Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are both 4 microtubule binding repeat tauopathy related disorders. Clinical trials need new biomarkers to assess the effectiveness of tau-directed therapies. This study investigated the regional distribution of longitudinal diffusion tensor imaging changes, measured by fractional anisotropy, radial and axial diffusivity over 6 months median interval, in 23 normal control subjects, 35 patients with PSP, and 25 patients with CBS. A mixed-effects framework was used to test longitudinal changes within and between groups. Correlations between changes in diffusion variables and clinical progression were also tested. The study found that over a 6 month period and compared to controls, the most prominent changes in PSP were up to 3±1% higher rates of FA reduction predominantly in superior cerebellar peduncles, and up to 18±6% higher rates of diffusivity increases in caudate nuclei. The most prominent changes in CBS compared to controls were up to 4±1% higher rates of anisotropy reduction and 18±6% higher rates of diffusivity increase in basal ganglia and widespread white matter regions. Compared to PSP, CBS was mainly associated with up to 3±1% greater rates of anisotropy reduction around the central sulci, and 11±3% greater rates of diffusivity increase in superior fronto-occipital fascicules. Rates of diffusivity increases in the superior cerebellar peduncle correlated with rates of ocular motor decline in PSP patients. This study demonstrated that longitudinal diffusion tensor imaging measurement is a promising surrogate marker of disease progression in PSP and CBS over a relatively short period. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are both sporadic atypical parkinsonian disorders associated with abnormal 4 microtubule binding domain (4R) tau protein accumulation in specific central nervous system neurons and glia, causing progressive disability and death –3. PSP iAs new pharmacologic agents targeting tau accumulation are being developed to treat 4R tauopathies, there is an urgent need for powerful biomarkers that can accurately measure disease progression and assess the effectiveness of therapeutic interventions. Previous biomarker studies of disease progression in PSP and CBS using MRI have focused on measuring rates of regional gray matter atrophy –14. ReceThis multicenter study investigates the progression of regional microstructural degeneration in PSP and CBS using longitudinal DTI measurements. To the best of our knowledge, a longitudinal DTI study of the regional distribution and rates of progressive microstructural degeneration in PSP and CBS has not been reported before. The main goals are: first, to determine the pattern of regional microstructural changes in PSP and CBS as well as the degree to which the changes exceed those seen in normal aging, potentially providing an imaging marker of disease progression; second, to test the degree to which regional microstructural changes correlate with growing clinical disability in PSP and CBS.Participants were recruited as part of two neuroimaging initiatives: the Four Repeat Tauopathy Neuroimaging Initiative 4RTNI), which enrolled PSP and CBS patients, and the Neuroimaging Initiative for Frontotemporal Lobar Degeneration (FTLDNI), which enrolled healthy subjects. The study was approved by the Institutional Review Board of each participating site and all subjects or their legal guardians gave informed written consent. Both initiatives were managed by the University of California at San Francisco (UCSF) and followed the same principle study design and protocols for collecting clinical data and 3T Tesla MRI scans at three sites: UCSF, University of California at San Diego (UCSD) and University Health Network (UHN), University of Toronto. At UCSF, the MRI data were centrally checked for quality and processed. A total of 92 subjects had two sequential MRI scans with a six months median scan interval (range: 5 to 16 months). Data from six subjects  had to be excluded because of egregious imaging artifacts. Of the remaining 86 subjects, 35 met criteria for probable PSP RTNI, whi, 2 had cAll 73 subjects who were enrolled in this study had a comprehensive neurological examination at baseline and follow-up visit that included: the PSP Rating Scale (PSPRS)  and the 3 isotropic voxel resolution. Parameters of T2-weighted images with fluid-attenuated inversion recovery were: TR/TE/TI = 6000/390/2100ms and same resolution as MPRAGE. DTI was acquired using a standardized 2D single-shot EPI sequence, which was initially optimized at UCSF and then installed at the two other centers. The scan parameters are: with TR/TE = 9200/82ms, a 128×128 matrix in-plane and 44 contiguous slices, yielding 2.7 mm3 isotropic resolutions. Four images with no diffusion sensitization (b0 image) and 41 directional diffusion-weighted images (b = 1000s/mm2) were acquired using parallel imaging with twofold acceleration to reduce susceptibility distortions and signal loss. A standardized DTI protocol for diffusion time, gradient strength, and spatial resolution was used to reduce variability between scanners. In addition and when appropriate, statistical tests were performed with and without the addition of scan centers as co-variate to determine the degree to which scanner variations potentially biased results.Three MRI types, T1-weighted, T2-weighted, and DTI were collected using Siemens  or GE  3T MRI machines. Acquisition parameters of the T1-weighted images, using a three-dimensional magnetization-prepared rapid gradient echo (3D-MPRAGE) scheme, were: TR/TE/TI = 2300/3/900ms, flip angle of 9°, sagittal orientation with 256×240×160 matrix size, 1 mmThe structural MRI and DTI data were processed using a largely automated processing pipeline that is illustrated in http://www.r-project.org/). Regional variations in FA, rD, and aD changes were separately entered as dependent variables using linear mixed-effects regression model, in which a time-by-diagnosis interaction term was included to estimate a fixed group effect on the rate of DTI changes while variations in scan intervals across subjects were treated as random effects. Group differences were tested pairwise. Laterality of DTI changes were further tested by including a side-by-time interaction term. Following a similar design in our previous study [PFDR<0.05.All statistical tests were carried out using the R Project of Statistical Computing  and total UPDRS score (p = 0.001) over the six months. In comparison between PSP and CBS, CBS patients declined clinically faster than PSP patients based on total PSPRS (p = 0.01) and PSPRS Limb-motor subscore (p = 0.02). Other clinical declines over time were not significant.Demographic and clinical performance data at baseline and follow-up are summarized in Regional patterns of group differences in FA, rD, and aD at baseline are illustrated in PFDR = 0.01, right: 2.6±1.2%, PFDR = 0.02) and to some degree also the left inferior frontal white matter region. PFDR = 0.004; right: 17.6±6%, PFDR = 0.003) and to some degree the thalamus and midbrain. Furthermore, PSP patients had higher than normal rates of increased aD bilaterally in the caudate nuclei , and to some degree in the left thalamus and bilateral midbrain.Compared to control subjects, PSP patients exhibited higher rates in FA reduction predominantly involving the superior cerebellar peduncles . CBS patients further showed higher than normal rates in aD increase bilaterally in the caudate nuclei , as well as in the superior longitudinal fasciculus, mid-posterior part of the cingulum, and the supramarginal white matter regions.Compared to control subjects, CBS patients exhibited a diverse pattern of increased DTI abnormalities over 6 months. In detail, CBS patients showed higher than normal FA reduction rates between 2 to 4%±1% bilaterally in white matter regions including the frontal, parietal, occipital and temporal lobes. PFDR<0.001; aD: 8.4±3%, PFDR = 0.002). No brain region in PSP had higher DTI rates than CBS in any region.Compared to PSP, CBS was associated with higher rates of up to 3±1% FA reduction over 6 months in the pre- and post-central, superior parieto-occipital as well as the temporal white matter regions, and higher rates of rD and aD increases in most of these regions, with the highest rates of rD and aD increases in the right superior fronto-occipital fasciculus  higher than normal rates of FA reduction than control subjects in bilateral superior fronto-occipital fasciculus and bilateral midbrain was well as in left pre- and post-central white matter areas and right thalamus. Patients also had higher than normal rates of rD increase that reached up to 25±6%, (PFDR<0.001). The regions included bilaterally the caudate nucleus, the thalamus and the midbrain, and to some degree the mid-posterior cingulum as well as pre-central and supramarginal white matter areas. In addition, the patients had higher than normal rates of aD increase that reached up to 15±4% (PFDR<0.001) bilaterally in the caudate thalamus and midbrain.Given the difficulty in pathologically separating CBD and PSP, an analysis was also performed with the patients pooled into a single group. Patients had around 2±1% . In CBS, rates of decline in PSPRS-Limb subscores correlated with rates of all three DTI variables in the post-central white matter region . Correlations between decline in total PSPRS  and DTI changes were not significant. For other clinical deficits , significant correlation were mainly observed in PSP group. In particular, decline in MoCA and SEADL correlated with rates of FA decline in the post-central region, and decline in MMSE correlated with changes over time of FA and rD in the mid-posterior cingulum.Correlations between DTI changes and clinical decline are summarized in The main novel result of this study is that PSP and CBS are each associated with a distinct pattern of longitudinal DTI changes in white matter relative to normal aging. These patterns are consistent with histopathological studies –40 of thIn PSP, the finding of progressive FA reduction particularly involving the superior cerebellar peduncle is consistent with histopathological reports of high vulnerability of this region to tau accumulation . The supOther prominent regions with high rates of diffusivity changes in PSP included the caudate, thalamus and midbrain. These regions are consistent with neuropathological distributions of tau-positive astrocytic inclusions in the basal ganglia, and the thalamus . HoweverThe distribution of the rapid DTI changes over time in CBS than control and PSP subjects is largely consistent with histopathological findings of diffuse cerebral tau accumulation in this disease . Unlike Our findings from evaluating DTI data of PSP and CBS together versus evaluating them separately are worth a discussion in the context of difficulties mapping the clinical features of PSP and CBS to a common pathology . Based oWe found that aD changes in the superior cerebellar peduncle best correlated with decline in PSPRS-Ocular motor subscores, although this correlation was significant only for aD, but weak for FA and rD. The lack of statistic powers of this correlation may due to short follow-up time, small sample size, or relatively later stage of the disease. However, the potential role of DTI changes of the superior cerebellar peduncle as marker of PSP progression should not be neglected, given the knowledge that selective damage to the superior cerebellar tracts contribute to the gaze palsy .The dominance of increased regional rD rates as compared to regional FA rates seems a prominent feature in CBS and PSP. Although the biological underpinning of various DTI measures is notoriously difficult, increased rD is generally thought to indicate demyelination , whereasA limitation of the study is that diagnosis was based on clinical symptoms without autopsy confirmation in the majority of cases. While the clinical criteria are relatively accurate for identifying PSP pathology, they are known to lack specificity for CBD pathology . ComorbiS1 FigPatterns of baseline group difference in FA (row A), rD (row B), and aD (row C).