Despite the importance of adequate, un-crowded housing as a prerequisite for good health, few large cohort studies have explored the health effects of housing conditions. The Social Housing Outcomes Worth (SHOW) Study was established to assess the relationship between housing conditions and health, particularly between household crowding and infectious diseases. This paper reports on the methods and feasibility of using a large administrative housing database for epidemiological research and the characteristics of the social housing population.This prospective open cohort study was established in 2003 in collaboration with Housing New Zealand Corporation which provides housing for approximately 5 % of the population. The Study measures health outcomes using linked anonymised hospitalisation and mortality records provided by the New Zealand Ministry of Health.It was possible to match the majority (96 %) of applicant and tenant household members with their National Health Index (NHI) number allowing linkage to anonymised coded data on their hospitalisations and mortality. By December 2011, the study population consisted of 11,196 applicants and 196,612 tenants. Half were less than 21 years of age. About two-thirds identified as Māori or Pacific ethnicity. Household incomes were low. Of tenant households, 44 % containing one or more smokers compared with 33 % for New Zealand as a whole. Exposure to household crowding, as measured by a deficit of one or more bedrooms, was common for applicants (52 %) and tenants (38 %) compared with New Zealanders as whole (10 %).This project has shown that an administrative housing database can be used to form a large cohort population and successfully link cohort members to their health records in a way that meets confidentiality and ethical requirements. This study also confirms that social housing tenants are a highly deprived population with relatively low incomes and high levels of exposure to household crowding and environmental tobacco smoke. In New Zealand infectious diseases emerged as an increasing public health problem during the 1990s. Hospitalisation rates from infectious diseases increased by about 50 % during that decade . In addiA case–control study of meningococcal disease conducted in Auckland from 1997 to 1999 showed the risk of disease in children was highly associated with household crowding, as measured by the number of adults and adolescents per room . Other NDespite the intuitive logic that household crowding contributes to the spread of infectious diseases there is a surprisingly small published literature on the health effects of this exposure and few published studies on the effects of housing interventions to reduce household crowding . A New ZThe Housing and Health Research Programme (He Kainga Oranga) was formed in response to concerns about the health consequences of poor housing and how these could be addressed. One of its core projects, the Social Housing Outcomes Worth (SHOW) Study, was established to investigate the health effects of housing conditions, particularly household crowding . The stuThe SHOW Study has the following aims: (1) To describe the characteristics of social housing applicants and tenants and their use of social housing over time; (2) To assess the relationship between household crowding and other household exposures and health outcomes; (3) To assess the impact of placement in social housing on the health status of tenants; (4) To assess the impact of housing improvements on the health of tenants.Here we report on the methods and feasibility of this study and the first of its aims to describe the characteristics of social housing applicants and tenants.This research uses a prospective open cohort design to follow a defined population of people over time to measure the relationship between their housing conditions (exposures) and hospitalisations and mortality (outcomes). Planning for this study began in July 2001 with data collection starting in February 2003.This study was made possible by the support of New Zealand’s largest provider of social housing, Housing New Zealand Corporation (HNZC). HNZC provides housing for approximately 5 % of the population of New Zealand and in the process collects a considerable amount of information to assess the housing needs of applicants and respond to the changing circumstances of tenants.Social housing represents a relatively small proportion of housing in New Zealand compared to similar European welfare states. Consequently, it has become the housing option of last resort, with tenants generally being amongst the most socio-economically deprived groups in New Zealand.To meet its aims, this study collected data on key ‘contextual’ factors (notably household exposures) as well as ‘compositional’ aspects of the housed population (notably socio-demographic characteristics) along with linked health outcome data Table .Table 1MThe study utilises the fact that HNZC obtains and stores detailed records on all applicants and existing tenants Table . InformaThese administrative processes allow for collection of key demographic variables , crowding  and confounders (household income). A voluntary smoking question was added to the IRR form for completion by all adult household members (those 18 years of age and above). The question is based on that used in New Zealand census questionnaires and reads: “Do you smoke cigarettes regularly (one or more a day)?”Household crowding can be measured in a number of ways. The simplest is household occupancy, which is the number of people per house. Density measures consider the number of people in relation to the size of the house, for example people per room or bedroom. Crowding measures consider the density according to a defined standard. An example is the Canadian National Occupancy Standard (CNOS), which defines household crowding as a situation where one or more additional bedrooms are required to meet the sleeping needs of the household . StatistThis research uses, as the measure of health outcomes, hospitalisations and mortality recorded by the New Zealand Ministry of Health (MoH). The MoH obtains coded data on all publicly funded hospital admissions and deaths in New Zealand Fig. . Each evData on housing applicants and tenants are transferred from HNZC to the MoH for matching with the individual’s NHI Fig. . The MoHThe MoH has also supplied the researchers with a file of all hospital discharges and deaths for New Zealand with the encrypted NHI for each record Fig. . The encThe investigators generate the study dataset by merging the anonymised tenant/application data with the anonymised housing data using the encrypted NHI Fig. . This stThe analysis reported in this paper has focussed on assessing the feasibility of the study and describing the characteristics of the study population. Key indicators of feasibility are the level of data matching achieved and the completeness of key data fields. The characteristics of the cohort study population include its size and dynamic movements over time and its socio-demographic characteristics and levels of household crowding.Further analysis of the cohort study will use a range of outcome (dependent) variables based on specific diseases  and categories of diseases  as well as non-infectious diseases and injuries.The study proposal and associated consent forms were supplied to all 12 New Zealand Ethics Committees. After some discussion, the study was approved under the agreed multi-centre process coordinated by the Wellington Health Ethics Committee.An important step in setting up the study was to inform HNZC housing applicants and tenants that the study was being carried out using their records but that they would not be identifiable to the researchers. Information about the study is included in a privacy statement on the NA and IRR forms. A separate pamphlet about the study was included with NA interview and IRR forms. Versions of this pamphlet were prepared in other languages  and made available as required. A free phone information number was set up and staffed by University of Otago staff for HNZC clients who wanted more information about the study. Information was also included in HNZC tenant newsletters and press releases. HNZC tenancy managers received information packs about the study and training material for use with their staff.During the 8-year period Jan 2004 to December 2011 the MoH matched approximately 96 % of subjects to their unique NHI numbers. The initial electronic matching was 66 % with the remainder by manual matching. Consequently, some applicants (3.6 %) and tenants (4.3 %) were excluded from the study. A small number of tenants (2.7 %) were not included in the study because they did not apply for subsidised income-related rent (IRR).Analysis of HNZC data shows a high degree of completeness for the fields of interest, including date of birth (100 %), sex (100 %), ethnicity (99 % for Needs Assessment and 98 % for IRR) averaged across 8 years. These are required fields in the HNZC tenancy management system so this result was not surprising, but it does illustrate the benefits of using administrative data. Response to the voluntary smoking question added to the IRR was considerably lower, averaging 70 % during the course of the study.Figure This analysis was conducted on a cross-section of housing applicants and tenants as at 31 December 2011. Important characteristics of the housing applicant and tenant population are summarised in Table This analysis shows that housing applicants and tenants are a young population compared with the total New Zealand population, with half less than 21 years of age. Māori and Pacific people make up 59 % of applicant and 74 % of tenant households. Single parents with children make up 36 % of the applicant households and 35 % of the tenant households. Household incomes are comparatively very low for applicant and tenant households. The majority of applicants (87 %) and tenants (96 %) received income from a Government benefit. A higher proportion of adult housing tenants smoke (30 %) than for New Zealanders as a whole (21 % in the 2006 census and 15 % in the 2013 census). Similarly, a higher proportion of tenant households (44 %) compared with New Zealand as a whole (33 %), were potentially exposed to passive smoking, based on the households containing one or more smokers.About 10 % of New Zealanders are exposed to household crowding, as