’s contralateralgate increases visibility. The Endurant® II device received FDA approval in June2012.Recently, renovation of the EndurantTM stent-graft is deployed and the delivery system advancedproximally as far as 3 cm apart from the suprarenal stent [see manufactureinstructions for use (IFU) for system details]. The next step is very crucial andfailure to withdraw the delivery system until the spindle is retracted into thefabric portion of the stent-graft results in trapping of a suprarenal crown withinthe tapered tip sleeve.This scenario assumes that the main body of the bifurcated component of theEndurantTM stent-graftsystem may be followed accurtely, in some cases, especially severe angulated necks(≥ 60°), the markedly flexible delivery system will follow the aortic configurationand stack within the hooks of the suprarenal stent. To avoid the need for openconversion, three simple techniques to successfully remove the delivery system ofthis endograft are described:Even though the steps described in the IFU for the EndurantTM, Ontract, ArcherTM or Lunderquist)inside the delivery system, and then rotationally withdraw the deliverysystem. Removing the wire allows the graft to follow the natural aorticanatomy. Under straightforward circumstances, the device may bend along thebody–ipsilateral endograft, possibly avoiding stacking at the level of theanchoring pins.• The first action is to completely remove the stiff or superstiff guide wire the molding balloon at the pins’ level prior to downwardremoval of the delivery system • When compelling anatomical conditions exist, another option is to place alarge introducer sheath (e.g. Cook 16- or 24-Fr), through the alreadycatheterised docking limb, advancing above the suprarenal stent beforedelivery system withdrawal. This manoeuvre leads to aorto-iliac axis‘technical remodelling’ with further proximal neck straightening, acondition that may help to alter the path that the system follows whenrotated downwards for removal. The proximal neck might also be straightenedafter placing a super-stiff or extra-stiff guide wire from the left brachialartery and through the endograft to exit from the contralateral femoralside.• The last option replaces the guide wire with a snare device that isintroduced through a 7-, 12- or 14-Fr sheath via the left brachial arteryaccess, and captures the spindle while simultaneously retracting thedelivery system with slow rotational movements In this situation the delivery system moved slightly upwards. The troubleshootingtechnique includes first deployment of the contralateral limb in the standardfashion, followed by insertion of a moulding balloon , which is inflated in the same manner as required to push the deliverysystem to the ipsilateral endograft wall, when the latter is retracted slowly Two moulding balloons  are required in thissituation. They are inserted through a 14-Fr Cook introducer sheath from thecontralateral site after the contralateral limb is completely liberated and dilated.One moulding balloon is positioned above the flow divider and the second one at thebody-to-contalateral limb overlapping area. They are simultaneously dilated and keptin a constant position, thus stabilising the endograft while the delivery system iswithdrawn from the ipsilateral limb The same concept may be applied with a larger balloon coming from above through theleft brachial artery. In this case the balloons are inflated and retracted inopposite directions. This bidirectional balloon retraction allows more powerfuldownward movement of the delivery system.The only way to avoid open conversion in this scenario is to perform a balloonangioplasty of the external iliac artery. Catheterise the delivery system, insert asecond 180-cm (0.035-inch) hydrophilic wire between the delivery system and thearterial wall, and place it into the aneurysm sac TM trapped delivery systems should prove especially usefulfor procedures involving adverse proximal aortic necks and iliac anatomies. It isimportant to remember that hostile infrarenal aortic aneurysm anatomy such as a veryshort, severely angulated or dilated proximal neck still remains a major cause ofearly failure of EVAR and jeopardises long-term efficacy.Improvements in the endovascular stent-graft design, device delivery and deploymentcharacteristics have all resulted in increased use of EVAR for not onlystraightforward cases but for those with more complex and challenging aneurysmanatomies. The tips and tricks presented in this report regardingEndurantIntroduction of new endograft devices into the vascular realm will most likely expandthe indications for procedures once considered not feasible in the past. Anatomicalmorphology and measurements of the aneurysm will be crucial to device selection, anddevice choice critical to the successful positioning and adaptation of thestent-graft to the aneurysm environment for its exclusion from the circulation.TM stent-graft is part of a next-generation system that wasdesigned with the clear intention of expanding the applicability of EVAR for AAA.Initial clinical experience has demonstrated that it can be used in challenginganatomies and can be delivered and deployed safely, even in highly angulated (> 60°)and short (< 15 mm) proximal necks.TM device remains to be demonstrated, intra-operativeperformance of this endograft in hostile aneurysm morphology adds valuableinformation to other recently reported clinical short- and mid-term results.12The Endurantshort < 1 mm proxiulated > 0°and shshort < 1 mm proxiTechnical manoeuvres may occasionally be required in difficult anatomies in order toavoid severe complications. Although not confirmed in all Endurant clinicalstudies,In a recent study, comparing the performance of the newly released Edurant II®endograft in patients with friendly and hostile infrarenal aortic anatomy eligiblefor EVAR, the necessity of troubleshooting techniques was significantly higher inthe hostile group.10Its easy, accurate and controlled deployment, coupled with its unique highflexibility and conformability contributes to its successful use, even in severelyangulated proximal necks and/or iliac arteries. Friendly and hostile groups hadequal performance regarding all primary outcome measures, suggesting that expandedEVAR indications can be applied with this stent-graft.TM delivery system becomes trapped inthe suprarenal stent anchoring pins or other graft segments. While this report iswritten specifically for the EndurantTM device system, lessons gleanedare applicable to similar endograft systems.The tips and tricks presented in this report should prevent or reduce conversion toan open procedure when the Endurant


CD4+ T cells are central to the induction and maintenance of CD8+ T cell and antibody-producing B cell responses, and the latter are essential for the protection against disease in subjects with HIV infection. How to elicit HIV-specific CD4+ T cell responses in a given population using vaccines is one of the major areas of current HIV vaccine research. To design vaccine that targets specifically Chinese, we assembled a database that is comprised of sequences from 821 Chinese HIV isolates and 46 human leukocyte antigen (HLA) DR alleles identified in Chinese population. We then predicted 20 potential HIV epitopes using bioinformatics approaches. The combination of these 20 epitopes has a theoretical coverage of 98.1% of the population for both the prevalent HIV genotypes and also Chinese HLA-DR types. We suggest that testing this vaccine experimentally will facilitate the development of a CD4+ T cell vaccine especially catered for Chinese. Over 30 million people have died from HIV/AIDS related illnesses since HIV was discovered in the 1980s. There are currently 33 million of HIV carriers . Highly Env, Gag, and Pol) and regulatory  genes. The pol gene encodes for reverse transcriptase which is error prone. This leads to high mutation rate, 15–20% divergence between the nucleic acid sequences of different HIV clades, and 7–12% variability within each clade [HIV genome is comprised of nine structural  and AIDSVAX . These vaccines are theoretically capable of eliciting both CD8+ T cell response and neutralizing antibody response. Despite neither vaccine worked alone, in the combination, they unexpectedly lowered the HIV incidence by 31.2% in vaccine recipients; however, they did not reduce viral load [Due to the extreme sequence diversity and high mutation rate of HIV, it has been difficult to develop an efficacious HIV vaccine. A successful HIV vaccine requires inducing neutralizing antibodies and cytotoxic T cell responses, both of which can only be optimally induced and maintained in the presence of a concurrent CD4+ T helper cell response . Despiteesponses , 10. Desesponses . Later iIn order to stimulate a CD4+ T helper cell response, antigens need to be processed and presented through MHC class II molecules. The form of antigen could be either whole protein or peptide epitopes. A previous study with a subunit vaccine comprised of 18 CD4+ T helper cell epitopes has demonstrated an efficient induction of robust helper T cell response in a Phase I clinical trial in Caucasian population . WhetherTo select antigenic epitopes for a vaccine, one must address