Oncological neurosurgery relies heavily on making continuous, intra-operative tumor-brain delineations based on image-guidance. Limitations of currently available imaging techniques call for the development of real-time image-guided resection tools, which allow for reliable functional and anatomical information in an intra-operative setting. Functional ultrasound (fUS), is a new mobile neuro-imaging tool with unprecedented spatiotemporal resolution, which allows for the detection of small changes in blood dynamics that reflect changes in metabolic activity of activated neurons through neurovascular coupling. We have applied fUS during conventional awake brain surgery to determine its clinical potential for both intra-operative functional and vascular brain mapping, with the ultimate aim of achieving maximum safe tumor resection.During awake brain surgery, fUS was used to image tumor vasculature and task-evoked brain activation with electrocortical stimulation mapping (ESM) as a gold standard. For functional imaging, patients were presented with motor, language or visual tasks, while the probe was placed over (ESM-defined) functional brain areas. For tumor vascular imaging, tumor tissue (pre-resection) and tumor resection cavity (post-resection) were imaged by moving the hand-held probe along a continuous trajectory over the regions of interest.A total of 10 patients were included, with predominantly intra-parenchymal frontal and temporal lobe tumors of both low and higher histopathological grades. fUS was able to detect (ESM-defined) functional areas deep inside the brain for a range of functional tasks including language processing. Brain tissue could be imaged at a spatial and temporal resolution of 300 μm and 1.5–2.0 ms respectively, revealing real-time tumor-specific, and healthy vascular characteristics.The current study presents the potential of applying fUS during awake brain surgery. We illustrate the relevance of fUS for awake brain surgery based on its ability to capture both task-evoked functional cortical responses as well as differences in vascular characteristics between tumor and healthy tissue. As current neurosurgical practice is still pre-dominantly leaning on inherently limited pre-operative imaging techniques for tumor resection-guidance, fUS enters the scene as a promising alternative that is both anatomically and physiologically informative. The ultimate surgical aim is reaching maximum-safe tumor resection, in which most of the tumor is removed, while preserving functional brain areas to prevent post-operative neurological and cognitive deficits . Given tin vivo surgery following craniotomy MRI and DTI, which are linked to intra-operative neuro-navigation systems. These imaging modalities allow the surgeon to pre-operatively acquire anatomical and functional data of the tumor and surrounding eloquent areas. However, due to the inevitable brain shift after cranio- and durotomy, pre-operative images only provide a rough estimation of the 3D-locus of the tumor during aniotomy , complicThe widespread introduction of awake craniotomy surgery with ESM has greatly improved the intra-operative identification of eloquent brain areas adjacent to tumors. Intra-operative use of ESM to remove low-  or HGGs Other conventional and experimental imaging techniques such as Laser Speckle Contrast Imaging (LSCI) , OpticalThese limitations of currently available pre- and intra-operative imaging modalities greatly warrant the need for the development of new real-time image-guided resection tools, which allow for reliable anatomical and functional information in an intra-operative setting. Recently, such an alternative emerged within the field of ultrasound imaging, to which we refer as fUS. fUS relies on HFR ultrasound and subsequent Doppler processing and interregional correlation analyses . As suchSo far, fUS has been applied successfully in brains and spinal cords of mice , rats O, ferretsvascular features and at the functional level to delineate healthy brain activity patterns surrounding the tumor during motor and cognitive (language-related) tasks.In this work, we apply fUS to a cohort of patients undergoing awake neurosurgery following craniotomy for the indication of tumor removal near eloquent areas of the brain. We present a range of anatomically informative images acquired intra-operatively, discussing their potential for both clinical applications and functional brain-mapping. More specifically, we present here for the first time whether fUS can be exploited at the clinical level to reveal tumor-specific After obtaining approval from the METC  and a written informed consent accordingly, participants were included in the study. All participants were recruited from the Department of Neurosurgery of Erasmus MC in Rotterdam. Participants were eligible for inclusion when diagnosed with a brain tumor planned for tumor removal using awake craniotomy surgery with ESM. Participants were excluded if they were < 18 years old. Some patients underwent fMRI pre-operatively per conventional clinical protocol.Functional ultrasound-data acquisition was conducted around three time-points as indicated in After acquisition of tumor vasculature images, the conventional ESM procedure was performed. Using a bipolar electrode connected to a cortical stimulation unit , square-wave pulses were delivered to induce depolarization of relevant cortices. According to standard protocol, the intensity of the working current