measured by a deficit of one or more bedrooms in 2006 . By contThis initial analysis has also investigated changes in household crowding levels that occur when housing applicants become HNZC tenants. During the 8-year observation period, an average of 7229 households a year went from being applicants to tenants. This population included 2941 households a year known to have household crowding (1+ bedroom deficit), with the majority (an average 94 %) having a reduction in crowding after moving to a HNZC house. This group is important for the investigation of one of the main hypotheses of the study that a decrease in crowding level is associated with a drop in disease risk.This research has demonstrated that it is possible to establish a large cohort study using administrative data collected by a public housing provider. It has also shown that a high proportion of subjects in this database can be linked to their health records in a way that is ethically acceptable and protects privacy. This population of social housing applicants and tenants is characterised by its young age, high proportion of Māori and Pacific peoples, and sole parent households. It has a low income and high level of receipt of Government income support.These results also show that this population is highly exposed to household crowding and household smoking, compared with the New Zealand population more generally. It has also demonstrated that the majority of housing applicants who became tenants decrease their level of household crowding in the process. This study therefore has the potential to add to the relatively small evidence base of research on the health effects of housing conditions. A further advantage of this study is that by focussing on social housing tenants, who are a particularly vulnerable population, it partly redresses the balance in other New Zealand cohorts which are disproportionately European.Using administrative databases, such as that collected by HNZC, has the advantage of providing a potentially large cohort population at relatively low cost. Similarly, using established national hospitalisation and mortality databases to identify health outcomes in this cohort allows a far larger study size than would otherwise by possible. This study design also lets the researchers investigate multiple health outcomes potentially allowing the study to quantify a larger proportion of the overall burden of disease that can be attributed to household conditions than could be done with individual disease studies. It also enables researchers to analyse the effect of important changes to social housing policy that have occurred during the course of the cohort.This study design and methods have a number of potential weaknesses and limitations that are common to many observational epidemiological studies, notably confounding, selection bias, information bias, and issues of generalisability.The high level of matching of cohort members with health data is important for minimising potential selection bias. Such a bias could occur if, for example, the relationship between crowding and disease risk was different for those included (matched) compared with those who were not included (unmatched) . Given tHousehold crowding is highly associated with other measures of socio-economic deprivation such as low income, unemployment, low education level and fewer material resources. Other risk factors for respiratory disease, notably active and passive smoking, are also more prevalent in crowded households . These cSome study data are dependent on the accuracy of information that housing applicants and tenants supply to HNZC, which introduces potential for information bias of exposures and covariates. This particularly applies to information on the number of people living in the applicant and tenant households. Housing applicants may tend to over-state the number of people in their homes to increase their priority on the waiting list. Housing tenants may under-count the number of people staying with them to minimise their rent . Consequently, if there truly was an association of reduced hospitalization rates due to reduced household crowding after placement from an applicant to tenanted house, we may only detect such a reduction for apparent reductions in household crowding that exceeded those purely due to biased recording. This effect will be considered in a sensitivity analysis of the findings.Because this study is restricted to social housing users, who are by definition a socio-economically deprived group in New Zealand, the generalisability of the findings to the total population may be limited. However, as noted previously, a major aim of this cohort is to track the impact of the move to social housing for this economically-deprived population rather than for the New Zealand population in general. Because of the cohort design, this study will also allow researchers to see whether the role of household crowding that has so far been mainly seen for infectious diseases in children, can be generalised to a wider range of infectious and non-infectious diseases where such a role seems plausible.The SHOW Study has demonstrated that an administrative housing database can be used to form a large cohort population and successfully link cohort members to their health records in a way that meets confidentiality and ethical requirements. It confirms that social housing tenants are a highly deprived population with relatively low incomes and high levels of exposure to household crowding and environmental tobacco smoke.This study provides a mechanism for investigating the role of housing conditions, such as household crowding, as a risk factor for a range of diseases and injuries. By taking advantage of a ‘natural experiment’ where large numbers of housing applicants are re-housed in public housing, this study could also add to the small literature on the health effects of housing improvements .This study also demonstrates the value of partnerships between researchers and service providers. By building research and evaluation into service deliver processes it is sometimes possible to provide research findings in a more efficient way than with ‘stand-alone’ research projects. Now that it is established, this study could be extended at relatively low cost to investigate other links between housing conditions and health outcomes. Such mechanisms provide benefits for the service provider as well as the research and policy end-users.


We wanted to depict fibers of the dentatorubrothalamic tract in patients with Parkinson’s disease and multiple sclerosis in order to use this knowledge for clinical routine and to show its relation to the corticospinal tract for deep brain stimulation. Fibers of these white matter tracts were depicted between February 2014 and February 2015 in nine patients of all ages. There were seven men and two women. The mean age was 60 years. We used a 3DT1 sequence for the navigation. Additional scanning time was less than 9 min. Both tracts were portrayed in all patients.We were able to successfully portray these white matter tracts in all patients. We visualized the medial and lateral parts of the corticospinal tract by using a region of interest which covered the whole motor cortex. Furthermore we segmented the motor cortex. The fibers ran from this area of the brain through the internal capsule and they could be followed until their entry in the brainstem. The dentatorubrothalamic tract was smaller than the corticospinal tract. It was situated medio-posteriorly of the corticospinal tract. After decussation to the contralateral red nucleus it was localised next to the midline when it entered the motor cortex. From the thalamus on, it proceeds medially and posteriorly of the corticospinal tract further to the motor cortex. Depiction of the whole tract is essential for the differentiation of the dentatorubrothalamic tract with the corticospinal tract.The depiction of the dentatorubrothalamic tract might be useful for neurosurgeons when deep brain stimulation is planned. Knowing its relation to other white matter tracts can help physicians like neurosurgeons or neurologists avoid side effects and deal with patients with DBS. The position of the electrode might be crucial for a satisfactory outcome. PD is a neurodegenerative disease associated with neuropsychiatric illness . It is cDiffusion tensor imaging (DTI) is a technique that enables neurosurgeons to portray white matter tracts (WMT) in vivo in healthy and non-healthy patients . It can 2, slice thickness 2 mm, and the acquisition matrix of 96 × 96 yielding nearly isotropic voxels of 2 × 2 × 2 mm. 3T-MRI was performed strictly axial using 32 gradient directions and one b0-image. b value was 800 s/mm2. We used EchoPlanar-Imaging (EPI) and ASSET parallel imaging with an acceleration factor of 2. The additional scanning time was less than 9 min. One day after surgery a computed tomography of the brain was performed. We processed the DTI data on a standard commercial workstation . This software uses a straightforward fiber tracking approach known as fiber assignment by continuous tracking (FACT). Parameters for the tractographies were a maximum angle of 45° for the CST and 60° for the DRT, an FA Start Value of 0.10 and an ADC Stop Value of 0.20. First we segmented the motor cortex (MC) on both cerebral hemispheres. Then we tracked the CST from this area. A region of interest (ROI) was put in the brain stem. The fibers were tracked also from the brain stem to the MC. It is possible to use a ROI in place of the segmented area of the MC. For the DRT we acted in a similar way. The fibers were tracked from the dentate nucleus (DN) of the cerebellum to the red nucleus of the contralateral hemisphere and later to the MC. Therefore, we used two ROI. One of them was put in the DN of the cerebellum and the other one in the contralateral red nucleus. As mentioned before it is possible to use another ROI instead of the segmented area of the MC. In that case this white matter tract would be portrayed using three ROI. The ROI measured approximately 1 cm in the red nucleus and DN of the cerebellum whereas the ROI for the MC measured approximately the size of the MC.We included in our study between February 2014 and February 2015 nine consecutive patients. These were seven men and two women. There was no limit of age. The mean age was 60 years. There were eight patients suffering from PD and one