several issues. One, HIV exhibits high mutation rates, and thus conserved sequences may be needed to cover a given population. Two, the human leukocyte antigen (HLA) is highly polymorphic, and it restricts the proportion of individuals who will respond to a particular antigen , 15. To α and a highly polymorphic β chain. There are over 400 class II alleles identified, spreading among HLA-DM, HLA-DO, HLA-DP, HLA-DQ, and HLA-DR loci. Among them DRB1 is the most polymorphic gene, consists of 221 alleles; followed by DPB1 and DQB1 that has 84 and 39 alleles, respectively. Whereas other gene loci may have only 1 or 2 alleles [MHC class II is a heterodimer that is comprised of a monomorphic  alleles . Therefo alleles . The aboTo overcome these complex issues of vaccine design, bioinformatics methods may help to determine common features of vaccine antigens that have potential to deal with divergent population and HIV quasispecies. Specifically, bioinformatics-based approach is the most feasible method in screening a large set of peptide epitopes and selection of promising vaccine antigens. In this study, we extracted 821 HIV sequence and 46 Chinese DRB1 alleles from public information and compiled a database. A combination of 7 public available epitope prediction algorithms was used to screen the database and identify CD4+ T cell epitopes as HIV vaccine antigens. We selected a set of 20 epitopes, which in combination could cover more than 98% of our target population.http://www.hiv.lanl.gov/) [http://www.allelefrequencies.net/) [In total, 821 HIV whole genome sequences of Chinese population were retrieved from HIV Database (nl.gov/) , and thees.net/) .Seven existing methods available in Immune Epitope Database (IEDB)  for MHC 50 = 500 nM or below. A selected epitope was removed from the epitope pool before the next prediction. The process is repeated until all epitopes were selected. All calculations of epitope selection process were conducted in INFORSENSE Knowledge Discovery Environment (KDS) software platform [All epitopes are 15 amino acids in length. To be a potential epitope, it must have a MHC binding affinity threshold of ICplatform . The matα represents the epitope; C(j) is the percentage coverage of number j DRB1 allele; δ(α) is the function to indicate whether the epitope exists in the combination of HIV sequence and DR allele, existence scored 1, and absence scored 0. S(α) is the sum of number of times of the binding of HIV sequence i and DR allele j after being standardized to the proportion of DR allele j in all DRB1 alleles. All DRB1 alleles included in the study cover 95.2% all Chinese HLA-DR alleles [In the first equation  alleles .50 was considered. Next, we ranked all epitopes based on the coverage score . After an epitope has been selected, it was removed from the database before next selection. This process was repeated until 20 epitopes were selected. The workflow diagram of this procedure was illustrated in We selected epitopes from a combined pool of epitopes through KDS platform using 7 prediction methods from IEDB with a dataset that consisted of 821 circulating HIV genome sequences in China and 46 Chinese HLA-DRB1 alleles. The epitopes bind to MHC class I molecules that were removed first, and then the value of ICA total of 46 HLA-DR alleles were identified from AFND . The allWith a combination of 7 existing epitope prediction methods in IEDB, using database comprised of 46 different DRB1 alleles and 821 full genome sequences of HIV isolates circulating in China, we then predicted 38,460,402 potential epitopes. After duplicates were removed, 21,007,527 potential epitopes remained. We scored these epitopes based on the allele coverage and total coverage score, which was in general normally distributed. As shown in  gag, env, pol, and nef genes. Six of them were in gag gene, 6 in env, 2 in pol, and 6 in nef.By using the methods described above, we obtained 20 epitopes, which in theory covered all 46 DRB1 allelic genotypes and 821 Chinese HIV sequences . All 20  gag, pol, env, and vpu genes. One published epitope that has a HIA binding IC50 above our threshold of 500, Env 566 IKQFINMWQEVKAMY, was not listed. For these epitopes, HIV coverage is from 2% to 43%, DR coverage is between 35% and 98%, and specific coverage is at highest of 41% and in sum of 69%.We then applied the new method to a previously published HIV vaccine comprised of T helper epitopes and tested in clinical trial . The tabIn this paper, we described a novel method for designing a peptide-based T helper cell vaccine for HIV, which is specific for Chinese HIV strains and Chinese MHC class II genotypes. The current method has several advantages. First, our methodology of epitope prediction is easily accessible to public use. In fact, it is a combination of all seven existing methods publically available in IEDB. The IEDB database comprises a series of most up-to-date and evidence based methods specifically created for the prediction of MHC restricted T cell epitopes. In contrast to other studies that only used one of the methods, we used them all for more accurate prediction of MHC class II restricted T helper epitopes.50 value, to determine epitopes. The other relies on machine learning, and NN-align and NetMHCIIpan methods belong to this category. New sequences are subjected to computer simulated models to predict whether any epitopes can bind to a particular MHC II to high enough affinity. The third type combines several methods together to predict epitopes. These include Consensus method and ComLib method.So far, there are three major types of bioinformatics methods for the prediction of MHC class II restricted T helper cell epitopes. One is called matrix alignment algorithm, and these are SMM, ARB, and Sturniolo methods. This algorithm uses published T cell epitopes and their respective binding affinity to MHC class II, in terms of the ICConsensus method was reported to provide highest true positive rate, followed by NN-align and ARB . NetMHCI50 value as a filter to select T cell epitopes that have the broadest population coverage. Our method did not use all 8 IEDB recommended methods but integrated 7 of the IEDB methods because the 8th IEDB method is an integration of the other seven and thus not an independent measurement. The method we used could be considered as “greedy” algorithm in the bioinformatics field, which predicts the best epitope among all in a pool of potential epitopes. Thus, we believe an integrated method that uses a combination of all seven original algorithms might be the best to predict more accurately MHC class II epitopes.In this study, we used all above seven methods simultaneously, scored the potential epitopes independently, and then used ICAnother unique feature of our study is that we designed candidate helper T cell vaccine targets specifically to the Chinese population. Most common world circulating HIV subtypes are B and C, and recombinant forms are AE and AG. In contrast, the common subtypes are B and recombinant forms are BC and AE in China , 39, 40.In comparison to a previous paper that selected MHC class II binders according to the binding affinity to multiple HLA-DR subtypes , we focuOne limitation in our study, as shown in By using our method, we obtained 20 helper T cell epitopes which covered 98.1% of HIV strains known to have been circulating in China and all Chinese HLA-DR genotypes. There are limited studies that have tested designed peptide T helper vaccine in humans. In a published paper that contains 18 T helper epitopes , our comWIILGLNKIVRMYSP was reported to stimulate strong CD4+ T responses [WIILGLNKIVRMY exhibited superior HLA-DR binding capacity [ nef gene but not vpu gene, whereas Walker's study did not cover nef but vpu. These comparisons suggest that a vaccine designed predominantly for Caucasian may not be optimal for Chinese population. One epitope, for instance, Env 566 (IKQFINMWQEVKAMY) [There was one core epitope WIILGLNKIVRMY, appeared in both studies, showing very high HIV, HLA-DR, and specific coverage. The Gag epitope with two amino acids modification esponses ; anothercapacity . AnotherQEVKAMY) , given iOur method predicted epitopes, in theory, together covered 98.1% of HIV-1 genome and Chinese specific DRB1 alleles. In comparison, Walker's study reported 18 T helper cell epitopes that cover 100% of the global population. By using a prediction algorithm which based mostly on HLA supertypes . HoweverThe allele coverage of DRB1 for Chinese was based on 1704 subjects of whom 1569 were from mainland China and 135 were from Hong Kong and Singapore. All Chinese allele data regarding DRB1 frequencies were extracted from AFND, and all 1704 subjects were Chinese Han ethnics. There is no information on other minor national groups in China available. This may lead to inaccuracy in prediction of helper T cell epitopes for the Chinese. Larger sample size may improve the quality of our prediction.In this study, we report a novel bioinformatics method for designing peptide epitope based T helper vaccine for HIV. We suggest further in vitro and in vivo experiments to be performed to test the immunogenicity of this vaccine and improvement of method of prediction to be made when necessary.