was increased from 6 to maximum 12 mA , depending on whether a functional effect was evoked. In some cases, no functional effect was found, even at maximum current intensity. Eloquent areas, if found during ESM, were labeled with numbers.During fUS-imaging, the probe was partially placed over the (expected location of) the tumor and partially over the surrounding functional areas as identified by ESM, ensuring that both types of tissues were in the field of view. If ESM did not allow us to identify any functional area, the probe was placed over the tumor and surrounding tissue most likely to be functional as extrapolated from the local anatomy.Based on the expected eloquent area under the probe, patients were presented with appropriate, matching tasks for that area. These tasks were anticipated beforehand as much as possible, based on both anatomy as well as pre-operative fMRI-data if available. Each task consisted of a total of 60 s, with alternating three blocks of tasks (8 s each) and three blocks of resting conditions (10 s each), all preceded by a 6 s baseline. Functional tasks as used in this study ranged from motor tasks , to language tasks   and visuDS). An overview of the details of all the functional tasks as used per patient can be found in Patients were neurolinguistically assessed for the task prior to surgery and informed about the tasks by a clinical linguist, who also presented the tasks to the patients intra-operatively  interfaced with a 5 MHz, 128 element linear array  driven with a three cycle burst at 5.2 MHz. Baseband quadrature sampling was applied as implemented by the Verasonics system in order to reduce the overall data-rate. For all scans we acquired continuous angled plane wave acquisition  with a PRF ranging from 6 to 8 kHz depending on the imaging depth. The average ensemble size (number of frames used to compute one PDI) ranged between 120 and 140 frames from which the PDIs were computed, providing a live Doppler FR ranging between 3.6 and 4.8 Hz. The PDIs as well as the raw, angle compounded beamformed frames  the PDI stack over time and computed for every pixel the PCC r . The optAll the post-processing software and the visualization was done in Matlab . We used Paraview , an open-source software tool, for visualizing the 3D vascular scans.Between October 2018 and June 2019, a total of 10 participants  were included in the study . IncludeA total of 44 functional measurements were performed in 10 patients, ranging from 2 to 5 functional measurements per patient. Of these 44 measurements, 14 involved finger tapping, 6 lip pouting, 18 verbal or silent word or sentence repetition, and 6 visual checkerboard stimulation  across a range of functional tasks. As demonstrated by the vascular patterns mapped with submillimeter resolution, fUS also provides a potential new means for tumor delineation based on vasculature characteristics of tumor and healthy tissue.The work presented here is the second study to demonstrate the power of fUS for neurosurgery as a real-time technique to asses local brain functionality. With respect to the study by n = 35), the use of an inappropriate functional task could also be a possible explanation. However, problems either due to shifted brain functionalities in space due to oncogenesis, too much in- and out-of-plane motion of the hand-held probe or placement of the probe over an incorrect or non-functional area, form alternative explanations. The latter two explanations are especially plausible, as the majority of the measurements where we found a functional signal (6 out of 9), were made in patients who did show ESM-related functional deficits intra-operatively. Furthermore, almost all (8 out of 9) measurements presenting with functional signal showed below average displacement in the x-axis (<0.22 mm), indicating a relatively low level of motion during the measurement  slow hemodynamic response function, (2) inaccurate timing between start of the acquisition and presented functional task, and (3) delayed or anticipatory response of the patient to the presented task. Determining the potential bias that for example anticipatory effects might have during functional imaging, and how to design proper functional paradigms to exclude them, will be part of our future studies.In those cases where we did not find functional signals  vascular detail, including intra-cortical arterial vessels. The resolution with which these vascular images are now made in a real-time, intraoperative setting, is unprecedented. The ability to capture high-resolution vasculature intra-operatively could also have anatomical delineation purposes, not just for tumor-brain delineation, but also delineation of healthy tissue structures, as becomes clear in an incidental imaging session of the thalamus . This inCompared to conventional intra-operative mapping using ESM, fUS provides higher spatiotemporal resolution and higher depth-penetration. In our implementation, temporal resolution can be as high as 1.5 ms, while maintaining real-time display for the surgeon (up to 4.8 Hz) and continuous raw frame storage (up to 667 Hz). Compared to conventional pre- and intra-operative imaging techniques such as (f)MRI, fUS proves to have higher temporal resolution using a more mobile system. Surprisingly, several of our functional imaging sessions showed activation maps also involving concentrated areas at deeper levels of the brain, which would otherwise not have been interrogated intra-operatively