patient suffering from MS. The MRI was performed in order to prepare an eventual DBS. An MRI-scan was acquired on a 3T General Electric SignaHDxt Scanner preoperatively. We performed a 3DT1-sequence to navigate. Furthermore T2-and DTI-sequences were carried out. The FOV was 200 × 200 mmUsing DTI we were able to successfully portray fibers of two main WMT, the CST and the DRT, in all our patients. We visualized the medial and lateral parts of the CST by using a ROI which covered the whole MC. A segmentation of the MC was performed in order to enhance the accuracy. The fibers ran from this area of the brain through the internal capsule and they could be followed until their entry in the brainstem. Our main interest was, however, the portrayal of the DRT. This WMT begins in the DN of the cerebellum. The fibers arise from the DN dorsolaterally of the fourth ventricle and project through the superior cerebellar peduncle Figs. , 3. TheyDTI is a technique which can visualize WMT in vivo in healthy and non healthy patients by measuring anisotropic water diffusion of the brain –20. ThisThe portrayal of other WMT like the DRT might be also of considerable importance for neurosurgeons during DBS in patients with PD for tremor control. This tract has its starting point in the cerebellum in the DN, then it continues to the contralateral red nucleus and ventral anterolateral nuclei of thalamus from where the fibers proceed to the MC . This WMThere have been two publications which suggest that tremor control with low voltages in the posterior subthalamic region might be attributed to stimulation of the DRT , 28. As Depending on the position of the electrode the CST might be affected by a high voltage if the electrode is situated in the lateral portion of the DRT or by the electrode itself if this one is localized outside the DRT. There have been suggestions that the optimal position is inside in the anterior third of the DRT . By meanPostmortem studies show that PD affects the thalamus in its own way . It can DTI was used for the visualization of DRT and CST. It has, however, some limitations. It is difficult to determine with accuracy the starting point and ending point of the fibers , 35. TheThe authors are aware of the limitations of the current study. On one hand we are portraying here a small number of patients and on the other hand there is no control group. However, we have to say that, when compared to the existing literature, we found that our results concerning the depiction of the DRT are in accordance with the results of other authors who have worked in this direction. Coenen et al.  confirm On the other hand, further limitations concern the portrayal of WMT by means of DTI, e.g. the portrayal of crossing or kissing fibers might be difficult and the fact that the starting and ending point of the WMT cannot be visualized correctly , 35. WheOur study shows that portrayal of DRT fibers is possible for everyday routine use with a little amount of time. All the results are easily reproducible. From our point of view it is necessary to visualize the CST along with the DRT before surgery in order to have a better idea about the relation between these two WMT which are situated very close to each other in order to avoid unwanted side effects postoperatively Fig. . Identif


One of the most important challenges about the Membrane Bio Reactors is membrane fouling. Fouling has been at the centre of a globe debate for more recent years. It leads to high operational and maintenance costs such as membrane damage and replacement of membrane. Membrane fouling is attributed to the physicochemical interactions between the bio fluid and membrane. In order to decrease the fouling in bioreactors there are common anti fouling strategies such as operation at low flux, Optimization of aeration flow-rate and Physical and chemical cleanings. However, often they are not effective.This work deal with fouling crisis by a new and innovative method in order to reduce of fouling on membrane surface by injection of parallel air jet on membrane bio reactor. This is a new idea and fundamental study about the influence of wall jet on fouling of membrane surface. This study is included both experimental and numerical investigations. In order to polarize the stream path on the surface of the membrane, four symmetric nozzles were implemented at the bottom of the membrane surface upon the sparger. The changes in the fouling resistance were experimentally measured at five various jet velocities and all of them recorded by a computer system. In addition the effect of air jet velocity and shear stress on fouling resistances was also investigated by computational fluid dynamics at the similar conditions.It was revealed that the permeate flux and resistance of fouling can be related to shear stress of air flow at the membrane surface. When the velocity of air jets increase, the permeate flux increase too. Also, results illustrate that jet injection can partially remove the cake which was formed on the surface of the membrane.Correlations were developed for estimating each resistance of the membrane surface via the shear stress. The resistances of the cake are removed by the jet velocity changes, from 20% in lower jet velocity up to 40% in higher jet velocity. Submerged membrane bioreactors (SMBRs) are widely used in wastewater treatment. One of the SMBR types is airlift membrane bioreactor (AMBRs) which contains two baffles that separate the bioreactor into a riser and two downcomers. Although the downcomer is filled mainly from the liquid, but the riser is gassed. As a result of the density difference between the bubbly mixture in the riser and the liquid in the downcomer, the flow circulates between these two sections .The hydrodynamic properties and mixing pattern in MBRs depend on many factors, such as gas properties, liquid properties, gas entrance conditions and distributor geometry. Complexity of the hydrodynamics and development of efficient numerical methods have led researchers to employ computational fluid dynamics (CFD) to study the hydrodynamics of two-phase flow in MBRs –7.The MBR filtration performance inevitably decreases with filtration time. This is due to the deposition of soluble and particulate materials onto and into the membrane, attributed to the interactions between activated sludge components and the membrane. This major drawback and process limitation has been under investigation since the early MBRs, and remains one of the most challenging issues facing further MBR development .In recent reviews covering membrane applications to bioreactors, it has been shown that, as with other membrane separation processes, membrane fouling is the most serious problem affecting system performance. Fouling leads to a significant increase in hydraulic resistance, manifested as permeate flux decline or transmembrane pressure (TMP) increase when the process is operated under constant-TMP or constant-flux conditions respectively. In systems where flux is maintained by increasing TMP, the energy required to achieve filtration increases. Alternatively frequent membrane cleaning is therefore required, increasing significantly the operating costs as a result of cleaning agents and production downtime. More frequent membrane replacement is also expected .A usual method to reduce the fouling on the membrane is to put a sparger below the membrane surface to inject air near the surface of the membrane and removing the fouling through the shear stress exerted on the surface. Some researchers have studied the effect of aeration on the membrane fouling and filtration of waste water –14. AccoIn order to illustrate the results of workout wall jets, the effect of shear stress which is produced by flow of gas on the membrane surface at various conditions should be known accurately. Many researchers have measured the shear stress at the surface of the membrane in the liquid phase by using electrochemical method ,21. CompThe experiments were carried out in an airlift SMBR (H × W × D = 70 cm × 24 cm × 18 cm) that is shown in Figure 2. A gas sparger was placed under the membrane for aeration. The gas sparger was a flexible porous rubber (3 cm × 21 cm) with 25 holes/cm2. In addition four nozzles were fixed at each side of the membrane which nozzle slots were 5.82 mm × 0.72 mm. They used to evoke the air jet for removing the fouling cack which was formed on membrane surface.The reactor had 22 litre capacities; it contained two baffles (31 cm high and 24 cm width) which divided the bioreactor. It involved a riser and two downcomers. In the middle of the MBR, a flat sheet membrane module, made by KUBOTA Co. (Japan) with a mean pore size of 0.45 μm, was installed vertically which is located between the two baffles. Effective filtration area was 0.116 m−1 was used in the experiments. Sludge retention time was about 20 days and the organic loading rate was 0.18–0.19 gCOD/gMLSS/day. Composition of the wastewater is presented in Table The activated sludge which was used in experiments was taken from the wastewater treatment plant of Tehran Oil Refining Co. (Iran). The trans-membrane pressure (TMP) was monitored by a pressure gauge and was kept constant at 0.4 bars during the experiments. The concentration of mixed liquor suspended solid (MLSS) of 10 ± 0.1 grLJ) is calculated by following equation:The membrane flux was calculated by measuring the total weight of permeate which was leaving the membrane module. Permeate flux (−2hr−1). This value was measured each 15 second by flux of passing purified water. When the permeate flux became constant, it was used for calculation of membrane resistance (Rm):Where m|t is the weight of total permeate flow at time t and A is membrane surface. Here ∆t is time increment (sec), J is value of membrane flux (LmP is pressure (Pa)J is permeate viscosity (mPas−1)μRt), can be evaluated by the series model [After membrane fouling flux approximately becomes constant, the resistance of fouling in this situation (es model :3\documeRm is resistance of clean membrane (m−1)Rj is jet resistance (m−1)t is total resistance (m−1)RRpb is pore blockage resistance (m−1)c is resistance of cake that couldn’t be removed by aeration and need to special physical washing (m−1)RJt is the flux of water before cleaning (Lm−2hr−1)Jj is the flux of water after surface cleaning with jets (Lm−2hr−1).), Jm is value of flux of clean membrane (Lm−2hr−1)In