Cystinosis is a rare lysosomal disorder leading to end stage renal disease in more than 90 % of patients before 20 years of age. Data about safety and efficiency of renal transplantation in patients with cystinosis is scarce. We evaluated long-term outcomes of renal transplantation in adult patients with cystinosis.n = 31) in 30 adult patients with cystinosis in 5 French university transplant centers between 1980 and 2013 were retrospectively analyzed. A control cohort of 93 patients was matched for age, graft date, living/deceased donor status and transplant center.Data of renal transplantation (p = 0.013). Multivariate analysis confirmed that cystinosis was an independent protective factor for graft survival (Hazard Ratio (HR) 0.11; CI95 [0.02-0.61]). Specific complications of cystinosis occurred during follow up: diabetes mellitus (n = 4), hypothyroidism (n = 1), liver involvement (n = 1), neurologic involvement (n = 2). Proportion of post-transplant diabetes mellitus (PTDM) was not statistically different in cystinosis group compared to control group: 4 (13.0 %) compared to 5 (5.0 %), respectively (p = 0.25), with no differences regarding calcineurin inhibitors and steroids treatments during follow-up.Median age at transplantation was 20.4 years (7–36.5). At transplantation, all patients with cystinosis had corneal cystine deposits, 3 had diabetes and 7 had hypothyroidism. Graft survival was better in patients with cystinosis than in control patients (Renal transplantation appears to be safe with excellent long-term outcomes in patients with cystinosis. These patients may receive standard immunosuppressive regimens with steroids and calcineurin inhibitors. CTNS, was identified in 1998 [Cystinosis is a rare autosomal recessive lysosomal disorder with an estimated incidence of 1 per 100 000 to 200 000 live births[ in 1998 , 4. Cyst in 1998 . All org in 1998 , an incr in 1998 ,and acti in 1998 .Clinical symptoms generally appear several months after birth and kidney involvement is the most serious clinical event, because it leads to end stage renal disease (ESRD) before the age of 20 in more than 90 % of patients , 9. NeveSystemic treatment with a cystine-depleting agent, cysteamine, delays the time between diagnosis and the onset of ESRD, but is not sufficient to prevent ESRD . Renal tHere, we report the long-term outcome of kidney transplantation in adult cystinosis patients in a multicenter French cohort.Thirty adult cystinosis patients who received a kidney transplant at one of five French university centers were included in this retrospective study. A control cohort of 93 patients was established from the French database DIVAT (Données Informatisées et VAlidées en Transplantation) , with cyFor deceased donor, extended criteria donor (ECD) was defined as: donor > 60 years old, or donor between 50 and 60 years old with at least hypertension, serum creatinine > 1.5 mg/dL or death of cerebrovascular cause . StandarLeukocyte cystine levels, reported as nmol hemi-cystine/mg protein were centrally measured (Dr Chadefaux-Vekemans) using liquid chromatography-tandem mass spectroscopy  with previously described methods . Normal t-test was used to compare quantitative data, and the Fischer exact test was used to compare qualitative data. Kaplan-Meier curves with a log-rank test were performed for the survival analysis. A multivariate Cox model was secondarily used to identify factors associated with graft survival. A p-value < 0.05 was considered significant.Quantitative data are expressed as median (range). Statistical analysis was performed with GraphPad Prism 5 software . The Student We collected data from 31 renal transplantations performed in 30 patients with cystinosis between 1980 and 2013 and established a control cohort of 93 patients who underwent renal transplantation during the same period.p < 0.001).Median age at transplantation was respectively 20.4 (7.1–36.5) and 21.8 (13.6–32.0) years for patients with cystinosis and controls. Rate of adolescent patients younger than 19 at transplantation was significantly higher in cystinosis than in control group , urinary tract malformations or vesico-ureteral reflux , renal genetic disease excluding cystinosis , hemolytic and uremic syndrome  or unknown cause .Causes of ESRD in the control group were glomerular disease  had diabetes mellitus, and 7 (22.6 %) had hypothyroidism.CTNS gene. The remaining patient had a mutation that partially impaired protein function (late-onset cystinosis).All but one patient with available genetic data (20/30 patients) had loss of function mutations in the p < 0.05), respectively. Proportion of extended criteria donor was similar in both groups (3.2 % in both groups). Proportion of patients with donor specific anti-HLA antibody was similar in both groups.Nine (29.0 %) cystinosis patients and 26 (28.6 %) control patients received a kidney from a living donor. Median deceased donor age was respectively 30.0 (0.6–64) and 37.0 (10–62) years for patients with cystinosis and control patients (p = 0.006)Induction treatment was similar in both groups excepted for azathioprine .The proportion of patients who underwent a preemptive transplantation tended to be higher in the cystinosis than in the control group: nine (29.0 %) vs12 (13.0 %) patients, respectively, 2, respectively (p = 0.18).During a median follow-up of 144.1 months (5.9–340.6) in the cystinosis group and 72.0 months (0.1–240.0) in the control group, 6 (19.4 %) and 29 (31.0 %) patients respectively developed ESRD. Median eGFR (MDRD) at 180 months tended to be higher in cystinosis group compared to control group: 53.7 (19.0–103.0) and 47.4 (7.7–111.4) ml/min/1.73 mAt the end of follow up, patient survival was 97.0 and 98.0 % in the cystinosis and the control group, respectively.p = 0.01), even when excluding patients with recurring diseases .The proportion of patients experiencing graft rejection or infection was similar in both groups (Table p = 0.7). Cellular rejection was involved in 62.5 % of rejections in the cystinosis group and 60 % of rejections in the control group. Antibody mediated rejection occurred in only three patients with cystinosis and six control patients. Resistance to treatment was similar in both groups .Graft survival at 5 and 10 years was 92.0 and 86.5 % in cystinosis group, respectively, and 86.0 % and 72.0 % in control group. Graft survival was significantly better in cystinosis group than in control group  and graft survival.The following parameters were selected for multivariate analysis of factors influencing graft survival Table : sex, cyA protocol biopsy was performed one year after transplantation in 13 patients with cystinosis and cystine crystals were observed in the renal biopsy from only one patient Fig. . Howeverp = 0.25). The median time to diabetes onset was 78 months (3–180) in the cystinosis group, compared to 3 months (0.1–187) in the control group. The prevalence of vascular complications was also similar in the two groups: one patient with cystinosis had a stroke 3 years after transplantation, whereas one control patient had a myocardial infarction 2 years after transplantation.Proportion of post-transplant diabetes mellitus (PTDM) was not statistically different in cystinosis group compared to control group: 4 (13.0 %) compared to 5 (5.0 %), respectively (p = 0.1), with similar proportion of patients treated by ciclosporine A and tacrolimus (Table p = 0.6).Maintenance treatment was similar in both groups: in particular, calcineurin inhibitors were given to 29 (93.0 %) cystinosis patients and 74 control patients (79.0 %) p = 0., with sin = 4), hypothyroidism (n = 1), hepatic complications (n = 1) and neurological involvement (n = 2). Neurological complications consisted in progressive distal myopathy in two patients, leading to interdigital amyotrophy. One of these patients also had restrictive pulmonary disease and swallowing dysfunction. The other patient had pseudo-ischemic stroke lesions on magnetic resonance imaging (MRI). He presented 3 years after transplantation with behavioral disorder without any motor or sensitive deficiency. MRI revealed T2 hyperintensity in the middle cerebral artery territory, but MR angiography did not showed any evidence of vessels stenosis. Carotide artery doppler was normal. In this context, cystinosis-related encephalopathy was suspected. The patient with hepatic involvement presented with cholestasis.. Ultrasound liver examination found moderate portal hypertension, without bile duct dilation or mass. Antibodies against smooth muscle, actin, mitochondria liver kidney molecule (LKM), and soluble liver antigen were negative. There was no infection for HBV, HCV or HIV. There was no iron overload. No liver biopsy was performed but cholestasis was probably related to cystinosis.Complications associated with cystinosis occurred during follow up, including diabetes mellitus  at day 0, and 1.9 (0.5–10.0) during follow up (objective below 1). All patients who developed cystinosis complications had cystine leukocyte content above 2 at the time of the complication.One patient developed cavum post transplantation lymphoproliferative disorder, successfully treated with chemotherapy. One patient experienced ankle melanoma successfully treated with surgery.We report, to our knowledge, one of the largest cohorts of adult patients with cystinosis undergoing renal transplantation with long-term follow up. Cysteamine therapy has greatly improved the prognosis of cystinosis, and delayed the onset of end-stage renal disease, but is not sufficient to avoid dialysis , 15, 20.n = 44) was 86% at the era of cysteamine therapy [p = 0.01) and 53 % of patients with cystinosis have a functional graft at 340 months of follow up. We confirmed, by multivariate analysis, that cystinosis is an independent protective factor for graft survival.In pediatric cohorts, the outcome of kidney transplantation in patients with cystinosisis generally better than that for other patients undergoing transplantation , 21. Ind therapy . Here, wp < 0.05), but this small difference is unlikely to explain the large difference in long-term graft survival. Actually, the proportion of well-defined standard criteria donor was strictly similar in both groups. We compared patients with cystinosis with age-matched control patients, including the usual renal diseases observed at this age: 9 control patients (9.7 %) had a renal disease with potential recurrence in the transplant: 7 had primary focal and segmental glomeruslosclerosis and 2 had hemolytic and uremic syndrome. These diseases are known to have bad prognosis after kidney transplantation, and could participate in the long-term difference in graft survival we observed. But, after exclusion of these 9 patients, we confirmed that graft survival was better in patients with cystinosis than in control patients. Furthermore, multivariate analysis including