(TIF)Click here for additional data file.S2 FigIndividual trajectories of FA changes in A: the superior cerebellar peduncle, and B: the post-central white matter region of the control, PSP, and CBS groups. Thick solid lines represent the mean change in each respective group.(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Interventions are needed to reduce poor perinatal health. We trained community health workers (CHWs) as home visitors to address maternal/infant risks.In a cluster randomised controlled trial in Cape Town townships, neighbourhoods were randomised within matched pairs to 1) the control, healthcare at clinics , or 2) a home visiting intervention by CBW trained in cognitive-behavioural strategies to address health risks , in addition to clinic care . Participants were assessed during pregnancy  and 92% were reassessed at two weeks post-birth, 88% at six months and 84% at 18 months later. We analysed 32 measures of maternal/infant well-being over the 18 month follow-up period using longitudinal random effects regressions. A binomial test for correlated outcomes evaluated overall effectiveness over time. The 18 month post-birth assessment outcomes also were examined alone and as a function of the number of home visits received.Benefits were found on 7 of 32 measures of outcomes, resulting in significant overall benefits for the intervention compared to the control when using the binomial test (p = 0.008); nevertheless, no effects were observed when only the 18 month outcomes were analyzed. Benefits on individual outcomes were related to the number of home visits received. Among women living with HIV, intervention mothers were more likely to implement the PMTCT regimens, use condoms during all sexual episodes , have infants with healthy weight-for-age measurements , height-for-age measurements , breastfeed exclusively for six months , and breastfeed longer . Number of visits was positively associated with infant birth weight ≥2500 grams , healthy head-circumference-for-age measurements at 6 months , and improved cognitive development at 18 months .Home visits to neighbourhood mothers by CHWs may be a feasible strategy for enhancing maternal/child outcomes. However, visits likely must extend over several years for persistent benefits.NCT00996528ClinicalTrials.gov  Pregnancy and early childhood is a critical developmental period that creates lifelong advantages or costs for children living in poverty, including in South Africa The most robust intervention to date for low income, high risk mothers has been nurse home visiting over the first two years of life by Olds and colleagues in the US The effects of poverty on children are pervasive and long-lasting We implemented a cluster randomised controlled trial in Cape Town townships to examine maternal and child outcomes when trained CHWs implement home visits to all women in a neighbourhood. Home visitors were selected from community role models and trained in basic strategies to change thoughts, feelings, and behaviours, and targeted the specific health challenges of South Africa Consistent with our trial design The Institutional Review Boards of University of California Los Angeles (UCLA), Stellenbosch University, and Emory University approved the study, whose methods have previously been published Aerial maps, observations, and street-intercept surveys of residents were conducted in order to match township neighbourhoods Pregnant women were identified by recruiters conducting house-to-house visits every other month to all households in one intervention and one control neighbourhood. Potential participants were pregnant women at least 18 years old living in the neighbourhood from May 2009 to September 2010. Recruiters obtained consent-to-contact and then scheduled transport to a research site for interviewers to obtain informed consent and a baseline assessment. Transportation was also provided for the post birth interviews at 2 weeks post-birth, 6 months and 18 months. Pregnant women were recruited at an average 26 weeks of pregnancy . Only 2% of pregnant women refused participation.As described in an earlier publication http://www.mobenzi.com/researcher/). Interviewers recorded infants' physical and developmental status, and gathered data from the infant's government-issued Road-to-Health card. Supervisors monitored and gave feedback on the data quality weekly. Data collection concluded in October 2012.We recruited, trained, and certified township women to interview participants, entering responses on mobile phones (Nokia E61i and 2630) programmed by Mobenzi  and disclosure of serostatus to partners; asking partners to test for HIV; and consistent condom use . Among women living with HIV (WLH), managing one's health and stopping transmission to others requires knowing one's CD4 cell count (or not), adherence to antiretroviral medications (ARV) over the last week, and complete regimens to Prevent Mother-to-Child Transmission (PMTCT). To PMTCT, mothers must adhere to ARV starting from week 28 of pregnancy; take ARV during labour; provide ARV to infants post-birth; test infants for HIV and retrieve results at 6 weeks post-birth; use one feeding method (either breastfeeding or formula) for the first 6 months; and exclusively breastfeed.Child health status was assessed by LBW (<2500 grams) and by converting infant anthropometric data (collected from birth records and growth monitoring) to z-scores based on the World Health Organisation's (WHO) age-adjusted norms. A z-score below -2 standard deviations was considered a serious health deficit Healthcare was assessed by self-reports of antenatal clinic visits, post-birth complications , and tuberculosis (TB) testing. Immunisation data were extracted from Road-to-Health cards.Depressive symptoms were reported on the Edinburgh Postnatal Depression Scale (EPDS), using a cut-off of >13 to indicate depressed mood Social networks' size and frequency of contact and paternal acceptance of the child were self-reported. Receipt of the government child grant was documented.http://www.westerncape.gov.za/eng/directories/services/11500/6389). In our sample of women who gave birth in Cape Town, approximately 79% of women gave birth in a hospital, 20% gave birth at a non-hospital facility, and 1% gave birth at home.Standard clinic care in Cape Town is accessible and provides free HIV testing, dual regimen therapies for WLH, consistent access to milk tins (formula), TB and CD4 cell testing, co-trimoxazole for infants until HIV testing, HIV polymerase chain reaction (PCR) testing for infants at six weeks, postnatal visits at one week, treatment for WLH, and HIV testing for partners of WLH (th–12th grade education around 40 years old (range 34–59) who were trained for one month in cognitive-behavioural change strategies and roleplaying. They also watched videotapes of common situations that CHWs might face. CHWs were women selected to have good social and problem solving skills, having raised healthy children through their own coping skills, and were trained to provide and apply health information about general maternal and child health, HIV, alcohol use, and nutrition to township women. CHWs were certified and supervised biweekly with random observations of home visits.In addition to clinic care, CHWs provided home visits to participants. CHWs were women with 10CBW from Philani implemented the intervention. Eight health messages were delivered regarding a healthy pregnancy, HIV/TB testing and PMTCT, reducing alcohol use and malnutrition, and encouraging breastfeeding, with the aim to deliver these messages in at least four antenatal visits and four post-natal visits within the first two months of life We first looked for significant differences in baseline demographics between conditions at baseline and among those re-assessed (or not) at post-birth, six and 18 months. To control for multiple comparisons and measure the intervention's overall effect on well-being, our primary analysis of the intervention's impact was conducted using one overall test which compared 32 different outcomes simultaneously. On many of the outcomes, almost all mothers would have accomplished the task, without an intervention . The potential benefits of an intervention are relatively small for such outcomes. Comparing 32 outcomes, chance would lead one to observe up to three significantly different outcomes between the control and the intervention conditions. The binomial test evaluates the number of significant differences between the control and intervention conditions to determine if there is a significant overall difference between conditions. Thus, a binomial test evaluated the number of significant effects favouring the intervention among 32 correlated binary outcomes tested at a one-sided, upper-tail alpha = 0.025 . As the binomial test was the primary analysis, we considered our analyses of individual outcomes to be exploratory and retained the model p-values in lieu of further multiple-testing adjustments.To examine if early intervention impact was sustained for the 12 outcomes that were created by combining data from multiple time points , a second exploratory analysis compared these measures between intervention and control using 18-month data only, using the regressions described above.as-treated outcomes, investigating the association between each outcome and the number of CHW visits received (using the regressions described above). We included the number of visits between each assessment point as a covariate in order to systematically control for the number of home visits. Thus, post-birth outcomes were a function of the number of antenatal visits; six month outcomes were a function of postnatal visits between birth and the six month assessment; and 18-month outcomes were a function of the number of home visits between six and 18 months post-birth. By definition, women in the control arm had zero visits. Intervention mothers who received zero CHW visits were excluded from the as treated analysis .An exploratory analysis examined the Late-entry participants' data were included in all analyses. Based on their age at the late-entry assessment, data from infants of late-entry mothers were split between post-birth  and 6-month  outcomes. Overall, results were similar whether or not late-entry participants' data were included; results are available upon request.As previously reported The analysis of individual outcomes identified significant treatment differences in HIV-related prevention strategies and child health status. More intervention mothers used condoms consistently than control mothers . Infants of intervention WLH were more likely to receive nevirapine at birth  and azidothymidine post-birth . Intervention WLH were significantly more likely to report using one feeding method for the first 6 months post-birth than control WLH . Over 18 months, intervention mothers were more likely to have infants with weight-for-age z-score ≥−2 , breastfeed their infants more than the median number of months , and exclusively breastfeed their infants for 6 months . Intervention mothers tended to have fewer LBW infants (birth weight ≥2500 grams) than control mothers . There were no significant differences on measures of healthcare, risky alcohol use, depression or social support.For the 12 outcomes that were created by combining data from multiple time points, we did not find any significant differences between the intervention and the control arms when we analysed these measures using the 18-month data only (available upon