this equation, Rj is the resistance of membrane fouling that is reduced by jet injection. Rc is the remaining resistance of fouling that can be cleaned by physical washing such as relaxation, backwashing or cleaning by sponge balls:and Rm). This difference is called RpbThe remaining resistance of fouling after physical washing is not equal to the resistance of the clean membrane ρiis density of phase i (kgm−3)v is jet velocity (ms−1)ui is velocity of phase i (ms−1)g is gas phasel is liquid phaseC1ε is constantC2ε is constantCμ is constantc is gravitation acceleration, 9.81 ms−2gG is velocity gradient, s−1k is turbulent kinetic energy, m2s−2In the present work, it was considered that the jet comes out of a slit as a turbulent jet. The geometry and flow of the boundary layers in the simulation were considered to be as the same as in the experiments. The membrane was modeled as a wall since permeate flux from the membrane is negligible compared to the jet flow. Time averaged Navier–Stokes equation for the turbulent boundary layer is:According to the above Reynolds-averaged momentum equations, the diffusion terms and derivative of Reynolds stresses in the axial direction were neglected . Also, mu′ is fluctuation of turbulent shear stresses and v′ is fluctuation of turbulent shear stresses also Here k-ε model. It is worth mentioning that other turbulence models were also tried and it was found that k-ε is the best for simulation of the jet.For finding the best solution of the turbulent boundary layer equations, the use of a turbulence model is necessary. For this purpose, the shear stresses or turbulent stresses were modelled by the k-ε model is a semi-empirical model based on transport equation model for the turbulence kinetic energy (k) and its dissipation rate (ε).The most appropriate turbulence models are two-equation models in which solution of two separate transport equations allows the turbulent velocity and length scales to be independently determined. The standard k is derived from exact equation, while the transport equation model for ε was obtained using physical reasons [The transport equation model for  reasons .−1 because of the creation of fouling on the membrane. At time t =90 min., air jet was injected with various velocities of 1.47, 3.67 and 4.9 m/s. The jet was injected when the bioreactor was in steady state situation and the permeate flux is in its minimum. Figure Various permeate flows vs. time are shown in Figure Rj) increased and the cake resistance decreased. In other words, the resistance of the remaining cake on the membrane surface (Rc) is decreased. Also, the amount of removed cake is increased by raising the jet velocity.In each experiment, there is a total resistance which related to the fouling resistance before jets injection. Figure The percentage of reduction in the cake resistance due to jet injection is shown in Figure . Figure Results of the shear stress in CFD simulation are as the same as the experiments which are shown in Figure Figure −2)τ is shear stress (Nmτi is stress tensor of phase i(Nm−2)The cake resistance can be a multiple linear function consistent of shear stresses of both gas and liquid phases. In the experimental work, resistance fall by increasing shear stresses, thus, it can be assumed that the total resistance is a linear function of shear stresses of both gas and liquid. In order to find a proper equation, the following general multi-linear equation was considered:The coefficients of this multiple linear equation calculated according to the experimental data by using the multiple linear regressions and the least square technique . The equThe correlation coefficient of this equation was calculated to be 0.999. Figure On the whole, membrane fouling is a controversial issue and it always leads lots of costs. Flux reduction occurs because of membrane fouling and formation of cake on the membrane surface. In this study, it is possible to remove part of fouling by using the air jets, which leads to the increasing in the permeate flux. By imposing proper shear stress on the surface of the membrane through jets of air, the cake can be removed and fouling reduced. In addition, the resistances were determined experimentally, also, the shear stresses on the membrane surface for air and sludge were evaluated by CFD simulation. It was shown that there is an acceptable correlation between the resistance and shear stress. It was shown that, higher velocity of air passing across the membrane causes more shear stress on the surface and incredibly leads to improvement of cleaning process.


The growth of material by MBE has led to the growth of cubic GaN material. The changes in these crystal phases has been investigated by Electron Energy Loss Spectroscopy, where the variations in the fine structure of the N K‐edge shows a clear difference allowing the mapping of the phases to take place. GaN layers grown for light emitting devices sometimes have cubic inclusions in the normally hexagonal wurtzite structures, which can influence the device electronic properties. Differences in the fine structure of the N K‐edge between cubic and hexagonal material in electron energy loss spectra are used to map cubic and hexagonal regions in a GaN/InGaN microcolumnar device. The method of mapping is explained, and the factors limiting spatial resolution are discussed. The cubic form has a lattice parameter of a = 0.450 nm, the cubic and hexagonal forms being related, most simply by a change of stacking sequence on (111) planes  for solid state lighting, promising lower defect densities, lower carrier densities and reduced or eliminated piezoelectric fields, compared to conventional 0001)‐oriented thin films  spectra for the atoms within the material. These differences are seen in both the Ga and N spectra. The most apparent differences are seen in the fine structure of the the N K‐edge, seen at 401 eV. Previous studies  to map the different phases present. This work has been performed using a combination of transmission electron microscopy and scanning transmission electron microscopy.The InGaN/GaN microstructures have been grown on patterned c‐plane GaN‐on‐sapphire substrates using two growth techniques. The first stage in the growth has been performed using continuous flow metal organic vapour phase epitaxy (MOVPE), producing defect free n‐doped GaN microrods with a high aspect ratio. The second growth stage has been performed using molecular beam epitaxy (MBE) to produce multiple InGaN layers and subsequent p‐doped GaN Fig. . The groThe samples have been prepared for analysis using a dual‐beam focused ion beam (FIB) to ensure an accurate sample location. The initial FIB preparation has been performed with an operating voltage of 30kV. To reduce the surface damage created by the Ga ion etch process, a lower energy (8 kV) polish has been used.The samples have been studied using a JEOL 2010 TEM, and a JEOL ARM 200F TEM/STEM both operating at 200kV. The EELS characterisation has been performed using a Gatan GIF Quantum 965 ER, utilising the Dual EELS capability to correct for drift in the core‐loss signal. Analysis of the spectra has been performed in Digital Micrograph, using the multiple linear least square (MLLS) fitting routine to determine a fit to assigned spectra.o to the c‐plane within the h‐GaN. The cubic structure at the top region of the microstructure has been confirmed by selected area electron diffraction, with a clear (111) orientation. The basal plane stacking faults are clearly visible in the hexagonal region extending across the structure, along with stacking faults visible in the cubic material.Initial studies of the samples by TEM and diffraction show microstructures with a high aspect ratio defect free core, and a highly defective region towards the top of the structure containing a high density of basal plane stacking faults. As seen in Figure Analysis of the sample by high angle annular dark field (HAADF) has been used to view the Z‐contrast within the structure. A HAADF image is shown in Figure In order to map the cubic regions of the microstructures, an area known to contain both crystal forms was mapped with a large pixel size to ensure a high signal to noise ratio. To create a fuller representation of the pixels studied, subpixel scanning was applied during the acquisition of the EELS spectra. During this process, the STEM beam is rastered across the entire pixel dimensions instead of moving from one pixel to the next. Due to the large area covered in the scan, Dual EELS was used to record the zero‐loss peak simultaneous to the core‐loss signal. This technique is important as it allows for drift correction of the core‐loss signal. The acquisition of the zero‐loss peak has also allowed the sample thickness to be determined and used to normalise the acquired maps as a function of thickness. For the selected area, the thickness varied in the range 80–120 nm.In order to create a crystal phase map for the top of the microstructure, a large pixel size of 50 nm was used, with a scan area of 1.5 μm × 2 μm. A MAADF image showing the scan area is shown in Figure To increase the resolution of the phase maps obtained, the pixel size of the spectrum images was reduced to 10 nm pixels. The ultimate resolution of the maps is limited by the signal to noise ratio, along with the ratio of the peaks within the fine structure. A map was performed with a size of 250 nm × 500 nm, with the scan area shown in Figure InGaN/GaN 3D microstructures grown by MOVPE and MBE have been studied via a range of electron microscopy techniques to characterise the crystalline nature of the material. The structures have been studied using electron energy loss spectroscopy to reveal differences in the N K‐edge present in the c‐GaN and h‐GaN spectra. These differences have revealed the presence of cubic GaN at the top of the structures in the region immediately after the growth of the InGaN active region. This growth is believed to occur as a result of the lower growth temperature required to prevent changes to the In concentrations within the InGaN layers. The studies have revealed that with a pixel size of 10 nm it is possible to clearly distinguish between the different phases present. Further work in this material will aim to reduce the pixel size to sub nanometre resolution allowing the properties of the material containing a high density of basal plane stacking faults to be studied.