recurring disease in the analysis, confirmed that cystinosis was an independent protective factor for graft survival.Interestingly, preliminary unpublished data suggest that the mTORC1 pathway is down-regulated in cystinosis patients, which may explain the very good long-term outcome of renal transplantation in these individuals, and the previously suggested better immune tolerance of patient with cystinosis . In our We confirmed that ABMR is a pejorative factor. However, surprisingly, immunization tended to be a protective factor, but statistical significance was not reached. These data are probably not clinically relevant, since our cohort is too small.We also found that the rate of patient survival was excellent (97.0 % at 10 years), whereas prognosis in the ANZDATA study was poorer, with 88 % survival at 10 years in patients treated with cysteamine . HoweverOne of the limits of our study is that patients with cystinosis have been followed longer than controls . Indeed, because cystinosis is a rare disease, patients may be followed longer in tertiary centers, introducing bias into the very long-term data. However, a longer follow-up, as well as a more important proportion of adolescent patients in cystinosis group, should drag survival data down. Indeed, it has been shown that adolescent patients have lower rate of graft survival compared to other age groups . FurtherProximal tubular disease does not occur in the transplanted kidney because cystine lysosomal efflux transport system is functional in the engrafted kidney. However, retention of a native kidney can result in the persistence of renal tubular Fanconi syndrome. Interestingly, one year after transplantation, one patient developed cystine crystals in the transplanted kidney, which were diagnosed on protocol biopsy. Nonetheless, the outcome of renal transplantation in this patient was excellent, and serum creatinine was 186 μM more than 20 years after transplantation. Indeed, protocol biopsies have shown that cystine crystals may be deposited within the interstitial tissue and less frequently within glomeruli without any clinical or biological manifestations. These crystals are present in the host’s own mononuclear cells which have subsequently infiltrated the transplant , 27.Renal transplantation does not correct the systemic metabolic defect of cystinosis and cystine continues to accumulate in most organs and will lead to late systemic complications. In particular, the cystinotic process is known to gradually alter beta-cell function over the years . BecauseTwo patients developed neurological complications of cystinosis during follow up, with myopathy leading in one patient to a restrictive pattern of chronic respiratory failure. These neurological complications were first described many years ago, but their incidence after transplantation and the effectiveness of cysteamine therapy in preventing them are poorly documented , 30.All cystinosis-related complications during follow up occurred in patients with high cystine leukocyte content, showing that maintaining cysteamine treatment is critical for the management of these patients. We recommend regular monitoring of cysteine leukocyte content and treatment with cysteamine must be continued to maintain cystine levels below 1 nmol hemicystin/mg of protein.In summary, we report that the long-term outcome of cystinosis patients undergoing renal transplantation is excellent. Furthermore, our findings show that renal transplant recipients with cystinosis have a better long-term outcome than other renal transplant recipients, and that cystinosis is an independent protective factor for graft survival. The moderate risk of post-transplant diabetes mellitus does not necessitate the use of specific immunosuppressive agents in cystinosis patients. Our work supports recently published consensus guidelines for the diagnosis and treatment of cystinosis . AlthougAll procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the 'Declaration of Istanbul on Organ Trafficking and Transplant Tourism’.


The torque sensor is used to measure the joint torque of a robot manipulator. Previous research showed that the sensitivity and the stiffness of torque sensors have trade-off characteristics. Stiffness has to be sacrificed to increase the sensitivity of the sensor. In this research, a new torque sensor with high sensitivity (TSHS) is proposed in order to resolve this problem. The key idea of the TSHS comes from its 4-bar linkage shape in which the angular displacement of a short link is larger than that of a long link. The sensitivity of the torque sensor with a 4-bar link shape is improved without decreasing stiffness. Optimization techniques are applied to maximize the sensitivity of the sensor. An actual TSHS is constructed to verify the validity of the proposed mechanism. Experimental results show that the sensitivity of TSHS can be increased 3.5 times without sacrificing stiffness. Industrial robot manipulators have been widely used to improve productivity in various industries such as automotive, electronics and shipbuilding. To increase the intelligence of the robot manipulator, many kinds of sensors have been developed. Among these, sensors to measure force and torque have been increasingly used in robot manipulators. These sensors can improve the performance of the robot manipulator .1 −T6T are the torque at the joints of the manipulator. z, Fy, Fz, Tx, Ty, TzF are forces and torques at the end effector of the manipulator. J is the Jacobian matrix of the manipulator.Forces and torques of end effector and joint torques are related by the Jacobian matrix as follows (1)Γ=JTFAs shown in On the other hand, joint torque sensors b measureNowadays, more and more robots are working together with people. These kinds of robots should have safety functions to prevent collision accidents in an unstructured real environment . Safety-There are many previous studies on joint torque sensors. In previous research studies, the sensitivity and the stiffness of torque sensors have trade-off characteristics. To increase the sensitivity of the sensor, the stiffness has to be sacrificed. High torsional stiffness is important because the deflection by sensors adds position errors that cannot be compensated by the joint servo controller. However, it is desirable to design a sensor structure that generates a large strain for a given payload to increase the Signal-to-Noise (S/N) ratio and sensitivity of the sensor. Therefore there are two conflicting requirements: high stiffness and high sensitivity for torsion. In this paper, a new torque sensor with high sensitivity (TSHS) is proposed to resolve this problem.This paper is organized as follows. In To increase sensitivity without sacrificing stiffness, a new torque sensor with high sensitivity (TSHS) is proposed as shown in 4 rotates F at point P34 of the 4-bar linkage. The motion is transferred to the short link L2 by connecting link L3. If 2 , the angular velocity ratio is as followsThe angular velocity ratio theorem can be used to obtain the angular velocity ratio . In the 12P24A and triangle P14P24B are similar triangles. The angular velocity ratio can be obtained as follows2 and l4 are the length of each link L2 and L4 respectively, and In the 2 is thinly designed. Links receive a bending moment as well as compression/tension forces. Bending by 2 is larger than that of L4.The 4-bar linkage shape of TSHS is different from the ideal 4-bar linkage mechanism. There are no real joints. If the links are too strong, amplification by the 4-bar linkage shape does not work. Hence, L2 of the 4-bar linkage shape while the stiffness of the torque sensor is proportional to the angular deformation of the sensor. The sensitivity and stiffness of the torque sensor are defined as follows2 of the 4-bar linkage shape, z is the external moment. The performance index When the external moment force is loaded on the torque sensor, the sensitivity of the torque sensor is proportional to the strain on the strain gauge attached to short link LThe joint torque sensors are usually assembled with reducers. The stiffness of the joint is related with not only the torque sensor but also the reduction gear and the link. The characteristics of the entire joint is another research topic. In this paper, the stiffness of the torque sensor is discussed. Torque sensors are matched with the reduction gear with rated torque of 40 Nm (harmonic driver SHG-32-80-2UH) .The boundary condition of the TSHS is defined as shown in 3. In this paper, FEA software ANSYS [The material comprising the sensor is hard aluminum alloy AL6061-T6. The material parameters are as follows: the elastic modulus re ANSYS  is used The TSHS has many design variables and the sensitivity of the TSHS is related to these variables. The optimization by the ANSYS software is used to maximize the sensitivity of the TSHS. The ANSYS optimization routines use three types of variables that characterize the design process: design variables (DV), state variables (SV) and objective variables (OV). These variables are represented by scalar parameters in the ANSYS Parametric Design Language (APDL) . Figure In this paper, a 3-beam torque sensor and the TSHS are compared. Fixed parameters and design variables (DV) of the two models are shown in To improve the sensitivity without reduction of the stiffness of the torque sensor, the strain After optimization to improve the sensitivity of the torque sensor, the optimal design of both the TSHS and FEA results are shown in The actual 3-beam torque sensor and TSHS are both constructed to verify validity of the proposed mechanism as shown in To verify the FEA result of By analyzing the data of the FEA and the experimental results, the ideal strain, the FEA strain and the experimental strain with respect to the torque input can be obtained as shown in In this paper, in order to improve the sensitivity of torque sensors without compromising stiffness, a new concept of torque sensor with high sensitivity (TSHS) is proposed. The key idea of the TSHS comes from the 4-bar linkage in which the angular displacement of the short link is enlarged. Because the part of the sensor related to the sensitivity is separated from the part related to the stiffness of the sensor, the sensitivity can be improved without decreasing stiffness.The proposed mechanism is analyzed by FEA using ANSYS. To maximize the performance of the sensor, the proposed mechanism has been optimized. The actual TSHS is constructed to verify validity of the proposed mechanism.The sensitivity (strain) of the TSHS is 3.5 times higher than the sensitivity of the 3-beam torque sensor. The deflection of the TSHS is also reduced by 7%. That means that the stiffness of the TSHS also increased. The performance index As a further study, this concept of the TSHS can be extended to research multiple DOF torque/force sensors.