request).Each of the aforementioned outcomes was also significantly related to the number of home visits received. That is, the more home visits made by CHWs, the larger the effect sizes were on maternal and infant outcomes. In addition, the as-treated analyses found three significant differences that were related to the number of visits conducted, even though intention-to-treat analyses did not indicate a significant difference. CHW visits were significantly associated with higher odds of infant birth weight ≥2500 grams , infant 6-month head-circumference-for-age z-score ≥−2 , and infant cognitive composite score on the 18-month Bayley assessment ≥85 .The Millennium Development Goals are unlikely to be met by most LMIC, emphasising the need for effective interventions for mothers and infants living in poverty Similar to other home visiting programs Mothers also increased breastfeeding and HIV-related protective actions with adult partners. Infant outcomes in weight-for-age improved as well. The size of the effect was significant, but leaves substantial room for improvement. Similar to other RCT of breastfeeding interventions Each of the significant outcomes in our intention-to-treat analysis also was significant in the as-treated analysis. If the program were to be scaled up, the results likely would mirror the results in the intention-to-treat analyses. Notably, the number of home visits also was significantly related to children's cognitive development on the Bayley Scale at 18 months, having fewer LBW infants, higher birth weights overall, and larger head circumferences at six months. The finding of better cognitive development on the Bayley scales is particularly important, whereas benefits to measures of infant physical health were not sustained until 18 months. This RCT was designed to evaluate the intervention's impact over the first 18 months of life. Our primary analysis found significant benefits over the entire 18 month follow-up period. However, when the outcomes at only the 18 month assessment were examined, the benefits were not significantly different between the RCT's two arms, except in the as-treated analyses. To sustain efficacy, it may be necessary to continue home visits beyond the postpartum period.Recruitment of pregnant women by canvassing household-to-household proved to be a limitation. Although the samples were highly similar across matched pairs of neighbourhoods, 16% (n = 94) of mothers in the control arm were recruited late in pregnancy or in the first months following childbirth. With or without these women in the analyses, the result of the RCT is the same. However, external validity is higher when they are included; therefore, we added the late-entry women. Fortunately, 93% of women completed at least one follow-up assessment and 83% of the sample completed all assessments. In addition, there was one selection effect across the four assessments: mothers not reassessed at 18-months were a year older at recruitment. It is also possible that self-reports for behaviours may have resulted in socially desirable answers for some outcomes. We believe, however, that the significant effects are unlikely to be attributable to reporting bias. Growth measures, health visits, immunisations, and HIV-related health behaviours are recorded on the infants' Road to Health card, similar to the documentation of the child grant.We expected that there would be ceiling effects on many outcomes, and indeed more than 90% of participants in both arms reported positive outcomes for 8 of the 32 measures. This reflects partly the good clinical services available in Cape Town, which would be unusual in most of Africa and even South Africa. At baseline, 91% of pregnant Cape Town women were tested for HIV and received their results; this contrasts to 61% in Eastern/Southern Africa typically Home visiting long has been demonstrated efficacious when mounted by professionals The mean of 11 CHW visits in this trial is substantially more intensive than most vertical, single-disease-targeted interventions. Regular visits were typically stopped by about 6 months post-birth, with check-ins only once every six months after that. This appears to be too small a dose for this intervention. The failure to find additional benefits from 6–18 months post-birth, when only analysing the 18 month outcomes, suggests that to sustain significant benefits, home visiting must be sustained for several years. We anticipate that home visiting must be routine through the first five years of life, for the parenting challenges shift dramatically as the children age and families have received little preparation for readjusting their parenting behaviours, beliefs, and expectations.This intervention features a number of innovations. Typically, home visiting interventions focus on training CHWs in manualised interventions  that must be replicated with fidelity to a set of activities and scripts, and may not fit a specific situation In addition, home visits offer a viable strategy to circumvent challenges typically associated with obtaining healthcare from clinics. Clinic appointments are difficult to schedule; waiting lines are long; transport is expensive; and mothers must coordinate their own and infants' care across multiple clinics As the South African government begins to implement a model that targets multiple domains, we have demonstrated a strategy to implement and to evaluate such an intervention. This model may be useful for countries that aim to promote task shifting from professionals to CHWs, with a solid strategy for selection, monitoring, and consistently providing outcome feedback.Appendix S1Analysis details.(DOCX)Click here for additional data file.Checklist S1CONSORT Checklist.(DOCX)Click here for additional data file.Protocol S1Trial Protocol.(PDF)Click here for additional data file.


Admission to intensive care units is potentially stressful and usually goes together with disruption in physiological and emotional function of the patient. The role of the families in improving ill patients’ conditions is important. So this study investigates the strategies, potential challenges and also the different dimensions of visiting hours’ policies with a narrative review. The search was carried out in scientific information databases using keywords “visiting policy”, “visiting hours” and “intensive care unit” with no time limitation on accessing the published studies in English or Farsi. Of a total of 42 articles, 22 conformed to our study objectives from 1997 to 2013. The trajectory of current research shows that visiting in intensive care units has, since their inception in the 1960s, always considered the nurses’ perspectives, patients’ preferences and physiological responses, and the outlook for families. However, little research has been carried out and most of that originates from the United States, Europe and since 2010, a few from Iran. It seems that the need to use the research findings and emerging theories and practices is necessary to discover and challenge the beliefs and views of nurses about family-oriented care and visiting in intensive care units. Admission to intensive care units (ICUs) is potentially stressful and usually goes together with disruption in physiological and emotional function of the patient . The criHowever, open visiting hours can cause some major concerns for the nurses and the doctors: 1) it can increase the patients’ physiological stress; 2) it can interfere with nurses’ care and 3) it can lead to physical and emotional exhaustion of the families . EvidencTraditionally, intensive care unit visiting hours in Iran follow constrained and strict rules. Despite the importance of this issue in our country, there have been few studies concerning this issue and we believe that in order to implement the best visiting hour strategy, a transition in the culture is needed. This should be based on a review of texts relating to visiting hours strategies, this study investigates the strategies, potential challenges and also the different dimensions of visiting hours’ policies.A narrative review about visiting policies in Intensive Care Units was performed. Narrative reviews are the traditional approach mainly based on the experience and subjectivity of the author .The search was carried out in scientific information databases such as Web of science, PubMed, CINAHL, Google Scholar and All EBM Reviews (OVID) using keywords “visiting policy”, “visiting hours” and “intensive care unit” with no time limitation on accessing the published studies in English. In order to access published Iranian research, some Iranian databases, including the Iran Medex, Google, Scientific Information Database (SID) and the published information database of the country (Magiran) were searched with the same keywords in Farsi, the Persian language.We included all reviews, analytical designs and descriptive studies reported on visiting policies and visiting hours published in peer-review journals. Only articles in English or Persian were included. Studies not related to ICUs were excluded too.From 42 total articles gathered in our search, 22 were selected for reading. A total of 42 articles were found with from 1997 to 2013 with the keywords. Of these, 22 articles conformed to our study objectives of addressing strategies, potential challenges and different dimensions of visiting strategies in ICUs. The remainder did not particularly investigate visiting hours in intensive care units and were therefore outside the scope of this research. Some abstracts were also investigated when the full text was not accessible. Some instructions in the United States, UK, India, Belgium, Italy, and France and hospital statements related to visiting hours strategies were also studied. As seen in From 22 studies investigated, only English and three Persian articles in the internal scientific information databases, particularly discussed visiting hours in ICUs in Iran .Traditionally intensive care units have been open and welcoming and this may be a reason for patients’ concern about their privacy. The critical conditions of these patients or the possibility of their death make the need for their family to visit crucial. This has become a challenge because of the physical space constraints. Some studies indicate that visits should be possible at any time and are necessary, while others state that preserving the patients’ privacy and the dignity of their visitors is imperative. The visiting methods and policies have caused many arguments regarding how visiting in ICUs should be managed . No majo‘Visiting’ takes on a wide spectrum of meanings in the hospital environment. Limited visiting is a method that allows visitors presence during a specific time, while open visiting allow visitors to be with their family and friends at any time they want. The human conditions and compassion call for “flexible” visits between these two extreme strategies. Other names such as contractual, structured or unlimited visiting have also been used to describe what is meant. These strategies are different for public or private hospitals, special emotional conditions of the patients and various cultural differences .Vandijck et al. have shown in their studies that most ICUs in western Europe still follow a restricted policy in which the time and duration is priori specified . EvidencThis strategy allows families to visit their patient at any time they want during the day . EvidencDespite the fact that the information based on evidence shows that the visiting strategy in ICUs must be according to the patients’ needs and should not have limits regarding time, duration or the number of visitors. The clinical instructions should recommend strategies for unlimited visiting in ICUs because of the family oriented care. Visiting rules in ICUs are usually set by the ICU staff. They must