The Vacuum Assisted Closure (VAC) system has become an effective treatment for acute and chronic wound defects. Although its use has been reported in wound care of children and premature infants, the management of the device in this population has not been well established.We report the satisfactory results in two neonates (one full-term and one preterm) with complex wounds secondary to major abdominal surgery. In the premature baby an enterocutaneous fistula was also present. Complete epithelialization of the wounds was achieved in both patients within a few weeks thus avoiding any further surgical procedure.The use of VAC system in neonates is safe and effective in the management of complex wounds and should be considered as a first line treatment in the event of a major dehiscence. After the initial description by Morykwas et al. in 1997 , VAC sys[Fig. ]. VAC dressing was applied to the surgical wound including the three dehiscences. VAC GranuFoam (R) Dressing  was modeled on the three defects and covered by a large layer of VAC drape; suction was set at −75 mmHg. In the left lateral part of the wound, where the intestinal loop was exposed, a small sheet of VAC drape was interposed to the GranuFoam in order to avoid applying suction directly to the bowel. The dressing was changed at 48 h intervals for 12 days after which the fascial defect was healed and the other defects almost completely resolved. After VAC dismission Aquacel (R) Foam Dressing (ConvaTec 100 Headquarters Park Dr Skillman New Jersey 08558 USA) was applied to the wound for 7 days until it was completely epithelialized . On the 16th postoperative day a low-output enterocutaneous fistula appeared in the right upper quadrant. Initially the wound and the fistula were managed with daily wet-to-dry dressing changes but no improvement was observed in the healing process of both. In addition fluid loss through the wound and the fistula was difficult to quantify and the viable skin around the defect was progressively macerating up to an 8x5 cm defect. One month after surgery a VAC dressing was applied. The VAC GranuFoam was modeled over the abdominal wall defect and suction was set at – 50 mmHg. A piece of VAC drape was interposed between the fistula and the foam in order to avoid applying suction directly to the fistula. The dressing was initially changed every 3 days for 20 days. Due to the steadily high fluid loss from the fistula and the wound the suction was then increased to −75 mmHg and the dressing was changed every 48 h for the next 21 days. When a significant drop in fluid losses was observed the VAC dressing was dismissed and Aquacel was applied for further 12 days until the fistula healed completely and the wound was completely epithelialized. At 1 year follow up the baby shows a left incisional hernia and the enterocutaneuos fistula is closed [Fig. 4].A 24-weeks gestational age, (birth weight 650 g) female newborn underwent laparotomy for intestinal perforation at 7 days of life. Multiple perforations were found involving a 30 cm segment of ileum proximal to an ileal atresia which had not been suspected prenatally. Ileal resection and double barrel ileostomy were performed. Postoperatively the patient required ventilatory support, fluid resuscitation, and inotropic therapy. Ileostomy was taken down after three months. A few days after surgery a wide dehiscence of the surgical wound developed extending for 40 % of the abdominal wall surface The Vacuum assisted closure (VAC) is a widely accepted device for the treatment of chronic and acute wounds in adult population; its use is progressively extending to the pediatric patients for the treatment of dehiscences and a wide spectrum of different pathologies.In 2000 Moneey et al.  reportedSimilar favorable results were reported by Butter et al.  who descThe effectiveness of VAC in pediatrics was also demonstrated by Caniano et al. , in 2005The management of complex wounds in newborns is more challenging than in children. In fact such lesions can be a life-threatening problem for these patients because of the significant amount of extracellular fluid loss that can be expected due to the high surface-area-to-volume ratios. In his paper Arca  underscoThe application of the VAC system to neonates implies some necessary adaptations in terms of choice of the most appropriate kind of foam, pressure applied and protection of the surrounding skin and underlying viscera.VAC system is provided with 2 types of sponges with different cell sizes ; the latter comes pre-soaked in saline and has the smallest cell size, therefore it and is thought to be less adherent than the other thus preventing excessive risk of fistula formation. In our cases the GranuFoam (largest cell size) was used but direct contact to the fascial defect and the enteric fistula was prevented by interposition of a small piece of the same adhesive drape sealing the VAC system.Another relevant issue for application of VAC to neonates is the correct setting of negative pressure. The device can develop a negative pressure range of −25 to −125 mmHg. Though it is commonly set at −125 mmHg when used in adult patients, the recommended vacuum level for neonates is −50 to −75 mmHg. In our cases the vacuum was kept at - 50 mmHg at the beginning of VAC treatment due to exposure of an intestinal loop or the presence of an enteric fistula. Subsequently, once coverage was achieved with a thin layer of granulation tissue we modified the pressure setting to - 75 mmHg.Some Authors  suggest In order to prevent the underlying structures from being damaged by excessive vacuum a non-adherent dressing  may be applied to the wound bed, especially in those cases in which it is difficult to determine which structures are exposed , 6. In oEnteric fistulas have been considered as complications of VAC system . The AutThe optimal results in the two cases described confirm that VAC system is a safe and effective device in the treatment of complex wounds even in neonates or preterm babies.Written informed consent was obtained from the parents for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


A new class of immuno-oncology agents has recently been shown to induce long-term survival in a proportion of treated patients. This phenomenon poses unique challenges for the prediction of analysis time in event-driven studies. If the phenomenon of long-term survival is not accounted for properly, the accuracy of the prediction based on the existing methods may be substantially compromised.Parametric mixture cure rate models with the best fit to empirical clinical trial data were proposed to predict analysis times in immuno-oncology studies during the course of the study. The proposed prediction procedure also accounts for the mechanism of action introduced by cancer immunotherapies, such as delayed and long-term survival effects.The proposed methodology was retrospectively applied to a randomized phase III immuno-oncology clinical trial. Among various parametric mixture cure rate models, the Weibull cure rate model was found to be the best-fitting model for this study. The unique survival kinetics of cancer immunotherapy was captured in the longitudinal predictions of the final analysis times.Parametric mixture cure rate models, along with estimated long-term survival rates, probabilities of study incompletion, and expected statistical powers over time, provide immuno-oncology clinical trial researchers with a useful tool for continuous event monitoring and prediction of analysis times, such that informed decisions with quantifiable risks can be made for better resource and logistic planning.The online version of this article (doi:10.1186/s12874-016-0117-3) contains supplementary material, which is available to authorized users. Due to the life-threatening nature and the unmet medical need of certain diseases, such as cancer, the majority of randomized phase III clinical trials in late-stage drug development involve interim analyses, with the possibility of early termination of the trial due to unexpectedly large treatment effects or excess toxicity. They enable clinical trial researchers to better utilize limited resources and to discontinue a regimen as soon as it has been established to have an unexpected efficacy or safety profile. At each interim analysis, an external data monitoring committee (DMC) or data safety monitoring board (DSMB) is usually charged with reviewing the accumulating data to ensure the participants enrolled in the studies are not subject to unnecessary risk.Planning and executing analyses in event-driven studies can be challenging. First, the timing of these interim analyses is usually dependent on the number of events , which determines the statistical stopping boundaries. Second, major operational efforts and expenses are involved to ensure that the quality of the data meets the standard of regulatory submissions, especially when the analyses could potentially lead to unblinding of the trial. Third, convening DMC members requires advanced planning. Even if a study contains only one final analysis, it is imperative that the study team closely monitors the