The now well-known Zollinger-Ellison syndrome was recognized by Professor Zollinger at Ohio State University and his student, Dr. Ellison, based on their insightful observations of two young women who suffered from refractory peptic ulcers requiring repeated surgery . The indIn addition to the outstanding case reports mentioned above, there have been a number of amazing discoveries made by surgeons in their daily practice. Sir James Cantlie, a surgeon at the University of Hong Kong, started his anatomical research on the liver after he encountered an autopsy case of a remarkably shrunken right liver and a hypertrophic left liver arising from a liver abscess . Based oSurgical Case Reports, a sister journal to compliment Surgery Today. We welcome surgeons worldwide to submit case reports to our new journal, which will be a completely open-access online journal. I anticipate that our new journal will contribute significantly to the progress of surgery.The Japan Surgical Society has always encouraged young surgeons to submit interesting or educational case reports. Now, we have launched a new case report journal named


Israel Journal of Health Policy Research would like to thank all reviewers, both external and Editorial Board Members, who have contributed to the journal in 2015, and whose valuable support continues to be essential to the success of the journal.The Editors of  David AbramsUSABruria AdiniIsraelArnon AfekIsraelMoty AmarIsraelEric AmsterIsraelEmilia AnisIsraelPaul AppelbaumUSAJonathan ArbelleIsraelNachman AshIsraelShai AshkenaziIsraelToni AshtonNew ZealandAlexander AviramIsraelJudit Bar-IlanIsraelOrna Baron-EpelIsraelYehuda BaruchIsraelEliezer Be'eriIsraelRobert BellmakerIsraelJochanan BenbassatIsraelGabi Bin NunIsraelMarvin BirnbaumUSAHaim BittermanIsraelMalke BorowIsraelShuli Brammli-GreenbergIsraelDanny BromIsraelRonit Calderon-MargalitIsraelDavid ChinitzIsraelGabriel ChodickIsraelSarah ClarkUSAEyal CohenUSAArnon Dov CohenIsraelMarc CohenUnited Arab EmiratesNihaya DaoudIsraelEhud DavidsonIsraelRaz DekelIsraelSarah DineUSAFrancois DionneCanadaMilka DonchinIsraelDon DowningUSAErin DupreeUSAArthur EidelmanIsraelEldad ElnekaveIsraelLinda EmanuelUSARonit EndeveltIsraelLeon EpsteinIsraelDani FilcIsraelDiana FlescherIsraelGary FreedUSADavid GarrUSASaralee GlasserIsraelShimon GlickIsraelSherry GliedUSAAvishay GoldbergIsraelDan GreenbergIsraelPedro Greer JrUSAItamar GrottoIsraelNurit GuttmanIsraelJack HadleyUSAJonathan HalevyIsraelJames HalperinUSAPaul HansenNew ZealandYafa HaronIsraelAnthony HeymannIsraelRosemary HiscockUKOhad HochmanIsraelDominic HodgkinUSAMarcia JavittUSANir KaidarIsraelEddy KarnieliIsraelOrit Karnieli-MillerIsraelDavid KatzIsraelGalit KaufmanIsraelJean KervasdoueFranceYan KimUSAShmuel KlangIsraelEhud KokiaIsraelRichard KravitzUSAMooli LahadIsraelBruce LandonUSALuís LapãoPortugalLeonard LeiboviciIsraelEran LeitersdorfIsraelDebra LernerUSAMoshe LeshnoIsraelHagai LevineIsraelDaphna LevinsonIsraelItzchak LevyIsraelYoram MaaraviIsraelOrly ManorIsraelCarmi MargolisIsraelTalya Miron-ShatzIsraelBrian MorrisAustraliaYehuda NeumarkIsraelMarc NivetUSAJoseph PliskinIsraelLion PolesIsraelRosalind RaineUKNosaiba RayanIsraelShmuel ReisIsraelRonli RotemIsraelAlvin RothUSASiegal SadetzkiIsraelRichard SaltmanUSAStephen SchoenbaumUSASigal Shafran -TikvaIsraelVarda ShalevIsraelJeffrey ShamesIsraelIra SharkanskyIsraelYaniv ShererIsraelFiona SimUKJoann Sperl-HillenUSAShelley SternbergIsraelAviad Tur-SinaiIsraelBaruch VelanIsraelTim WatsonUKMichael WeingartenIsraelShimon WeitzmanIsraelRachel Wilf MironIsraelYael YishaiIsraelDeena ZimmermanIsrael


Degenerative disk disease, reflected as reduction in magnetic resonance T2 relaxation time, was weakly correlated with change in stiffness at low preloads. This study highlights the need to incorporate the observed non-linear increase in stiffness of the spine under high loading rates in dynamic models of spine investigating the effects of a fall on VFx and those investigating the response of the spine to vibration.Models of the dynamic response of the lumbar spine have been used to examine vertebral fractures (VFx) during falls and whole body vibration transmission in the occupational setting. Although understanding the viscoelastic stiffness or damping characteristics of the lumbar spine are necessary for modeling the dynamics of the spine, little is known about the effect of intervertebral disk degeneration on these characteristics at high loading rates. We hypothesize that disk degeneration significantly affects the viscoelastic response of spinal segments to high loading rate. We additionally hypothesize the lumbar spine stiffness and damping characteristics are a function of the degree of preload. A custom, pendulum impact tester was used to impact 19 L1–L3 human spine segments with an end mass of 20.9 kg under increasing preloads with the resulting force response measured. A Kelvin–Voigt model, fitted to the frequency and decay response of the post-impact oscillations was used to compute stiffness and damping constants. The spine segments exhibited a second-order, under-damped response with stiffness and damping values of 17.9–754.5 kN/m and 133.6–905.3 Ns/m respectively. Regression models demonstrated that stiffness, but not damping, significantly correlated with preload ( Vertebral fractures are the second most common fracture site for individuals with osteoporosis , the intervertebral disk joint confers mobility and provides static and dynamic load attenuation to the spinal column , the diagnostic tool of choice for clinical evaluation of spinal pathology  through the Harvard Anatomic Gifts program. Each segment was radiographed  to exclude existing pathology or fractures and then was submerged in a saline bath to simulate soft tissues. Bone Mineral Density (BMD) measured for each vertebra using a DXA scanner  was performed. The donor segments were dissected clean of all musculature, with care taken to leave the posterior structures and ligaments intact, wrapped in saline soaked gauze in plastic bags and then stored in a −20° freezer.2O) and saline, placed under the tubes during imaging, provided quantification of the hydration state of the disks. At the end of the imaging session, the segments were removed and returned to the freezer until the day of testing. This was necessary because of the time constraints of both the imaging and testing.The spines were removed from the freezer, allowed to thaw wrapped in saline gauze at 4°C for approximately 8 h and then vacuum degassed for a period of 8 h in polyethylene tubes filled with saline at 20°C. A GE 1.5 Tesla MR scanner  was used to obtain sagittal T2-weighted (TR/TE:2000/80) ms images and three sets of axial images  ms with a field of view: 150 mm and matrix size:128 × 128. The first and last axial image represented T2-weighted and proton density (PD) weighted images. A series of six phantoms with known volume fractions of heavy water (D2O) quantified using a linear regression.The axial T2 images were analyzed in a custom program  and the cross-sectional areas of the whole disk, the annulus and the nucleus were segmented. For each region, area and average intensity were computed and the mid-disk sagittal images used to measure the anterior, central, and posterior heights of the intervertebral disks, computed as the smallest distance between adjacent bony endplates. From the PD weighted images, relative intensity of disk areas to phantom intensity was computed and hydration level  with the specimens wrapped in plastic to prevent dehydration. The embedded spine was secured to the impact apparatus Figure . For allP0), examined for evidence of structural damage and, if none occurred, the test was repeated for the following compressive preloads; (P1): 30 ± 8 N, (P2): 79 ± 11 N, and (P3): 112 ± 14 N, respectively. To prevent the occurrence of an inadvertent rebound of the pendulum, the pendulum was restrained immediately post-impact. These preloads were applied using an increasing number of 7′′ rubber bands, with the order of preload applications randomized between specimens. This method allowed for free deformation of the spine under impact while keeping the test imposed kinematic constraints to a minimum. Using an FSU analog , preliminary tests found the computed error in the stiffness measurement to be <3% for the stiffness and 9% for the damping . Measurements of the change in stiffness due solely to the use of the rubber bands showed no significant effect on either stiffness or damping measurements at the different preload levels.The spine was first tested with no-axial preload (P0–P3) on the stiffness and damping constants. For each preload group, linear regression was used to test for the correlation between the dynamic stiffness and damping values and the T1 and T2 values and between these parameters and the ultimate failure strength. Statistical significance was set at 0.05.In MATLAB , fast Fourier transform (FFT) was applied to the force signal from the time where the pendulum left the end mass to obtain the peak frequency Figure . A finit2 for the L1–L3 vertebrae  with T2 relaxation correlated with normalized PD measures, i.e., PD/D2O phantom . In the nucleus, PD was negatively correlated with the increase in age (p < 0.05) while being positively correlated with T2 relaxation values . No such correlations were found for the annulus. No statistically significant association were found between BMD values and either the MR parameters or disk geometry , p > 