balance the needs of the members of the family, the needs of the patients to rest and the needs of the nurses to provide patients care. Being with the patients in ICU is as important for their family as being informed about their illness. Several studies have shown that patients prefer flexible visiting strategies. Open visiting hours realize the families’ needs and have a positive impact on the patients, improve patient satisfaction and may even reduce the stay in hospital . GonzaleTraditionally, some nurses believe that an open visiting strategy is potentially harmful to ill patients. They believe that it increases the intracranial pressure, blood pressure, heart rate and causes premature atrial and ventricular contractions. There is no research available to support negative physiological impacts of family visits on patients. To the contrary, researchers suggest that open visiting reduces stress and leads to tranquility and thus helps patients to rest. Different studies have shown that not only has there been no increase in cardiovascular indicators  in patients having visitors but in fact was even considerably lower  and had Another reason for disagreement on unlimited (open) visiting hours is that it interferes with nurses’ and doctors’ work and makes patient care more difficult for them. Studies show that families create more opportunities to facilitate patient-staff communications and even train patients to communicate better with staff . MembersSome researchers believe that open visits create problems for families or friends as they come with their own needs. However, the fact is that open visiting hours help to relieve the anxiety of the families as they can spend more time with their patients and feel more secure in being with them than not being there. Berwick et al. have shown that open visiting hours has a positive effect on 88% of the families and reduces anxiety in 65% of them .The foundation of patient care is the needs and demands of the patient. Patients having visitors are more satisfied as this is part of realizing the needs of their family and of their own. Several studies show that not only has visiting no undesired physiological effect on the patients, but provides them with comfort and convenience, reduces cardiovascular complications, creates a feeling of security and satisfaction for the patients and the family and improves their communication with the staff. The presence of the family is in most cases effective; e.g. providing information about patient history, helping nurses choose physical care, motivating the patient and helping in improvement and positive reinforcement of the patient . AlthougDespite nurses understanding the importance of open visiting, implementing this strategy still faces many obstacles in case of the ICUs . The lacNurses have a primary role in visiting hour’s strategies . DespiteThe trajectory of current research shows that visiting in ICUs has, since their inception in the 1960s, always considered the nurses’ perspectives, patients’ preferences and physiological responses, and the outlook for families. However, little research has been carried out and most of that originates from the United States, Europe and some from New Zealand and Australia  and sincNurses must be aware of the significance of open visiting for patients’ and their families’ benefits and consequently visitors must be aware of the patients’ privacy, current geographical space for care provision and their ability to help in patient care. Individual differences between patients and families  and allowing nurses to control and organize the ICU in developing the visiting strategy must be considered to result in an appropriate agreement between patients, families and staff concerns. Not only does open visiting not harm patients, but it creates a support system for them and forms familial environments . Open vi


The relationship of maternal glomerular filtration rate (GFR) in pregnancy to fetal size needs to be better characterized as it impacts an ongoing debate about confounding effect of maternal GFR in investigations of important environmental contaminants. We aimed to characterize the size of the association between maternal GFR and infant birth weight.A sub-cohort of 953 selected women (470 women with and 483 women without preeclampsia) in the Norwegian Mother and Child Cohort (MoBa), recruited during 2003–2007 were analyzed. GFR in the second trimester was estimated based on plasma creatinine. Birth weight was ascertained from the Medical Birth Registry of Norway. Multivariate linear regression was used to evaluate the association between maternal GFR in second trimester  and infant birth weight. Partial correlation coefficients were also calculated.Maternal GFR-CG  and GFR-MDRD  were associated with infant birth weight in models adjusted for maternal weight in kilograms, preeclampsia, and gestational age at delivery (days). Partial correlation coefficients for the association between infant birth weight and GFR were 0.07 for both formulas. Although the birth weight-GFR association was stronger among the women with preeclampsia, the difference from women without preeclampsia was not statistically significant.These data support an association between GFR during pregnancy and infant birth weight, and indicate that GFR may confound selected epidemiologic associations. The relationship of glomerular filtration rate (GFR) in pregnancy to fetal size needs to be better characterized because the size of the association impacts an important ongoing debate in environmental health. Perfluoroalkyl substances (PFAS) are environmental contaminants detectable in the serum of nearly everyone Direct measures of GFR in pregnancy and birth weight were made in two small studies In line with previous findings in the field, we hypothesized that there is an association between maternal estimated GFR (eGFR) in mid-pregnancy and fetal birth weight. The specific aim of this study was to characterize the association between maternal eGFR and fetal size at birth in a large sample of pregnant women from Norway. GFR can be measured either directly by clearance of inulin or iohexol, or estimated indirectly by using the patient’s plasma creatinine value. In this study GFR was estimated using three widely used indirect methods; the Cockroft and Gault (CG), the Modification of Diet in Renal Disease (MDRD), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) The analyzed data were obtained from a sub-study within the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health The subjects in the current study were originally selected for a case-cohort study on PFAS and preeclampsia, and were enrolled in the MoBa cohort from 2003 to 2007, as described in detail elsewhere The study was approved by The Ethics Committee of the Southern Healthcare Region of Norway (REK-SØR), the Norwegian Data Inspectorate and the National Institute of Environmental Health Sciences Institutional Review Board. Participants provided their written informed consent to participate in this study upon recruitment.Maternal non-fasting blood samples were collected at enrollment in the MoBa cohort (at the time of the second trimester ultrasound scan). Samples were shipped to the biobank facilities in Oslo from hospitals and maternity units throughout Norway and the majority were received and processed the day after collection Samples were shipped on dry ice to the National Institute of Environmental Health Sciences laboratory in Durham, USA and plasma creatinine (modified Jaffé) was analyzed with an Olympus AU400e Clinical Chemistry Analyzer , using reagents from Beckman Coulter Inc. . The between-assay coefficient of variation was 3%, based on 25 QA/QC specimens that were analyzed blindly (1 QA/QC specimen per batch). The mean level was 80.4 umol/l.−1.154×age−0.205×0.742) and the Chronic Kidney Disease Epidemiology Collaboration −0.329×(0.993)age in years, and for females with serum creatinine >62 µmol/L: GFR = 144 (serum creatinine [µmol/l]×0.0113/0.7)−1.209×(0.993)age in years). The latter is a recently developed equation to calculate eGFR.Plasma creatinine was used to estimate GFR based on the formula of Cockroft-Gault (CG: GFR = (140–age)×weight (kg)×1,04/serum creatinine (µmol/l)), the modification of diet in renal disease (MDRD: GFR = 175 (serum creatinine [µmol/l]×0.011312)Infant birth weight, maternal age in years at delivery, and gestational age in days was obtained from the Medical Birth Registry of Norway (MBRN). The latter was estimated based on ultrasound performed in week 18 at inclusion into the MoBa cohort. Maternal weight in kilograms was based on self-report from questionnaire 1, filled in prior to the ultrasound assessment. Preeclampsia is reported to the MBRN as a dichotomized variable. The sub-study cases were restricted to those whose diagnosis was verified after review of antenatal medical records, as described elsewhere Linear regression models in the total cohort were adjusted for maternal weight (in kilograms), preeclampsia (yes/no) and gestational age at delivery (days). Additional adjustment for gestational length at blood draw and maternal diabetes had no effect on the results. The birth weight-GFR relationship was statistically homogeneous across preeclampsia status , and underlying assumptions for linear regression were fulfilled. Partial correlation coefficients were also calculated with adjustment for the same covariates listed above. We also performed stratified analyses on women with and without preeclampsia, adjusting for maternal weight and gestational age at delivery. The two-sided level of significance for all analyses was 0.05. All analyses were conducted using SPSS version 20.0.The characteristics of the 953 included women are outlined in Adjusted coefficients with standard errors (SE) from multiple linear regression analysis of the association between infant birth weight and maternal eGFR in second-trimester by the CG, MDRD and the CKD-EPI formulas are outlined in In women with preeclampsia (n = 470) each ml/min increase in GFR (in second trimester) the infant weight at delivery increased by 1.1 gram  when using the CG-formula and with 1.3 gram  when using the MDRD-formula. The same analyses for women without preeclampsia (n = 483) were not statistically significant . However22 d.f. is 3.58 (p = 0.17).In We found a significant association between estimated maternal GFR in the second trimester and infant birth weight by using two different formulas (CG and MDRD) for calculating eGFR in the total cohort, but not when using a third recently developed formula (CKD-EPI). The absolute values and difference in GFR between formulas were in accordance with previous studies in pregnant women Although the estimates of the relationship between birth weight and GFR from the present two earlier studies To illustrate the importance of the birth weight-GFR relationship to epidemiologic results on birth weight and PFAS concentrations in pregnancy, we analyzed the data for the 953 subjects in a model of birth weight in relation to the concentration of perfluoroctanoic acid (PFOA), adjusted for pre-pregnancy body mass index (kg/m2), gestational age at birth, gestational weight gain, and preeclampsia.  http:/Hedwig.mgh.harvard.edu/sample_size/js/js_associative_quant.html). This number could be decreased by enriching the sample with SGA infants The major strength of our data was the large sample of women who had their GFR estimated compared to the previous studies These data support a modest, positive association between GFR during pregnancy and infant birth weight, and indicate that GFR may confound selected epidemiologic associations. The quantitative estimate of the relationship presented, although provisional until better estimates become available, will also inform pharmacokinetic studies of the extent of such confounding.