with ESM. In addition, the lack of need for electrical stimulation eliminates the risk of intra-operative seizure elicitation. It is also imaginable that several tasks can be performed at once before resecting the tumor, which could save time. Lastly, the movability and cost-effectiveness of fUS make it a highly clinically accessible technique.Nevertheless, the technique will need to be further validated and improved to reach clinical maturity. For fUS as used in its current form, real-time, automated image classification will be an important next step, which would allow for, e.g., automated brain-tumor delineation. In addition, hand-held fUS-imaging is inherently prone to problems such as motion, both in- and out-of-plane, which can either lead to (1) the inability to capture functional response, or (2) capturing of artifactual ‘functional’ signal. Using linear stages or other probe-mounting options in the OR-setting would be a solution. Future work will also need to focus on the tracking and integration of the probe in currently available neuro-navigation software. Not only will this facilitate the validation of fUS with (f)MRI images made pre-operatively, but it will also allow for better cross-patient comparisons. Comparison of fUS with fMRI in particular is interesting, as both techniques rely on different aspects within the neurovascular coupling mechanism. Where fMRI relies on the BOLD-signal, a measure of blood-oxygenation levels influenced by changes in blood volume and flow as well as the rate of oxygen consumption  to deterIn addition, replacing the currently used linear array with a 3D-probe will allow for intra-operative fUS-imaging of 3D volumes. Both in terms of functional as well as vascular anatomical information, this could constitute a huge improvement. Furthermore, with a 3D-vascular map, vascular-based calibration instead of the usual bone-based calibration for neuro-navigation, could also potentially solve the post-craniotomy brain shift problem. Most importantly, future work will also have to center around the actual patient outcomes in terms of tumor resection, post-operative neurological deficits, and survival when performing fUS-guided resections.The current study demonstrates that fUS has the potential to be a highly flexible technique for providing vascular as well as functional information in an intra-operative setting with high spatiotemporal resolution. As current neurosurgical practice is still relying on inherently limited imaging techniques for tumor resection-guidance, fUS enters the scene with great clinical potential.The raw data supporting the conclusions of this article will be made available by the authors upon reasonable request.The studies involving human participants were reviewed and approved by the Medical Ethics Review Committee (METC) of the Erasmus Medical Center in Rotterdam, Netherlands (MEC 2018-037). The patients/participants provided their written informed consent to participate in this study.SS, AV, SK, and PK were involved in the study design. SS, AV, DS, and PK were involved in the determination of appropriate intra-operative functional tasks. DS was involved in the intra-operative guidance of the patients while presenting the functional tasks. FM, SS, MS, SK, and PK were involved in the data-processing and -analysis of fMRI and fUS-data. AV included all patients and performed all surgeries and scans. SS, SK, and PK were involved in drafting the manuscript, with the critical input of AV, DS, FM, MS, CMD, CS, JB, AS, and CID.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The head-to-head AIDS Clinical Trial Group (ACTG) 5257 clinical trial found raltegravir (RAL) to be superior to atazanavir + ritonavir (ATV/r) and darunavir + ritonavir (DRV/r), when used in combination with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) by treatment-naive adults with HIV-1 infection, in a 96-week composite endpoint combining virologic efficacy and tolerability. The objective of this study was to estimate the total HIV treatment costs associated with these three regimens in the United States.Ninety-six–week costs for antiretroviral drugs, adverse event management, and HIV care for individuals initiating RAL, ATV/r, or DRV/r as first-line therapy for HIV-1 infection were estimated using an economic model. Efficacy and safety data  for each regimen through 96 weeks of treatment were taken from the ACTG 5257 clinical trial. Antiretroviral drug costs for each initial regimen and for each substitution regimen, as used by individuals who discontinued their initial regimen, were based on wholesale acquisition costs. Adverse event management costs and HIV care costs, stratified by CD4 cell count range, were taken from published sources and inflated to 2016 dollars. Scenario and sensitivity analyses were conducted to assess the robustness of the results. Cost outcomes were discounted at an annual rate of 3.0%.Total 96-week costs were $81,231 for RAL, $88,064 for ATV/r, and $87,680 for DRV/r, where differences were primarily due to lower antiretroviral drug costs for RAL than for ATV/r or DRV/r. These results were found to be robust in scenario and sensitivity analyses.Relative to the DRV/r and ATV/r regimens, the RAL regimen had the lowest cost for treatment-naive adults with HIV-1 infection in the United States. As of 2013, an estimated 1,242,000 people were living with HIV-1 infection in the United States (US) . ThiACTG 5257 clinical trial efficacy and tolerability