0.05.Vertebral BMD was found to have a [mean (SD)] of 0.72 0.19) g/cm9 g/cm2 fae Table . For ther2 value for a second-order fit was 0.84. Unloaded (P0), the spine exhibited a mean for dynamic stiffness of 135.3 (SD 127.6) kN/m and damping of 372.2 (SD 121.4) Ns/m. Increased preload yielded increased FSU dynamic stiffness;  kN/m, Figure P1: 361.4 (SD 111.3); P2: 383.1 (SD 168.6); and P3: 376.7 (SD 159.9) Ns/m]. Repeated measure ANOVA demonstrated significant differences in dynamic stiffness (p < 0.001) between the four preload groups (P0–P4), but not for the damping coefficients.Under applied impact, the FSU’s showed second-order, under-damped, oscillation Figure . AverageP0: r2 = 0.20, p = 0.05, Figure P3: r2 = 0.36, p < 0.01, Figure For each preload group, Tables Developing accurate dynamic spine injury based models is critical for establishing criteria for prediction of risk of VFx in the elderly and for modeling vibration transmission due to whole body exposure. The stiffness and damping characteristics of the spine are important components in models of impact and vibrational forces on the spine. This study is the first to experimentally investigate the role of preloading on the dynamic response of the elderly intervertebral disk in combination with high-rate loading simulating a fall. With MR being the standard for diagnostic imaging of the degenerative state of the intervertebral disk, the study did support that clinical MR parameters could be used to predict some changes in the dynamic properties of the disk (particularly those at low loads).The stiffness and damping characteristics of the intervertebral disk form a critical component in determining the spine’s dynamic response  to long term (E2) stiffness of the disk (Keller and Spengler, By contrast, higher viscoelastic damping coefficient of the disks demonstrated a stress dependent association with the increase in the estimated hydration of the disk Figure . These fIncreased disk degeneration, underlined by the biological (Bibby et al., in vitro study to the clinical setting. Although Panjabi et al. (This study suffers from the obvious limitations faced when attempting to translate an i et al.  found thi et al. . Axial cIn conclusion, stiffness during impact loading of L1–L3 spine segments was found to range from 17.9 to 755 kN/m and was significantly related to the preload applied. Models existing in the literature currently model the stiffness as a single, linear value. However, a non-linear stiffness component may be necessary to more accurately describe models of impact due to a backward fall in order to reflect the changes of the stiffness at different force levels as seen in this experiment. Degenerative changes in intervertebral disks, measured by decreases in MRI by T2 relaxation time and T2-weighted images, were found to be weakly correlated with stiffness. MR measurement of disk hydration were significantly correlated with the viscoelastic and ultimate strength of the FSU’s, suggesting fluid flow mechanism within the disk and vertebrae to be an important determinant of the ability of the spine to sustain high-rate loading.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.


The adjustment is achieved by changing the effective length of the cantilever by electrostatic pull-in. By applying a voltage between the cantilever and an electrode (with an insulating layer at the point of contact), the cantilever snaps to the electrode, reducing the cantilever’s effective length. An analytical model was developed to find the pull-in voltage of the system. Subsequently, a finite element model was developed to study the pull-in behavior. The working principle of this concept is demonstrated with a proof-of-concept experiment. The electrode was positioned close to the cantilever by using a robotic nanomanipulator. To confirm the change in stiffness, the fundamental resonance frequency of the cantilever was measured for varying electrode positions. The results match with the theoretical expectations. The stiffness was adjusted in situ in the range of 0.2 N/m to 27 N/m, covering two orders of magnitude in one single cantilever. This proof-of-concept is the first step towards a micro fabricated prototype, that integrates the electrode positioning system and cantilever that can be used for actual AFM experiments.The choice on which type of cantilever to use for Atomic Force Microscopy (AFM) depends on the type of the experiment being done. Typically, the cantilever has to be exchanged when a different stiffness is required and the entire alignment has to be repeated. In the present work, a method to adjust the stiffness  The Atomic Force Microscope (AFM) was invented by Binnig, Quate and Gerber in 1986 . An AFM in situ. An example of a potential application is Peak Force® Tapping mode, which is used for simultaneous imaging and Young’s modulus mapping [etc.The stiffness of the cantilever is very important to the type of measurement that needs to be performed; for a different type of measurement a different stiffness is needed . The ran mapping . The sti mapping , which r mapping  which rein situ tunable stiffness probe have been made. Mueller-Falcke et al. designed a switchable stiffness probe [et al. reported a resonance tuning of micro and nano-metric cantilevers by using proportional and differential gains of the oscillation feedback control [et al. presented an AFM probe of which the stiffness can be tuned by changing the second moment of inertia [in situ adjustable stiffness, which is both compatible with conventional AFM systems and has a large tuning range is presented in this paper. Results from analytical, finite element methods and experiments are presented.Earlier attempts to design an ss probe ,11. This control . For one inertia . A piezoE is the Young’s modulus, I the second moment of inertia and The change in stiffness is achieved by reducing the effective length of the cantilever. This is done by placing a parallel electrode close to the cantilever and applying a bias voltage spectrum ,15.et al. [When a voltage is applied, the cantilever will start bending towards the electrode. The mechanical restoring forces will increase linearly with displacement, while the electrostatic force increases inversely quadratic with displacement. When the electrostatic force is larger than the mechanical restoring force, pull-in will occur. This corresponds with the state which is indicated with the dashed line in et al.  and is mE and ν the Young’s modulus and Poisson’s ratio respectively), I the second moment of inertia, The pull-in voltage ( effects : (3)weffIn order to be able to calculate the electrostatic force, an assumption is made on the shape of the cantilever The deflection at the tip A finite element model was developed in COMSOL Multiphysicsz-axis in An experimental setup was developed to prove the change in stiffness of the cantilever. The setup is shown in The shape of the cantilever for a varying voltage is shown in The position of the electrode relative to the cantilever (in-situ by adjusting the effective length. We have adopted electrostatic pull-in method to prove this concept. Modeling of the concept gave a good initial insight into the behavior of the cantilever with electrostatic pull-in (The goal of this work was to show that the stiffness of the cantilever could be adjusted  pull-in . It also pull-in  describe pull-in . HoweverThe high precision nano-manipulator was used to place the electrode very close to the cantilever. The electrode used on top of the cantilever was manipulated by observing the cantilever through a microscope having a top view of the cantilever. A right angle mirror was used to have a side view of the electrode-cantilever system to adjust the gap between them. In ntilever  (see supWith the proposed technique, when operated in real AFM, as the cantilever clamps to the electrode, the effective distance from the cantilever to the photo-detector would change. Hence the optical lever sensitivity will be slightly reduced from the unclamped situation to the clamped situation. This could also lead to change in the laser position on the detector, and may even go beyond the detector zone. However, the cantilever shifts by the same distance for all the clamped situations. Therefore, for all the clamped situations, the optical sensitivity should remain same. Defining two sensitivities would suffice for this method: One for the unclamped condition and the other for the clamped condition. Once the cantilever is clamped, thermal resonance spectra can be measured, and by standard methods like Sader method, the stiffness of the cantilever can be obtained. With this information, the force sensitivity for each stiffness value can be calculated. Another aspect to note is that as the cantilever goes away from the surface, the effective tip height is compromised. One of the solutions could be to slightly change the angle of mounting to minimize the compromised range. This can be integrated in the chip design itself or use an adapter on the mounting stage of the AFM setup.Due to continuous bending of the cantilever, fatigue in the cantilever could be a concerning factor. There are numerous reports showing that fatigue in silicon has resulted in its failure ,20,21. TStiction of the cantilever to the electrode was not observed most of the time. However, in some cases the cantilever was not restored to its unadjusted state after the voltage was released. In order to prevent this, precautions like