Primary retroperitoneal parasitic cysts are rare. Here we report about a middle aged male patient from rural north India with a recent onset of central abdominal retroperitoneal lump, pain, and fever. After surgical resection due to diagnostic uncertainty, at histopathology, it turned out be a filarial cyst. After receiving a course of diethylcarbamazine, the patient is asymptomatic at 4 months' follow-up. Primary retroperitoneal parasitic cysts are uncommon , 2. MostA 35-year-old gentleman, from rural north India, presented with a progressive, central abdominal lump for one-month duration. Three weeks after the appearance of the lump, he developed intermittent high grade fever and dull aching abdominal pain. He did not have any significant past illness or comorbidities. On examination, he had a moderately tender abdominal lump predominantly in the umbilical region. Apart from nontender thickening of the right spermatic cord, there was no scrotal or testicular abnormality. The inguinal nodes were barely palpable and there was no lower limb edema.Complete blood counts and blood chemistry were within normal limits. Blood culture was sterile. Abdominal sonography revealed a large, well defined, unilocular cyst of 20 × 14 × 23 cm size, located behind the right colon and terminal ileum. There were no features suggestive of an abscess. The rest of the organs were normal. Contrast enhanced CT scan confirmed the sonographic findings without adding any other information. The origin and etiology of the cyst could not be delineated .Due to diagnostic uncertainty and association of symptoms like pain, the abdomen was explored revealing a large retroperitoneal cyst behind the right colon, mesocolon, and terminal ileum, stretching the organs over it. As there was well defined avascular plane around the cyst, the cyst could be excised completely without any spillage. A conglomeration of grossly dilated lymphatics was seen close to upper pole of the cyst and excised along with the cyst. The rest of the organs were normal. The cut section of the cyst revealed a thick walled cyst containing minute filamentous septations and mucoid material . PostopeCyst fluid analysis showed total cell count of 95/cmm with 60% lymphocytes and 40% neutrophils. Cyst fluid culture was sterile. Histopathology of the cyst showed numerous cystic spaces packed with microfilariae and dense mixed inflammatory infiltrate in the surrounding tissues . It was Primary retroperitoneal cysts are rare, often asymptomatic, and incidentally detected. They have been classified as (a) urogenital cysts, (b) mesocolic cysts, (c) cysts arising in cell inclusions, (d) traumatic cysts, (e) parasitic cysts, and (f) lymphatic cysts, depending on the origin and histology , 2. OfteFilariasis presenting as a retroperitoneal cyst is extremely uncommon. Reported incidence of filarial retroperitoneal cyst in hospitalized patients is 1/105000 , 7. To oKapoor et al. reported about a patient with similar presentation except the duration of symptoms was longer (6 months) and patient also had bilateral hydrocele . They es Wuchereria bancrofti. Common presentations are asymptomatic microfilaremia, acute adenolymphangitis, hydrocele, and lymphedema [Among all 8 species of filarial worms, the most common organism encountered in India ismphedema . Recent Even though filarial retroperitoneal cysts are uncommon, in endemic areas it must be included in the differential diagnosis of the retroperitoneal cysts.


Quantifying epidemiological dynamics is crucial for understanding and forecasting the spread of an epidemic. The coalescent and the birth-death model are used interchangeably to infer epidemiological parameters from the genealogical relationships of the pathogen population under study, which in turn are inferred from the pathogen genetic sequencing data. To compare the performance of these widely applied models, we performed a simulation study. We simulated phylogenetic trees under the constant rate birth-death model and the coalescent model with a deterministic exponentially growing infected population. For each tree, we re-estimated the epidemiological parameters using both a birth-death and a coalescent based method, implemented as an MCMC procedure in BEAST v2.0. In our analyses that estimate the growth rate of an epidemic based on simulated birth-death trees, the point estimates such as the maximum a posteriori/maximum likelihood estimates are not very different. However, the estimates of uncertainty are very different. The birth-death model had a higher coverage than the coalescent model, i.e. contained the true value in the highest posterior density (HPD) interval more often (2–13% vs. 31–75% error). The coverage of the coalescent decreases with decreasing basic reproductive ratio and increasing sampling probability of infecteds. We hypothesize that the biases in the coalescent are due to the assumption of deterministic rather than stochastic population size changes. Both methods performed reasonably well when analyzing trees simulated under the coalescent. The methods can also identify other key epidemiological parameters as long as one of the parameters is fixed to its true value. In summary, when using genetic data to estimate epidemic dynamics, our results suggest that the birth-death method will be less sensitive to population fluctuations of early outbreaks than the coalescent method that assumes a deterministic exponentially growing infected population. The control or prediction of an epidemic outbreak requires the quantification of the parameters of transmission and recovery. These parameters can be inferred from phylogenetic relationships among the pathogen strains isolated from infected individuals. The coalescent and the birth-death process are two mathematical models commonly used in such inferences. No benchmark on the performance of these models currently exists. We aimed to objectively compare two specific models, namely the constant rate birth-death model and the coalescent with a deterministic exponentially growing infected population. We compare coverage, accuracy, and precision with which they can capture the true epidemic growth rate parameter using simulated datasets. We find that the constant rate birth-death process can account for early stochasticity and is thus capable of recovering the epidemic growth rates more successfully. Provided one of the parameters is known, e.g. the sampling proportion of infected individuals, then the basic reproductive ratio can also be estimated reliably. We conclude that a birth-death-based method is generally a more reliable method than a deterministic coalescent-based method for epidemiological parameter inference from phylogenies representing epidemic outbreaks. Care should be taken if sampling is not constant through time or across individuals, such scenarios require so-called birth-death skyline models or multi-type birth-death models. In many applications determining the past dynamics of populations is of interest. In an epidemiological context in particular, the interest lies in knowing two quantities: the basic reproductive ratio SIR-type models have been widely used to describe epidemiological dynamics For an epidemic following SIR dynamics, the growth of the population size at the initial stage of the spread follows an exponential trend, although it slows down at later stages due to a depletion of susceptibles. We focus on a special scenario, where only the early epidemic outbreak, i.e. exponential growth of the infected population, is being considered. We can simplify the model to a constant rate birth-death process, where we assume no significant decrease in the number of susceptibles over time, formalized as Recent genetic sequencing efforts have produced many pathogen sequences from different hosts. To reconstruct their phylogenetic relationships, numerous methods have been developed , andthe population size is small enough to be able to trace back the MRCA.In most of the coalescent models, a further assumption is made:the population size changes deterministically.The coalescent can also be interpreted as a continuous time limit of the discrete time Moran process In an epidemiological context, the sampling proportion in a recent epidemic can be quite high. For instance, the sampling proportion of the HIV epidemic in Switzerland has been estimated to be 0.75 The birth-death model also requires assumptions 2) and 4) to be fulfilled. Additionally, the generation times are assumed to be exponentially distributed, instead of discrete generations as in the assumption 1). We see the major difference between the birth-death model and the coalescent in three factors:The birth-death process produces trees and analyzes phylogenies assuming stochastic population sizes, thus relaxing the deterministic population growth assumption 5) of deterministic coalescent models  is relaxed.The birth-death process explicitly models the sampling process while the coalescent conditions on sampling, assuming each lineage at a sampling point is equally likely to be the one included. The explicit modelling of sampling is an advantage if the sampling process is known, but a disadvantage if the sampling process is hard to estimate.In this paper, we want to shed light on the practical importance of the theoretical points raised above for parameter estimation. We investigate the comparative performance of the birth-death and the deterministic coalescent model in phylodynamic parameter estimation by doing a simulation study. We first simulated both constant rate birth-death model trees with incomplete sampling , and coalescent model trees with deterministic exponential infected population growth . We then applied phylodynamic methods based on the birth-death model and the coalescent model within the BEAST v2.0 software package to the simulated phylogenies. In this fashion, we estimate the phylodynamic parameters and compare coverage (measured as the fraction of simulated trees where the HPD captures the true parameter), accuracy (measured as the root mean square error (RMSE)) and precision  of the parameter estimates.We simulated 100 trees with 100 tips (for each parameter combination) under the birth-death model at different The ability of this specific birth-death model and the coalescent model to capture the true growth rate In the critical case where me , or  . The 95%When applying the birth-death method to coalescent trees, the growth rate coverage is higher than when applying the coalescent method to birth-death trees. The higher coverage of the birth-death model comes partially at the cost of a larger 95% HPD interval size see . The nornchanged . The incWe will now discuss the reason for biases when applying the birth-death method to coalescent trees and vice versa. When applying the birth-death method to coalescent trees, for  reached .When applying the coalescent method to birth-death trees, the coalescent misses the true growth rate value (the HPD does not contain the true growth rate) on the birth-death model trees more often than the birth-death model on the coalescent trees. This is accentuated with decreasing We observe this push-of-the-past effect and the resulting differences in coalescent and birth-death trees in our simulations. We investigated the difference between birth-death and coalescent trees for the parameter combinations where most stochasticity in population size variation over time and most bias of the inferred parameters was observed: As the population size growth curves in semi-logarithmic plots are parallel lines with the slope ntervals .When applying the birth-death model to the long coalescent trees we occasionally observed an overestimation of the growth rate. In most cases the growth rate is estimated correctly by the birth-death model though. The coalescent trees typically have long branches close to the root. In the following we will demonstrate that these early long branches do not strongly impact the overall likelihood calculation in the birth-death