progress of the trial. Each phase III trial rarely stands alone and usually belongs to a network of studies. A slight deviation from study assumptions established at the design stage may have a significant impact on the planning and execution of the clinical development program. Therefore, it is common practice that clinical trial researchers project the timing of interim or final analyses during the course of the study in order to make informed decisions for planning and logistical purposes.A new class of cancer immunotherapies , 2 has bVarious parametric and non-parametric models have been proposed to predict the timing of analyses –27. The Here, I propose an approach using the parametric mixture cure rate model, with the best fit to the empirical data, to predict the analysis times in immuno-oncology studies with time to event as the primary endpoint during the course of the study. In addition, the mechanism of action of cancer immunotherapies, such as a delayed or long-term survival effect, was taken into account by allowing the distribution of the expected time to event and the likelihood of the long-term effect among patients who are still at risk to be different based on their current on-study durations. Various parametric mixture cure rate models were evaluated in the context of cancer therapies with different mechanisms of action. The proposed prediction procedure was retrospectively applied to a randomized phase III clinical trial in treatment-naïve patients with advanced melanoma treated with dacarbazine with or without ipilimumab .To maintain the integrity of study conduct, treatment allocation is usually masked to the study teams in randomized clinical trials during late-stage drug development. Even if the actual treatments received by patients are known , the personnel directly involved in the study conduct should refrain themselves from accessing treatment records and from conducting any analysis by treatment arm during the course of the study. To mimic the real-world situation, the proposed method was performed based on the total number of events with the treatment arms combined.k treatment arms. Let N be the total target sample size and let N (τ) denote the observed total number of randomized patients by time τ (relative to the first randomization) at which the prediction is performed. Similarly, let D (τ) and G (τ) represent the observed total number of events and administrative censors . Suppose that ith patients enters the study at time Ei, where i = 1, 2, ⋯, N, and the event time Ti is independent of the censoring time Ci and the entry time Ei. At the time of prediction τ, we observe the time to event or censoring Xi = Ti ∧ Ci ∧ (τ − Ei)+ with censoring indicator variable of δi = I{Ti ≤ Ci ∧ (τ − Ei)+}, where a ∧ b = min and a+ = max.Assume a study was conducted with Y as the indicator variable representing the susceptible population (Y = 0). Let π (x) be the probability of patients never experiencing the event of interest . The survival function of the entire population can be written in terms of a mixture of two independent survival distributions:Mixture models assume that the study population is composed of the following: individuals who will experience the event of interest  and those who will not . Mixture models allow simultaneous estimation of incidence and latency. Define π (x) is the probability of cure with covariate vector of x = ; s is the survival function for the susceptible population with model parameters θ and covariate vector of z = . If key prognostic factors  were known, the prediction procedure described herein could be first applied to different subgroups of  before pooling subgroup data sets for the overall assessment. The statistical details of the parameter estimation are presented in the supplementary material  and δi(τ).where S(t|Y = 0)] can take any form of the parametric or non-parametric distributions. Among the parametric models, exponential, Weibull [s(t|Y = 0) and s(t) represent survival functions for the population that is subject to the event of interest and the entire population, respectively. Note that hazard rate h(t) is no longer constant in these models.The distribution of patients who are susceptible to the event of interest [i.e.,  Weibull , lognorm Weibull , and log Weibull  are commπ, θ1, θ2). It has been observed that ipilimumab induces a proportion of long-term survivors and a low percentage of objective responses, although durable, resulting in long-term progression-free survival [Figure survival , 8. The Due to the immaturity of accumulating data with a potential phenomenon of long-term effect during the course of the study, the shape of the survival curve is usually unstable. It is logical to fit these data with different survival distributions and select the model with the best fit to predict the timing of either interim or final analysis. The fit of the model was assessed both by graphically comparing the empirical and model-fitted curves and by using statistical criteria, such as Akaike information criterion (AIC) or Bayesian information criterion (BIC). As time elapses, the shape of the Kaplan-Meier curve may change. Therefore, different parametric mixture cure rate models may be chosen at different analysis times.T⋆ at which the prespecified number of total events D⋆ for the study is reached by means of a simulation study based on the accumulating data. A proportion of G(τ) patients who represent the event-free population were randomly removed in each iteration. The remaining patients represent the population who remains at risk of the event of interest, and the future event times are obtained via the chosen survival distribution. To account for the potential mechanism of action of cancer immunotherapy, future event times are generated conditioned on the times beyond the observed times. In other words, patients who have longer on-study times at time τ will have a higher likelihood of being event-free compared with those with shorter on-study times as the time starts to level off. The point estimate and the corresponding confidence interval of the prediction are obtained from the simulation. Specifically,Fit the empirical data pooled across treatment arms to the parametric mixture cure rate models and select the model with the best fit based on graphical assessment, as well as statistical criteria, such as AIC or BIC.Obtain an estimate of the long-term event-free rate N has not been reached, simulate the enrollment dates for the remaining patients.If the target sample size Draw a random sample Among patients who were still at risk at time τ, a proportion of patients were selected from the risk set to represent the cured population based on the estimated distribution of the long-term event-free rate G(τ) patients with (τ − Ei)+, the event times were generated based on the fitted parametric model exceeding the observed censored times. The random event times for patients with simulated enrollment times from Step 3  were generated using the entire estimated parametric time to event curve .For Calculate the calendar times with newly completed data.T⋆ when the targeted number of events D⋆ is reached. If the completed data set from Step 7 does not yield D⋆, set T⋆ equal infinity.Rank the calendar times in an ascending order and identify the time Our objective is to identify the time T⋆. Calculate the proportion of the iterations that does not contain sufficient number of patients to reach D⋆. This proportion represents the probability that the study will not conclude in a reasonable monitoring time window and can be used to determine whether the study needs to be terminated early, even if the prespecified number of events has not been reached. A high probability of study incompletion, P(SIC), could indicate a potential immaturity of the data or misspecification of the long-term event-free probability at the time of study design. The point estimate of the time of analysis is estimated from the remaining iterations by taking the median or the average of the calendar dates, and the α/2 and 1 − α/2 quantiles represent the 100(1 − α)% confidence limits of the prediction.Repeat steps 3–8 a large number of times to obtain a list of simulated target calendar time Ipilimumab is a fully human, monoclonal antibody (immunoglobulin G subclass 1) that blocks CTLA-4 binding to its ligands, B7-1 and B7-2, on antigen-presenting cells to overcome CTLA-4–mediated T-cell suppression, thus enhancing the immune response against tumors . CTLA-4 The proposed method was retrospectively applied to a phase III study. Permission to access the analysis data set was obtained from Bristol-Myers Squibb Company. This multicenter, randomized, double-blind 2-arm phase III study was conducted in patients with treatment-naïve stage III or IV melanoma receiving ipilimumab plus dacarbazine versus placebo plus dacarbazine . The priDuring the course of the study, 6 DMC meetings were held to monitor safety and efficacy between 2008 and 2010 at approximately 6-month intervals. The study randomized 502 patients from August 2006 to February 2008. The final analysis did not take place until March of 2011, almost 