decreasing contact area by surface roughening, incorporating dimples or chemically modifying the surface with an anti-stiction coating are recommended .et al. by encasing the cantilever inside a hollow structure [For operation in liquids, one of the potential problems that can be foreseen is the principle of electrostatics itself. For biological samples, which are usually kept in buffer solutions, the conductivity of the buffer might influence the intended function of clamping the cantilever. However, the principle should work in non-conducting solutions. One of the potential solution to work in conducting solutions could be to use the method proposed by Ziegler tructure . With a in situ stiffness adjusted cantilever will be to cover the entire stiffness range used in various modes of AFM operation (The concept of a stiffness adjustment in a commercial AFM probe was presented. The change in stiffness was achieved by a change in effective length by means of electrostatic pull-in. Analytical model till pull-in voltage and FEM simulation of the entire working range was presented. An experimental setup was built to prove the concept. By reducing the unadjusted length of a 450 µm long cantilever to 78 µm long in many intermediate steps, the stiffness was shown to change between 0.2 N/m and 27 N/m covering two orders of magnitude in a single cantilever. As the present setup was not compatible with any commercial AFM setup, no real AFM experiments were performed. However, the concept of stiffness adjustment with commercial AFM cantilevers has been proven. The next step would be to design and microfabricate a prototype that integrates the cantilever and a movable electrode in a single device. The ultimate goal of peration  in a sin


During 2011–2012, among children aged 6–17 years, 7.5% overall had been prescribed medication for emotional or behavioral difficulties during the preceding 6 months. By U.S. Census region, the percentages were 9.3% in the South, 8.0% in the Midwest, 6.3% in the Northeast, and 5.0% in the West.Source: National Health Interview Survey, 2011–2012. Available at http://www.cdc.gov/nchs/nhis.htm.Reported by: LaJeana D. Howie, MPH, lhowie@cdc.gov, 301-458-4611; Patricia N. Pastor, PhD; Susan L. Lukacs, DO.


We currently face a myriad of grand global challenges in fields such as poverty, the environment, education, science, and medicine. However, our current means of dealing with such challenges has fallen short, and ingenious solutions are required to overcome the inherent resistance to progress toward ameliorating such difficulties. Here, we highlight the promises and challenges of international collaboration in achieving success toward these trials. We note prior successes in fields such as education, medicine, science, and environmental issues made to date, yet at the same time we do note deficiencies and shortcomings in these efforts. Hence, the notion of international collaboration should be strengthened and encouraged by governments, non-profit organizations, and others moving forward using creative means to bring talented teams together to tackle these challenges across the globe. From flat, to round, back to flat, and now even considered hyper-connected, the world has (r)evolved to become a prolific pitch rife with collaborative ideas and practices opportunistically aimed at improving circumstances for humanity while systematically defying physical borders. Collaboration between entities in different countries has steadily increased over the past two decades secondary to improved mobility of information, ideas, and people across the globe. The promise of international collaboration is evident on a daily basis, with recent successes including the mobilization of resources to areas affected by the catastrophic natural disasters in Haiti (2010 earthquake) and Japan (2012 tsunami), the recent explosion of digital technology in the health care field, and even the re-emergence of Ebola in West Africa and the rapid global response to prevent a worldwide pandemic. Despite the imminent and present potential, the role of international collaboration needs to grow to meet the worldwide demands in business, trade, education, and health in order to address many of the global grand challenges that exist at the intersection of disciplines, geographies, cultures, economies, and policies.While the developed world tends to lead traditional metrics in terms of numbers of partners and publications stemming from international relationships,Among national governmental interest in international co-operation is the ability to break barriers between countries that might not have open and collegial relations using affiliations surrounding common scientific interests that are capable of transcending even the most deep-seated political rifts. Membership to communities of science and communities of practice has the potential to be universal. Collaborators can work behind the scenes on projects in an effort to establish small commonalities while promoting focused human advancements. One prominent example is that of Nobel Peace Prize-winning physician, James Muller, MD, who co-founded International Physicians for the Prevention of Nuclear War. This movement began as he, as a member of the faculty of Harvard Medical School, collaborated with Soviet physicians and scientists during the Cold War. These ties can extend to build lasting international relationships, upon which other diplomatic ties can be based. Additionally, governments can maximize their investment in certain projects by assembling multiple and diverse teams with various strengths to facilitate enhanced advancement of knowledge and discoveries along the continuum of “science to practice to policy.”4As diversity in both geography and gender—and the general empowerment of women globally—has become paramount in international collaboration, nowhere is the rise of female enablement more evident than in sub-Saharan Africa. The growing emergence of female leadership both as presidents and First Ladies has come to the forefront in nations such as Liberia where the leadership of Ellen Johnson Sirleaf has successfully navigated the Ebola outbreak. The female leadership has empowered others at the most remote village level to take responsibility for the health and well-being of themselves. A stellar example of this is the dramatic success of The US Presidents Emergency Plan for AIDS Relief (PEPFAR) which has corollary effects on the population scale with fewer children orphaned by HIV/AIDS and susceptible to the social determinants of health that impact orphans especially in sub-Saharan Africa. This has further impact on the next generation through improvements in maternal and child health that not only target survival, but mean that newborns, infants, and young children thrive through the promotion of exclusive breastfeeding, increased mother-and-child interaction during pregnancy and after birth, and improved nutrition through the first 1,000 days of life. These children now have the opportunity to reach their full developmental potentialPerhaps the most established and varied means by which international collaboration is evident is in the field of education. For centuries individuals have been traveling abroad to learn new skills to bring back to their homeland. Certainly world travel and the consequent learning was a substantial factor in the success of Drs Charles and Will Mayo in the early twentieth century, as they assembled a cutting-edge surgical practice ensconced in farmland, in spite of the lack of a thriving metropolis. While unwittingly setting precedent, the Mayo brothers were utilizing a recently trending educational model, “train the trainer,” whereby an individual or group in need of a skill is teamed up with an entity possessing more expert knowledge. The learning occurs through various mechanisms from agricultural and vocational skills in the most resource-challenged contexts to micro-lectures usually delivered through the help of the internet among other technological and communicative advances. Yet what is most critical about this model is that knowledge becomes more democratic and decentralized, furthering a participatory process by which the learning continues as those who have been trained by the “expert” quickly transition into resident experts and subsequently train others and disseminate knowledge .This allows propagation of knowledge and is increasingly effective in areas of the world lacking in either access to or quality of education (or both) at all levels—but particularly at university and professional levels. With improved mobility and the transfer of people and information, trainees can be educated either at home or abroad, bringing back valuable skills and resources to achieve additional dimensions of mobility: social and economic. This has been successful in many parts of the developing world and has most recently proved effective in engaging an emerging citizenry in Haiti, as it attempts to recover not only from a recent devastating earthquake but also from decades of corruption and political unrest, which have stifled planning and policy measures for the future. Individuals at the most decentralized level of society have been able to become educated in areas such as access, delivery, and protection of water and the corollary public health challenges with only limited direction from various US universities, multi- and bilateral aid organizations, and faith-based groups—and oftentimes facilitated