model.To investigate the impact of long early branches on parameter estimation under each model further, we changed the simulated trees systematically. We looked at trees simulated under ath tree .Re-analyzing the trees with Re-analyzing the trees with rbations . This isations  due to a depletion of susceptibles. In trees produced by an SIS model with small total population size  estimate from the final MCMC runs. We also report the maximum of the tree likelihood values (ML) of the final MCMC run. For uniform priors and fixed time to origin Under both the birth-death and the coalescent models, the times of coalescence or bifurcation are stochastically selected from the distribution of coalescence and bifurcation event times. The individual trees produced by both the coalescent and the birth-death process are thus stochastic realizations of the respective processes. However, the coalescent model with exponential growth of the infected population assumes deterministic changes in the population size. Therefore, the trajectory of the infected population size follows an exponential growth. It has been pointed out before It has been postulated earlier We show that the ability of the coalescent with deterministic exponentially growing infected population to properly estimate the dynamical parameters of the birth-death trees derived from early epidemics is questionable, which was previously suggested by the small simulation study in This claim is supported by three observations. First, the birth-death trees show systematic difference from the coalescent trees in their lengths due to the push-of-the-past effect. This effect is the strongest in low In contrast to the coalescent, stochasticity in population size is incorporated into the birth-death process. The birth-death model performs well not only on birth-death trees but also on most coalescent trees. This is due to the birth-death process interpreting variation in branching times as stochastic changes in population size over time leading to large HPD intervals. The birth-death model therefore accepts many different parameter combinations that may have given rise to the observed tree. Furthermore, the ability of the birth-death model to correctly estimate the parameters from the coalescent trees decreased only in those trees that were simulated under combination of high The birth-death model is sensitive if large parts of the tree depart from the birth-death model assumption, as the birth-death model averages over observations throughout the whole tree. This sensitivity becomes particularly apparent in the analysis of SIS/SIR trees and of trees with varying sampling probability over time. Both the birth-death skyline The differences of the birth-death method and the coalescent method are mainly observed in the 95% HPD intervals, while only minor differences were apparent in the point estimates, i.e. the maximum a posteriori and maximum likelihood estimates. When comparing the performance of inference methods, it is therefore crucial to always assess the capability of recovering the uncertainty in parameter estimates.While our study only compared the birth-death and the coalescent methods on simulated trees, previous work also compared the two models on empirical data. A higher estimate of the growth rate parameter of the HCV epidemic in Egypt was reported previously when data were analyzed with the coalescent model as compared to the birth-death model In the present study we estimate epidemiological parameters based on fixed trees. We note that the tree probability only depends on the branching (transmission) and removal times. Thus, the Bayesian estimates of growth rate Birth-death based methods explicitly parameterize epidemiological parameters beyond the growth rate In general, when one knows what kind of population dynamic process gave rise to the tree, the appropriate method should be applied for phylodynamic parameter estimation based on such trees. In case of doubt of the underlying process generating the genealogy, our results show that in scenarios of constant sampling and exponential population growth, especially when the samples were drawn early in the epidemic outbreak, the constant rate birth-death process with incomplete sampling is a better choice than the coalescent assuming deterministic exponential infected population growth.The assumption of exponential spread of a pathogen with constant sampling is limiting since many epidemics are better characterized by SIS or SIR dynamics with time-varying sampling, for example. Recent work proposed birth-death based SIS and SIR models We used three epidemiological SIR-type models to simulate transmission trees growing forward in time, namely the constant rate birth-death process (epidemic outbreak), the SIS model and the SIR model. All of the models are implemented as a Gillespie algorithm All models have a common birth or transmission rate These models induce transmission trees in the following way. Each infected individual is represented by a lineage. A transmission event results in a branching event, while a removal event results in the termination of a lineage, thus a tip in the tree. We assume that we sample each tip from the complete transmission tree with probability Initially, the population size of infected individuals simulated by these models is increasing at the rate The constant rate birth-death process always stays in the exponential growth phase. Under the SIS model, we have a finite total population size Under the SIR model, there is only a single one-way flow of individuals from For each chosen parameter setting of We produce trees generated both by SIR-type models  and by coalescent models for optimal comparison of performance of the birth-death and the coalescent model in estimation of phylodynamic parameters.We used the BEAST v2.0 package The constant rate birth-death model with incomplete sampling and the coalescent model with deterministic exponential population growth were applied to the simulated trees to infer the posterior distribution of parameters. For this purpose, we used For the analysis of the simulated trees, we assumed that the epidemiological parameters did not change at any time during the time span encompassed by the phylogenetic tree; meaning we assumed simple exponential growth of the epidemic. We explored performance of the MCMC implementation of the birth-death skyline serial model with 1 interval and the coalescent model with exponential growth rate as implemented in BEAST v2.0  computational procedure, which explores the posterior parameter surface by taking samples from their combined posterior distribution. We run the MCMC chain in BEAST v2.0 We picked uniform priors for all parameters. Priors for the two parameters growth rate In the birth-death model, we put priors on sampling probability time between the origin For the birth-death skyline analyses we set the interval number for sampling probability Figure S1Comparison of the birth-death model and the coalescent model in estimating epidemic growth rate at . For each plot, 100 trees simulated under the constant rate birth-death (BD) model with incomplete sampling  or coalescent (CE) model with exponential growth of the infected population  using various parameter combinations (see the header of each subfigure) were analyzed. See the legend of (TIF)Click here for additional data file.Figure S2Tracking of cumulative infecteds, infecteds and sampled individuals over time in the birth-death tree simulations: . For each selected (TIF)Click here for additional data file.Figure S3Influence of fixing the age on the growth rate parameter estimation. For setting (TIF)Click here for additional data file.Figure S4Influence of increasing the sample size on the growth rate parameter estimation. For setting (TIF)Click here for additional data file.Figure S5Influence of branch length extension in various parts of the tree on the growth rate parameter estimation at . We display a summary in form of the median values of the start and the end of the 95% HPD intervals, and the median of the medians of the posterior estimates for all 100 trees per each setting: (TIF)Click here for additional data file.Figure S6Influence of sampling scheme on the growth rate parameter estimation at . We display a summary in form of the median values of the start and the end of the 95% HPD intervals, and the median of the medians of the posterior estimates for all 100 trees per setting: (TIF)Click here for additional data file.Figure S7Interchangeability of sampling probability in estimation of the growth rate parameter by the birth-death model. We analyzed the 100 trees simulated with the birth-death  and the coalescent  at (TIF)Click here for additional data file.Figure S8Interchangeability of sampling probability in estimation of  parameter by the birth-death model. Simulations and analyses are the same as in (TIF)Click here for additional data file.Figure S9Interchangeability of sampling probability in estimation of  parameter by the birth-death model. Simulations and analyses are the same as in (TIF)Click here for additional data file.Figure S10Interchangeability of sampling probability in estimation of  parameter by the birth-death model. Simulations and analyses are the same as in (TIF)Click here for additional data file.Figure S11Interchangeability of sampling probability in estimation of  parameter by the birth-death model. Simulations and analyses are the same as in (TIF)Click here for additional data file.Figure S12Interchangeability of sampling probability in estimation of  parameter by the birth-death model. Simulations and analyses are the same as in (TIF)Click here for additional data file.Figure S13Fixing  or  in parameter estimation by the birth-death model. Trees simulated with (TIF)Click here for additional data file.Figure S14Effect of different information used in the  parameter inference at . From trees simulated under the setting (TIF)Click here for additional data file.Figure S15Comparison of the birth-death model and the coalescent model in estimating growth rate parameter from trees with tips sampled at one point in time at . For each plot, 100 trees simulated under the constant rate birth-death (BD) model at (TIF)Click here for additional data file.Figure S16Comparison of growth rate point estimates of the birth-death model and the coalescent model from trees with tips sampled at one point in time at . For (TIF)Click here for additional data file.Figure S17Comparison of growth rate point estimates of the birth-death model and the coalescent model for different  values. For (TIF)Click here for additional data file.Figure S18Comparison of growth rate point estimates of the birth-death model and the coalescent model for different sampling probabilities. For (TIF)Click here for additional data file.Table S1Summary of growth rate parameter estimation statistics at various  corresponding to the same . For each of the 100 trees simulated under the respective model , with (PDF)Click here for additional data file.Table S2Summary of growth rate parameter estimation statistics in various sampling scenarios. For each of the 100 trees simulated under the respective model , with periods of (PDF)Click here for additional data file.Table S3Summary of growth rate parameter estimation statistics for trees with tips sampled at one point in time. For each of the 100 trees simulated under the birth-death model, with (PDF)Click here for additional data file.Supplementary Material S1First part describes the derivation of waiting times until coalescent under discrete time Wright-Fisher, discrete time Moran, and continuous time Wright-Fisher and Moran population models. Second part discusses parameter correlations under the birth-death process.(PDF)Click here for additional data file.File S1An example xml file for simulation of coalescent trees, using sampling times from the birth-death process, by sampling from the coalescent tree prior in BEAST v2.0 is provided.(XML)Click here for additional data file.