2 years after what was originally anticipated. At the time of the final analysis, the study had not reached the prespecified 416 events. During the last 2 years of blinded study monitoring, it was clear that the event rate had decreased drastically, which contributed to the prolongation of the study. The long-term survival phenomenon was confirmed upon unblinding of the study [The Weibull mixture cure rate model was the best-fitting distribution to the empirical data of this phase III randomized clinical trial, with both treatment arms combined for all 6 interim databases Fig. –f, accorP(SIC), defined as the number of iterations that resulted in T* = infinity, estimated long-term survival rate from the Weibull mixture cure rate model, number of observed events, and the statistical power based on the protocol assumptions and observed number of events at each DMC review are shown at the bottom of Fig. Figure The high study incompletion probability of 98.8 % and the relatively wide confidence interval among completed iterations in the first prediction were an indication of the immaturity of the data, at which time the enrollment had not been completed with only 62 events. The number of events tripled in the next 6 months, which led to an earlier estimate of the timing of the final analysis and lower likelihood of study incompletion (16.9 %). The estimated long-term survival rate also decreased from 45 to 0.01 % based on the accumulating data. The similar event rate continued through the third DMC analysis in April 2009. This was reflected in a narrower confidence interval of the final analysis time and relatively stable projected calendar times.The upward trajectory of the projection and increasing width of the confidence interval for the next 2 predictions, as well as the rebounding probability of study incompletion from 9.21 to 57.6 %, indicated the decreasing event rate among remaining patients at risk. At the time of the last DMC meeting, the data showed that the probability of study incompletion dropped to 18.1 % because the observed 406 events were approaching the final number of events. The stability of the data was reflected on the estimated long-term survival rate which began to stabilize at around 16 % after the fourth DMC review in September 2009, and the associated confidence intervals of the final analysis times also covered the actual date of study completion. Although the fitted curves did not completely account for patients with the longest follow-up towards the end of the observed Kaplan-Meier curves in the second and third predictions, the subsequent three predictions with additional and more mature follow-ups confirmed the goodness-of-fit of the Cure-Weibull model. The statistical power had reached a minimum of 86 %, with more than 361 events for the last 3 DMC analyses. Nevertheless, the impact of a decreasing event rate was reflected in the delay of the analysis time projection, with the probability of study incompletion as high as 18 % when the number of events was only 10 less than the target of 416. A decision to unblind the study was made with 414 events in the first quarter of 2011.Large, randomized clinical trials usually take a considerable amount of resources and time. During conduct of the trial, DSMB or DMC review is usually instituted to ensure that individuals are not exposed to unsafe or ineffective treatments. In addition, unexpected large treatment effects may also lead to early termination of the study. These activities require upfront and careful planning, especially if DMC reviews could lead to unblinding of the study. It is also not trivial to plan the timing of DMC meetings when the studies are event- driven.A recent understanding of the biology of some diseases, such as advanced melanoma, has led to the development of a new class of cancer immunotherapies that has shown a significant survival benefit. Several immunotherapies have demonstrated delayed clinical effect and a long-term survival phenomenon, in contrast to cytotoxic chemotherapy from which patients usually derive early benefit.Clinical trials with time-to-event endpoints are usually designed based on an exponential distribution assumption in which we assume that anything that affects the hazards does so by the same ratio at all times . This implies the clinical effect of the experimental arm over the control is observed from the beginning and that the survival curves will eventually drop down to zero survival probability. The OS phenomenon exhibited by cancer immunotherapy potentially violates the constant hazard assumption, as the plateau of the survival curve implies a decreasing risk as time elapses. Therefore, it is imperative that clinical trial designs are tailored to the emerging evidence of these new therapies. Nevertheless, a slight misspecification of the study assumptions, such as the cure fraction, could still lead to a significant prolongation of the study and derail the clinical development program, even if an appropriate study design was implemented.It has become standard practice for clinical trial researchers to predict the times of interim or final analyses during the course of the study for the purpose of resourcing and logistical planning. Various parametric or non-parametric prediction approaches have been proposed to determine the analysis times based on accumulating information of the study. These existing approaches operate under the assumption that most patients will succumb to the event of interest during the trial monitoring window.An approach using the parametric mixture cure rate model was proposed to monitor event-driven studies when a cure fraction is anticipated. The proposed methodology was retrospectively implemented to a phase III study conducted in patients with treatment-naïve stage III or IV melanoma who received ipilimumab plus dacarbazine versus placebo plus dacarbazine. It is important to note that the use of such models should be restricted to problems in which strong biological evidence suggests the presence of such a cure fraction. Another important aspect that needs to be considered when speaking of cure is whether the duration of follow-up is sufficient. The leveling off of a Kaplan-Meier curve to a non-zero proportion, and the presence of a long and stable plateau with heavy censoring at the tail, are an indication of the presence of functional cure with reliable follow-up duration. A robust estimate of the cure fraction can only be determined with sufficiently long follow-up. The fluctuation of the cure fraction over the course of the study serves as a good indication of the maturity of the data and prevent clinical trial researchers from making untimely decisions of altering study designs. The sample size of the study should be carefully chosen to ensure the planned number of events is attainable and to allow sufficient follow-up for all patients. This has been clearly illustrated in the example provided in this article. The lack of follow-up during the first DMC analysis led to an unrealistically high and incorrect cure fraction. The stabilization of the estimated cure fraction did not occur until 1.5 years after the last patient had been randomized at the fourth DMC analysis. At the time of the final analysis, the minimum follow-up duration was close to 3 years for all patients.It is also important to emphasize that study team personnel should refrain from accessing treatment assignments when the prediction analysis is being conducted, regardless of whether the study is blinded or open-labeled in order to maintain the study integrity. Therefore, the prediction procedure should be carried out by fitting the model to the data pooled across treatment arms. Alternatively, the proposed procedure can also be implemented by the DMC. Any decision related to drug development cannot be taken lightly, as it will have a profound impact on whether the efficacious treatments can be made available to patients in need. It is recommended that such a decision should be based on the totality of the information accumulated from the study over time, such as the probabilities of study incompletion, stabilization of the estimated long-term survival rate, and expected statistical powers. If the decision is to deviate from the original study design , a dialogue with regulatory authorities is also warranted to set the expectations.A greater understanding of tumor immunology has led to the development of cancer immunotherapy. It is logical that clinical trial designs and analyses should also be tailored to the emerging early evidence and increasing knowledge about these new therapies. Parametric mixture cure rate models possess the flexibility to accommodate varying treatment effects introduced by therapies with different mechanisms of action. The proposed method provides immuno-oncology clinical trial researchers with a useful tool for continuous event monitoring and prediction of analysis times, such that informed decisions with quantifiable risks can be made for better resource and logistic planning. This will ensure that efficacious treatments are made available to patients in a timely manner.