by open-source web sharing platforms such as Google Earth, Google Drive, Dropbox, and Android-based applications used for data collection in the field.6As a growing community of social and public intellectuals emerges in an era of crowd-sourced data collected for studies published in open-access journals, it is important to channel these digital habits that are shaped by and shaping our incessant need to be connected toward international collaborations as the internet allows us to participate and engage in the world around us in productive and meaningful ways. The “train the trainer” model is growing in popularity because it keeps people in the context of the issues they are being capacitated to address, thereby circumventing the potential of brain drain. This model connects the learning with the challenges as they exist rather than removing the learning from the challenges so that the learning becomes only conceptual and theoretical. The “train the trainer” model acknowledges the relationships of interdependence that bind together the units of social organization that make up the global population Amidst the regional and global risks associated with brain drain, in the past few decades we see an increasing number of trainees coming to the United States for post-graduate education in engineering, business, science, education, and medicine. Estimates from 2012 put the number of foreign students in the US at nearly 800,000, with only 275,000 students from the US traveling abroad for education.The unbalanced incorporation of global educational resources is clearly evident in the medical field as the Educational Commission for Foreign Medical Graduates reports that over 170,000 foreign medical graduates achieved certification from 1998 to 2008.Despite attractive educational and occupational opportunities, the US and the rest of the developed world cannot simply stand by and passively recruit international academics. Lucrative offers from both the developed and developing world have increased the level of competition for talented trainees among centers of higher education. Economic impact is a chief driver as this component can drive as much as £10 billion for the UK economy.Nowhere is international collaboration more promising or necessary than in the field of medicine, specifically medical research. Large, multicenter, multinational, randomized clinical trials have become an evidence-based standard to validate new treatments or pharmaceuticals and to discern the most efficacious therapies in standard practice. Certainly the EU has been calling for their own institutions to be international leaders in medical science collaboration for over a decadeAnother recent example of the benefits of multinational studies and subgroup analyses rests in the TOPCAT trial which studied the effect of aldosterone antagonism in patients suffering from heart failure with preserved ejection fraction.22The Mayo Clinic Center for Social Media has taken the lead in driving the global conversation on (and through) social media in health, medicine, and science. Clearly social media help identify potential projects and facilitate the flow of ideas. This was highlighted by a recent report from The European Society of Cardiology Congress in 2014 where it was found that over 50% of conference attendees were active on some social media venue during the conference.25Despite the immense progress in international collaboration in just a few short years, challenges remain. Connecting potential collaborators, identifying funding sources, executing and sustaining the project, and evaluating both the project and partnership are all potential barriers to a successful project. Here we point out successes seen in both popular and scientific press over the past few years in an effort to spur on future affiliations. With a recovering, yet tenuous, global economy, and a plethora of global complexities that outpace any empirical advancement in science, there is an essential demand for large, international collaborations to confront the grand challenges we face today. Fortunately, we have been given the instruments and reasonably favorable conditions to accomplish these feats, as the world continues to (r)evolve at an unprecedented rate of change.


This is a report on the technique of neoglans reconstruction in a patient with amputated glans penis following guillotine neonatal circumcision. A 4 cm long and 2 cm wide lower lip oral mucosa graft was harvested and used to graft the distal 2 cm of the corporal bodies after 2 cm of the distal penile skin had been excised. One edge of the lower lip oral mucosa graft was anastomosed to the urethral margins distally and proximally to the skin. At six months of followup, patient had both satisfactory cosmetic and functional outcomes. Circumcision is the commonest operation performed on young boys . Like anPenile amputation at any level is rare but it is the most seriously reported complication of circumcision .The management of penile glans amputation depends on the duration before presentation and the acute phase management usually involves autotransplantation –10.We present a case report of the use of oral mucosa graft in neoglans reconstruction in a boy with total glans penis amputation following circumcision which can guarantee long term urethral opening and acceptable cosmesis and prevent further shortening of the penis.Traditionally oral mucosa grafts have been used in urethral reconstruction. In recent times, it has been used for resurfacing of the glans penis or reconstructing a neoglans penis after partial or total glansectomy for penile cancers .From online literature search and to the best of our knowledge, it appears that this procedure has not been utilized in the management of traumatic glans penis amputations following circumcision in late presentations as has been done in cancer associated glansectomies.This is a case of a 3-year-old boy that had total glans penis amputation at the time of guillotine circumcision by traditional circumcisionist  in the neonatal period. The circumcision injury had completely healed at the time of presentation. The mother brought him to our facility three years after the injury on account of difficulty in urination and a disfigured penis. The boy passed a poor stream of urine with straining.On physical examination, he was a well-looking boy with normal growth for his age. The glans penis and the coronal sulcus were absent. He had a pinhole urethral meatus with scaring at the distal end  but adeqHis postvoid residual urine volume was 80 mls. The bladder wall was thickened but there was no hydronephrosis on ultrasound scan. His renal function was normal and urine culture did not isolate any organism.From the clinical presentation above, the goals of management were to achieve a cosmetically acceptable neoglans penis, achieve a long term widely patent urethral opening, and prevent further penile shortening.Step  1.  Surgery involved a circumcising incision, degloving of the penile skin, and excision of the scar tissue at the distal end exposing the corporeal bodies in the process ( process .Step  2. The urethral end was identified and catheterized with a size 6 fr urethral catheter. The distal penile skin was shortened by 2 cm leaving raw surfaces of the corporeal bodies distally and sutured into place with vicryl 3/0 (cryl 3/0 .Step  3. A 4 cm long, 2 cm wide lower lip oral mucosa graft (sa graft  was harvsa graft . AnchoriPostoperatively, closed wound dressing with Vaseline gauze was applied to the recipient site and only changed on the fifth day. It was then changed at four-day intervals on two occasions.The urethral catheter was taken out on the 14th day after surgery.The graft improved in cosmetic appearance over time Figures  and 7. TPenile glans amputation like many others is a preventable complication of circumcision if proper attention is paid to detail and if it is carried out by properly trained personnel , 12, 13.Among other factors, the management of penile glans amputation depends on the duration before presentation and the acute phase management usually involves autotransplantation –10. In tPack and Ariel described a technique in which the penile skin is brought over the ends of the corpora bodies and sutured to the urethra after partial penectomy . This teSkin grafts have also been used to fashion out a neoglans penis after partial penile amputation or used for resurfacing the glans after tumor excision , 16. HowScrotal flaps have also been used for glanuloplasty after partial penectomy with satisfactory penile function and appearance . Again tPedicled myocutaneous flaps based on the inferior epigastric artery have also been used to reconstruct the glans penis after glans amputation , 18. UnfWe opted for the Venkov and Slavov method  of glanuOne potential problem with this method of glanuloplasty is the high risk of graft mobility at the recipient site which can hinder neovascularization for adequate graft adaptation. We prevented this by using anchoring stitches. Another potential problem is graft contraction with resultant meatal stenosis. However, we did not observe this complication in our patient with a minimum of six-month follow-up.Glanuloplasty with lower lip oral mucosa graft following total glans penis amputation from circumcision is simple and reproducible with satisfactory cosmetic and functional results and may be extended to the management of both traumatic and nontraumatic distal penile amputations.