However, in most studies neuroimaging was done after a significant postnatal period, and in those studies that performed neuroimaging on fetuses, the quality of data has been affected due to complications of scanning during pregnancy. To understand healthy brain development between 37–41 weeks of gestational age, our study assessed the in utero growth of the brain in healthy term born babies with DTI scanning soon after birth.Understanding healthy brain development A cohort of 93 infants recruited from maternity hospitals in Singapore underwent diffusion tensor imaging between 5 to 17 days after birth. We did a cross-sectional examination of white matter microstructure of the brain among healthy term infants as a function of gestational age via voxel-based analysis on fractional anisotropy.Greater gestational age at birth in term infants was associated with larger fractional anisotropy values in early developing brain regions, when corrected for age at scan. Specifically, it was associated with a cluster located at the corpus callosum (corrected p<0.001), as well as another cluster spanning areas of the anterior corona radiata, anterior limb of internal capsule, and external capsule (corrected p<0.001).Our findings show variation in brain maturation associated with gestational age amongst ‘term’ infants, with increased brain maturation when born with a relatively higher gestational age in comparison to those infants born with a relatively younger gestational age. Future studies should explore if these differences in brain maturation between 37 and 41 weeks of gestational age will persist over time due to development outside the womb. We hypothesize that among healthy term born infants, a younger gestational age at birth is associated with reduced white matter maturity in the brain in comparison to healthy term born infants born with an older gestational age at birth.To understand the establishment of brain connections within healthy term born infants, imaging soon after birth is essential to reduce the effects of postnatal brain maturation. To the best of our knowledge there have been no DTI studies to date that have examined differences brain maturation shortly after being born in healthy term infants. The aim of this study is to investigate the differences in One hundred eighty nine infants who participated in a birth cohort study, Growing Up in Singapore Towards Healthy Outcomes (GUSTO), also participated in the neuroimaging study. The GUSTO methodology has been published in detail The current study only included neonates with diffusion tensor imaging (DTI), gestational age at birth greater or equal to 37 weeks, birth weight larger than 2500 g, and the last recorded APGAR≥9, to exclude effects of intra-uterine growth retardation or co-morbidities. Neonates of mothers with gestational diabetes, hypertension, and hypoglycemia were excluded from this study, as were neonates of mothers who reported consuming any alcohol during pregnancy.Neonates underwent fast spin-echo T2-weighted MRI and single-shot echo-planar DTI scans using a 1.5-Tesla GE scanner at KKH’s Department of Diagnostic and Interventional Imaging between 5 and 17 days postpartum. The scans were acquired when subjects were sleeping in the scanner. No sedation was used and precautions were taken to reduce exposure to MRI scanner noise. A neonatologist was present during each scan. A pulse oximeter was used to monitor heart rate and oxygen saturation through out the entire scans.2 and 1 baseline with b = 0 sec/mm2 were obtained. All brain scans were reviewed by a neuroradiologist (M.V.F).The DTI imaging protocol is based on single-shot echo-planar DTI sequence . 40 to 50 axial slices with 3.0 mm thickness were acquired parallel to the anterior–posterior commissure line. Nineteen diffusion weighted images (DWIs) with b = 600 sec/mmDiffusion weighted images (DWIs) were first corrected within individual subjects for motion and eddy current distortions using affine transformation to the image without diffusion weighting. Six elements of the diffusion tensor were then determined, from which fractional anisotropy (FA) was calculated using multivariate least-square fitting.3, http://lbam.med.jhmi.edu/) We constructed a DTI atlas based on the unbiased diffeomorphic atlas generation algorithm DWIs of individual subjects were then aligned to the atlas based the same registration procedure as one used for the atlas generation. FA was obtained from the tensor calculation of DWIs in the atlas and used for the following voxel-based analysis.Voxel-based analysis was performed to investigate the association between gestational age at birth and neonatal brain microstructure (FA) using SPM8. The FA images were smoothed with a Gaussian kernel with full width half maximum of 4 mm. Linear regression was performed conducted at every voxel in the white matter region. The regression model included gestational age at birth as the main factor and controlled for age at MRI. Most infants were scanned at the second week after birth. Gestational age was highly correlated with the postmenstrual age-at-scan (r = 0.966). As the aim of this study is to investigate the effects of gestational age at birth on the neonatal brain to assess effects of fetal maturity, we controlled for age at MRI  in the regression analysis.We also adjusted for birth weight Birth weight was adjusted based on gestational age using linear regression with the mean-centered gestational age as a main factor on the GUSTO cohort. The residual was defined as adjusted birth weight that is statistically independent of gestational age. As small-for-gestational age has been identified as a risk factor for prematurity, we included birth weight as a covariate Among 189 neonates who underwent MRI scans, 93 were included in the current study. We excluded 13 neonates with gestational age at birth less than 37 weeks, 11 with birth weight less than 2500 g, 2 with a 5-min Apgar score less than 9, and 52 with no DTI data. Moreover, our study also excluded infants whose mothers had gestational diabetes (n = 22), hypertension (n = 5), and hypoglycemia (n = 1) during pregnancy. Mothers who reported consuming any alcohol during pregnancy (n = 3) were also excluded from this study. Hence, the total sample involved in this study was 93. We performed two additional analyses. First, we replaced gestational age at birth with post-conception age in the linear regression model. The effects of post-conception age on FA are the same as those of gestational age at birth. This is not surprising as the correlation of gestational age at birth and post-conception age at MRI is 0.966. Second, we examined the growth pattern of FA after birth, that is, the growth pattern of FA as a function of age at MRI, where age at MRI is defined as the difference between post-conception age and gestational age at birth. No significant statistical results were found after correcting for multiple comparisons. Hence, this suggests that the findings shown in Our cross-sectional findings show an association between gestational age at birth within the normal range and brain maturation measured with diffusion tensor imaging, shortly after birth. Specifically, younger gestational age at birth within the “term” window associates with reduced white matter organization in the CC, ACR, ALIC, and EC in comparison to older gestational age within the “term” window. These brain regions are parts of the cortical-striatal-thalamic neural circuit. This circuit is functionally important as is has been related to sensory functions, executive functions, and working memory Despite the fact that tracts, such as the CC, do not fully mature until adulthood, the majority, including the internal capsule (IC) with its extensions to the thalamus and basal ganglia, are in the limited myelinated brain regions at birth ex-vivo DTI in utero brain maturation in these early developing structures in healthy term infants. This is consistent with previously reported associations in studies with premature infants and as such implies a consistent pattern of white matter development in the fetal brain. Those studies indeed found an association between gestational age at birth and maturation of the posterior limb of the internal capsule (PLIC) During the second trimester of gestation, the commissural fibers And one previous study, although performed in very-low-birth-weight and premature children, also reported higher FA in the posterior regions within the CR. The same study found a positive association between gestational age at birth and the EC for Mean Diffusivity but not FA Previous work examining very preterm and near term infants has also documented an association between CC development and gestational age Indeed, most of this research demonstrates that FA and diffusion variations in the CC correlate significantly with gestational age in utero brain development.Other studies about CC compared preterm and term children with neuroimaging, but the timings of scanning were after a significant postnatal period Although other studies also found associations between gestational age and the thalamus in premature infants, we did not find this in our study. This can be explained by previous findings of myelination of the thalamus around the second trimester, and makes this structure more vulnerable for effects of prematurity instead of effects of gestational age within the “term window” in utero brain maturation in healthy term infants will also have implications for functional outcomes. It is known that there is rapid rate of growth of the brain, inclusive subcortical areas, during the first 3 months after birth Although some studies in preterm infants suggest that differences in brain trajectories at birth can be persistent over time A major strength of this study is the use of DTI techniques to image newborn infants soon after birth. Our study focused on a healthy sample, excluding infants born preterm as well as infants with very low birth weights, low Apgar scores and complications during pregnancy. These strict rules for subject inclusion allowed us to examine the effects of gestational age without the associated influences of pathologies common in pre-term and high-risk pregnancies. Although inclusion of infants with APGAR score ≥9 after maximum of 10 minutes may be over-conservative, we only excluded two infants based on an APGAR<9, which will not have changed our results.Still, our study has limitations. First, FA indices should be interpreted with caution without knowledge of the possible effects of water concentration in the newborn infant brain in utero brain development, such as effects on executive functioning.Third, because DTI is still a relatively new technique, the functional significance of these findings is unclear. Our study did not explore the functional outcomes of the differences in brain maturation in term born infants. However, the GUSTO cohort will be followed over the coming years, which will help us to explore not only if some variation in brain maturation will persist at later ages but also the functional significance of our findings of early variation of We report that a relatively higher gestational age at birth in healthy term infants is associated with more white matter maturity in the CC, as well as in ALIC, ACR and EC, in comparison to healthy term infants born with a relatively lower gestational age. Future studies in term infants are needed to explore the effects of variations in brain development at birth and later brain development and functional outcomes.