The V2 segment of the vertebral artery is very vulnerable to injury during cervical spine surgery. The incidence of vertebral artery injury during anterior cervical spine procedures is reported to be 0.22–2.77 %. This is partially due to its variable course while running in the transverse foramens of the cervical vertebrae.th nerve root passes in front of the vertebral artery in the 4th intertransverse space. Further exploration showed that although vertebral artery at first passed at the back of the nerve root it curved downwards again and after passing underneath the 5th nerve root entered the 4th vertebral body. After making a loop in the left half of the vertebrae, vertebral artery ran anterior to the nerve root and after entering the 4th transverse foramen showed up in the 3rd intertransverse space. The shortest distance of the vertebral artery to the midline at the 4th vertebrae level was 4.78 mm.The course of the vertebral artery in the dissected cadaver of a 79 year old female is presented. Dissection of the left vertebral artery showed that the 5To our knowledge this case is the first report of a nerve root lying anterior to the vertebral artery in the intertransverse space of the cervical spine. Additionally vertebral artery has never been reported to be so close to the midline. This report signifies the importance of obtaining MRI or contrast enhanced CT scan prior to any cervical spine surgery in the vicinity of the vertebral artery including corpectomies and also careful approach to the intertransverse space during the operation. The importance of vertebral artery is because it provides the posterior circulation of the brain and the inner ear. Intraoperative complications of anterior cervical spine surgery include injury to the nerve root, vertebral artery and spinal cord . VertebrMany landmarks are described to avoid iatrogenic laceration of the vertebral artery such as Longus colli muscle and uncinate process. Vertebral artery shows a considerable degree of variation in its origin, branches, and level of entry into the transverse foramen as well as course and turtosity. This article describes a rare anatomy of vertebral artery–the position of the artery was posterior to the nerve root in the–transverse space. According to our knowledge such case has never been described in the literature before. Considering such variations can limit the incidence of inadvertent vertebral artery injury during surgeries such as corpectomy and foraminotomy. Since this is a cadaveric case report no IRB approval was needed.Sixty-four formalin fixed cadavers were dissected in the anatomy lab from November 2007 to January 2008 with an average age of 77 years. The cadavers were decapitated at the level of C1–C2 but the rest of the cervical spine and its muscular attachments were intact. One of these cases presented us with an unusual anatomy of the vertebral artery.th intertransverse space was the nerve root. Then the vertebral artery was exposed in all other intertransverse spaces while still running in the transverse foramens. After removing the transverse processes, we found that the artery runs at the back of the 5th left nerve root  had a unilateral anomaly and two (0.8 %) had a bilateral anomaly. They concluded that the turtosity of the vertebral artery can lead to a potentially dangerous medial or a lateral artery displacement. Vertebral artery can loop medially either into a medially enlarged transverse foramen or into the proximal part of the intervertebral foramen [The anterior root of the transverse process is normally 1–2 mm thick. It can be less than 1 mm thick 24 %) or paper thin (16 %), or defective (5 %). These changes make the artery vulnerable to injury from the flakes of transverse process if fractured during the operation [ % or papAll the aforementioned variations can impose a considerable risk of injury to the vertebral artery. For example when the artery enters the transverse foramen at a level higher than C6, vertebral artery can be lacerated while removing the longus colli muscle. Our case signifies the importance of obtaining an appropriate imaging study to delineate the course of vertebral artery preoperatively. Magnetic resonance imaging (MRI), contrast enhanced computed tomography (CT) and angiography can all provide such information. The surgeon should suspect penetration of vertebral artery into the vertebrae if there was a defect in the cervical vertebral body on the preoperative CT scan.Since damage of the nerve root can be as disastrous as laceration of the vertebral artery, the surgeon should be very careful while approaching the intertransverse space. Such penetrations of the vertebral artery into the vertebrae can also complicate the corpectomy in which the artery can be lacerated by high speed burr which mandates review of appropriate imaging studies prior to cervical corpectomies. Since the course of the vertebral artery can be highly variable in the intertransverse space we speculate that the best approach to expose the artery is removal of the transverse process. After that the surgeon can follow the course of the artery. Such variation should also be considered in foraminotomies where the surgeon does not expect the vertebral artery to be present behind the nerve root while doing a posterior foraminotomy. Although the safe limit of corpectomy to the midline is 8 mm on each side it can have disastrous consequences in such inward looping of the vertebral artery.This case report describes a rare course of vertebral artery located at the back of the nerve root in the intertransverse space and penetration of the vertebral artery into the vertebrae as close as 4.8 mm to the midline. Though this is an unusual entity, surgeons have to be wary of such an anatomy. Further, radiological studies to visualize the course of vertebral artery prior to corpectomies and foraminotomies can be useful in preventing inadvertent arterial injury.Vertebral artery can be very close to the midline in subaxial cervical spine. This report signifies the importance of obtaining MRI or contrast enhanced CT scan prior to any cervical spine surgery in the vicinity of the vertebral artery including corpectomies and also careful approach to the intertransverse space during the operation.


Foucault regulator and a candle, Bloch concluded that “when the lighting duration varies from 0.00173 to 0.0518 seconds (…) the [visible] light is markedly in inverse proportion to its duration”—his famous law. As this law pertains to the more general and hotly debated question of accumulation of sensory information over time, it is timely to offer the public a full translation of Bloch’s original paper (from French) and to present it within the context of contemporary research.In 1885, Adolphe-Moïse Bloch asked the following simple question “Is there a law describing the relationship between the duration of a light and its perceived intensity?” Based on a series of experiments using a  Bloch’s Law  states tThe first linear systems approach to visual perception  and to stimulus duration (Bloch’s curve) via the temporal impulse response of the visual system is further exposed by The direct link between sensitivity to temporal frequency  in terms of the distance of such candle placed this time in front of the white paper so that the latter appear equally bright as when lit from behind.detection for which the transfer function and Bloch’s curve are—given the linear systems approach—interchangeable empirical descriptors (once the impulse response of the system is known). Nonetheless, starting perhaps with All studies above focused on sensory Drift-diffusion  models were and still are meant to account for subjects’ decision time and, critically, for its stochastic variability over time in the presence of an ongoing stimulation. In principle, they can also account for the stimulation intensity required to reach a decision as a function of stimulus duration (Bloch’s curve). Equivalently, the linear systems approach used to account for Bloch’s curve could also be enhanced to account for the decision time and its variability. The possibility of such enhancement has been only rarely pointed out . Based oThe use of an enhanced linear systems approach for the characterization of the temporal properties of higher order processes remains a valuable alternative to current drift-diffusion models.As information accumulation for a wide range of perceptual tasks remains a hot research topic, it is worth offering the public the original work of Adolphe-Moïse Bloch in its first and only English translation.Comptes Rendus de Séances de la Société de Biologie, Paris 37(28), 493–495. (Translation by A. Gorea with illustrations and notes)The present experiments mainly address the following question: Is it possible to present a luminous object sufficiently briefly so that it will not be seen?A certain number of physiologists have studied this problem, and, most recently, Mr. Richet and Mr. Breguet concluded affirmatively. They designed an ingenious device allowing fast and regular eclipses of a light presented in front of the observer; the visual excitation time was, according to these authors, of about 1/1000 seconds; under such conditions, the luminous body, partly attenuated by a smoked glass plate became invisible.quantitative is not entirely satisfying, and that it would be interesting to specify precisely the duration as well as the intensity of the visual excitation.I thought that this result that can be regarded as 1 I placed on the vertical axis that bears the blades a blackened cardboard box with two slots carved into two opposite faces and placed a candle at a specified distance in front of the box.To this end, I used a Foucault regulator.I observed the light through the end of a copper, meter-long tube whose end had been filled with wax and pierced with a half-millimeter diameter aperture.As the motor was running, I recorded the instrument’s vibrations on the blackened cardboard: double vibrations of 1/250 seconds.I could hence precisely assess the time for one slot to pass in front of the tube’s aperture and, as a consequence, the duration of the visual excitation produced by the candle for each turn of the motor. Skipping the computational details, I would say that for a slot of 0.5 mm, the duration was 1/1119 seconds.Under these conditions, the candle becomes invisible when a sheet of translucent paper is placed between the candle and the spinning box at 0.09 to 0.10 m from the former.2 to yield an equivalent lighting. The experiment can thus be summarized as follows:I subsequently compared, by means of standard photometric procedures, the intensity of this candle behind the screen and that of an isolated candle and found that the latter must be set at a distance of 1.65 m from a Bouguier photometerA luminous body of equal intensity to a white paper lit from behind by a candle 1.65 m away becomes invisible when it is displayed for 1/1119 seconds.However, the translucence of the paper varies with its thickness. It was therefore necessary to compare the lighting showing through this paper with the lighting reflected by a white surface lit by a candle placed in front of rather than behind it. The photometric measurement showed that the reflected light was 4.5 times more luminous. It can thus be concluded that a white sheet of paper directly lit for 1/1119 seconds by a candle 3.47 m away becomes invisible.If the duration of the light varies, how should its intensity vary such that visual perception still has no time to develop?Is there a law describing the relationship between the duration of a light and its perceived intensity?Can these experiments be applied to new photometric measures?This first experiment naturally raised a number of problems.These are questions that I can only raise today and that I’ll bring up in future studies. I shall only mention the following experiments:3 the lighting duration varies from 0.00173 to 0.0518 seconds4; when the distance of the screen, mounted on a cart in front of the candle, is varied, the [visible] light is markedly in inverse proportion to its duration. This is to say that, in order to obtain the cessation of visual sensation, doubling the intensity of the light requires halving its duration. These results are subject to pending verifications as they are not as yet sufficiently substantiated. They demonstrate nonetheless their putative practical use in photometry. This procedure should allow the measurement of light that current methods cannot assess as they are by construction comparative while my method is direct.The aperture of the tube being equal to the area of a 0.0025 m side square, when the slots in the box are 0.0005, 0.001, 0.0015, 0.0025, 0.007, and 0.010 m,As of the accuracy of my method, I believe it to be comparable to that of current photometers; suffice to mention that sun’s light compared with that of the moon is estimated to be 300 times larger by some measurement devices and 800 times larger by others, a range that demonstrates the poor precision of the scientific photometric experiments currently carried out.