Tailoring the electromagnetic field at the nanoscale has led to artificial materials exhibiting fascinating optical properties unavailable in naturally occurring substances. Besides having fundamental implications for classical and quantum optics, nanoscale metamaterials provide a platform for developing disruptive novel technologies, in which a combination of both the electric and magnetic radiation field components at optical frequencies is relevant to engineer the light-matter interaction. Thus, an experimental investigation of the spatial distribution of the photonic states at the nanoscale for both field components is of crucial importance. Here we experimentally demonstrate a concomitant deep-subwavelength near-field imaging of the electric and magnetic intensities of the optical modes localized in a photonic crystal nanocavity. We take advantage of the “campanile tip”, a plasmonic near-field probe that efficiently combines broadband field enhancement with strong far-field to near-field coupling. By exploiting the electric and magnetic polarizability components of the campanile tip along with the perturbation imaging method, we are able to map in a single measurement both the electric and magnetic localized near-field distributions. The progress made in the fabrication of nano-metamaterials at optical frequencies has led to light manipulation at the nanoscale exhibiting unprecedented artificial behaviours, such as negative or zero refractive index, optical cloaking and superluminal phenomena1245689111213141516171819202223The local SNOM probe acts as an optical antenna, converting the electromagnetic near-field into propagating radiation and vice versa, with a net energy transfer efficiency that defines the throughput of the antenna and with an imaging spatial resolution bounded by the size of the probe that interacts with the near-field. Conventional aperture probes require a trade-off between spatial resolution and throughput, since the transmission through a metal screen with a sub-wavelength hole scales as the fourth power of the hole diameter sizeStructures such as micro-disks, micro-waveguides, nanoparticles, nanoplasmonic resonators, and photonic crystal nanocavities (PCNs) are able to localize electromagnetic fields in very small mode volumes. Therefore, they represent successful platforms for investigating the nature of the signal detected by any SNOM probe2728151830141933131516At the same time, an enormous advance in nano-imaging techniques was pursued by the introduction of concepts from plasmonics, such as surface plasmon polaritons (SPPs) confinement along metal-dielectric interfaces, which have led to the design of high-performance near-field probes3536373840414243In this work, we bridge together the concept of perturbation imaging method and plasmonic near field probe to achieve, in a single scan, a concomitant subwavelength imaging of the electric and magnetic near-field intensities of the optical modes localized in a PCN. We exploit the structure of a plasmonic SNOM probe that resembles the shape of a campanile bell tower (hereafter referred to as “campanile tip”) which results in a high field enhancement at the nanoscale and a simultaneous effective electric and magnetic polarizability.The strength of the high fidelity tip-induced perturbation imaging relies on the fact that the shift can be analytically predicted and that it is proportional to the localized mode electromagnetic field intensity331315The approach of a simultaneous electric and magnetic imaging relies on the seminal idea of using concepts of discrete circuit elements, such as capacitor and inductance, to describe the tip effective interaction with the electromagnetic fields at the nanoscale46It is clear that the role of the campanile tip is twofold. On one hand, being formed by a glass core and two gold covered layers, as schematically reported in the inset of 11 cm−2) self-assembled InAs quantum dots (QDs) are grown, providing at room temperature photoluminescence (PL) in a broad spectral range centred around 1.3 μm. The PL signal can couple with the resonant photonic modes allowing us to address the optical properties of the nanocavity. The PCN is a sensitive platform to detect both dielectric and magnetic perturbations that result in a shift of the spectral resonances. The modes of the two-dimensional PCN on slab are mainly transverse electric , with the electric field polarized in the membrane plane and the magnetic field perpendicular to the plane. We consider two different TE-like modes, reported in the spectra of 50We consider the localized optical modes of PCNs on a 320 nm thick GaAs membrane grown by molecular beam epitaxyA commercial SNOM (Twinsnom by Omicron) is used in the illumination-collection geometry. The spectral response to a CW laser emitting at 1300 nm shows a FWHM of 0.11 nm. In this setup, the QDs are excited with a diode laser (780 nm) and the PL signal is coupled into the tip that is raster scanned at a constant height, smaller than 10 nm, on the sample surface. At every tip position a PL spectrum is collected, thus obtaining through the scan a hyperspectral image of the PCN. The scheme of the experimental set up is shown in A typical PL spectrum of the investigated nanocavity collected by the SNOM equipped with the campanile tip is reported in In analogy with the behaviour observed for dielectric and metal coated tips, the red (blue) wavelength shift can be interpreted as a signature of an electric (magnetic) interaction between the campanile tip and the localized photonic mode. These experimental results demonstrate the simultaneous electric and magnetic polarizability of the campanile tip as expected on the basis of the equivalence of the MIM apex structure with an LC circuit discussed in the methods section.The campanile probe response efficiency between the external magnetic and electric fields can be evaluated as the ratio (α) between the maximum blue and red shift amplitudes. For M1 mode it is equal to |−0.28 nm| / |0.60 nm|, which gives α(M1) = (0.47 ± 0.06). For M2 mode it is |−0.18 nm| / |0.33 nm|, which gives α(M2) = (0.55 ± 0.12). These values demonstrate that the campanile tip dielectric and diamagnetic responses are of the same order of magnitude. The reported uncertainties are evaluated from the errors associated to the peak wavelength estimation provided by the Lorentzian function fit. This characteristic gives a simultaneous access to both fields with similar sensitivity, which is intriguing if one considers that the magnetic response of normally occurring materials in the optical frequency range is usually many orders of magnitude smaller than the electric response.The different sign of the dielectric and diamagnetic response, together with the fact that for any standing wave the nodes of the electric field correspond to the maxima of the magnetic field and vice versa, are useful consequences of classical electromagnetism which allow us to clearly discriminate with high fidelity between the two field components in the same measurement. The experimental data show that the campanile probe has a concomitant positive electric and negative magnetic polarizability.In principle, similar properties could also apply to other plasmonic nanoantennas, but the use of a campanile probe has a double benefit, as it enhances the near field coupling and also makes the magnetic and electric perturbation interaction of comparable magnitude.α to evaluate the expected spectral shift (Δλ) distributions. These maps are constructed by a linear combination of the calculated FDTD electric and magnetic normalized intensities, assuming a negligible electric field at the position of magnetic field maxima, and conversely, that results in:To corroborate our understanding about the imaging of both electric and magnetic contributions of the TE-like modes in a single measurement, we perform finite difference time domain (FDTD) calculations of the field distributions of the localized photonic modes. The maps associated to M1 and M2 are reported in a priori to result in an imaging spatial resolution of 40 nm. We check this assumption by comparing the experimental spectral shift data profile and the theoretical profiles obtained by the convolution between the FDTD map of 2 distribution. In 13The experimental spatial resolution of the perturbation imaging method obtained with the campanile probe is estimated by analysing the mode map distribution along one-dimensional profile cut. We show in These data confirm that we experimentally succeed, during the same scan, in extracting high quality maps of the electric and magnetic field intensities of the localized modes with a sub-wavelength spatial resolution. There are many advantages of the perturbation method joined with campanile tip with respect to direct near-field signal collection imaging with standard coated tip employed in Ref. The excellent agreement between the experimental data and the near-field numerical calculations clearly indicates that the campanile probe induced-perturbation imaging is able to catch all the subtle details of the electric and the magnetic intensity distributions of optical modes, with an ultra-subwavelength spatial resolution.In conclusion, we experimentally demonstrate the concomitant deep-subwavelength imaging of the electric and magnetic near-field intensities of optical modes localized in a PCN by exploiting the campanile plasmonic nano-optical probe. With respect to direct signal collection through the tip as in Ref. Combined access to the near-field electric and magnetic components of optical modes, in conjunction with recent advances in fabricating nano-metamaterials, will help to bring together concepts from different disciplines, including nano optics, materials science and engineering, paving the way for innovative electromagnetic devices based on the interplay between the electric and magnetic optical response. One possible actual implementation could be coupling light nano-emitters (like molecules or quantum dots) to metamaterial or nanoresonator resonances for tailoring the spontaneous emission rate through electric and/or magnetic dipoles interaction, by exploiting the knowledge of electric and magnetic LDOS with an outstanding spatial resolution.