data  were useIn the model, individuals remained on their first-line ARV regimen until discontinuation due to virologic or tolerability failure  after 24, 48, or 96 weeks of treatment . VirologGrade 2, 3, or 4 adverse events with an incidence of at least 5% in any arm of the ACTG 5257 clinical trial were reported in Lennox et al. [Individuals in the model incurred costs for ARV drug treatment, adverse event management, and HIV care. For each first-line ARV regimen, total daily ARV drug costs were calculated as the sum of the daily wholesale acquisition cost of each individual component of the regimen . ResultiFor adverse event management costs, the model applied a cost per episode to the percentage of individuals who experienced each adverse event. Because adverse events typically occur soon after treatment initiation, the model assumed that these costs were incurred within the first 48 weeks of treatment. The per-episode management cost associated with each adverse event was taken from Simpson et al. , which eAnnual HIV care costs for disease monitoring and the treatment and prevention of opportunistic and other infections were taken from Gebo et al.  and inclPer-person 96-week costs, in total and by cost category, and the percentage successfully treated were estimated in the base-case analysis for each first-line ARV regimen. An annual rate of 3.0% was used to discount all cost outcomes [Scenario and sensitivity analyses were conducted to assess the robustness of the model results. In the scenario analysis, the total per-person cost was estimated for five additional scenarios: after 48 weeks of treatment; with first-line ARV treatment discontinuation for any reason; with no adverse event costs; with alternate adverse event costs ; and witThe joint impact of input parameter uncertainty on the model results was assessed in a probabilistic sensitivity analysis (PSA), in which all model input parameters for which there was sampling uncertainty were simultaneously varied according to the distributions summarized in At 96 weeks, the cost analysis indicated that RAL was associated with lower ARV drug costs and adverse event costs, similar HIV care costs, and lower total costs when compared with ATV/r or DRV/r . Total cThe RAL regimen was found to have the lowest total per-person cost when compared with the ATV/r and DRV/r regimens in all scenarios tested . The relIn all 10,000 simulations conducted for the PSA, RAL was found to have the lowest total per-person cost after 96 weeks of treatment see . The meaThe objective of this study was to estimate the total HIV treatment costs among treatment-naive adults with HIV-1 infection in the US for three first-line integrase and protease inhibitors: RAL, DRV/r, and ATV/r, each used in combination with FTC/TDF. RAL, DRV/r, and ATV/r are recommended as initial ARV regimens in the US treatment guidelines  and wereOur analysis is the first, to our knowledge, to directly compare these commonly used regimens in a US analysis, but several other studies provide context for our results. One previous study used ACTG 5257 head-to-head data to assess the economic impact of using DRV/r rather than ATV/r over 2 years in the United Kingdom . As in oThis study is characterized by several strengths. The analysis relied on efficacy, tolerability, and safety data taken directly from ACTG 5257, a large head-to-head clinical trial that specifically studied first-line ARV regimens in a US population not treated with efavirenz. Second, the model had a 96-week time horizon and used only the data available from the ACTG 5257 clinical trial, thus avoiding the need for assumptions about long-term efficacy and treatment pathways. Finally, the robustness of the model’s results was examined and confirmed in scenario and sensitivity analyses.Several limitations that are typical of pharmacoeconomic analyses should be considered when the cost-analysis results are interpreted. First, the analysis was limited to the three first-line ARV regimens studied in the ACTG 5257 clinical trial and did not include the once-daily formulation of RAL or other commonly used first-line ARV regimens for HIV treatment. The once-daily formulation of RAL has the same acquisition cost as the twice-daily version, with the potential for improved adherence, so we might expect slightly more favorable total cost results. This analysis should be extended to include other commonly used first-line ARV regimens if additional head-to-head clinical trial results become available. Second, because real-world adherence may be lower than in a clinical trial setting, HIV treatment costs observed in clinical practice may differ somewhat from those estimated in this analysis. In clinical practice, lower ARV drug costs (attributable to lower adherence) and higher HIV care costs  for all regimens may be observed. Further, this analysis estimated costs through 96 weeks of treatment and therefore did not capture potential long-term outcomes associated with RAL treatment, such as the benefits of RAL’s favorable lipid profile, as observed in the ACTG 5257 trial [For treatment-naive adults with HIV-1 infection in the US, RAL + FTC/TDF had the lowest per-person total cost after 96 weeks of treatment when compared with DRV/r + FTC/TDF and ATV/r + FTC/TDF. This result was primarily due to lower ARV drug costs and adverse event costs for RAL + FTC/TDF than for the other two regimens. Scenario and sensitivity analyses revealed these findings to be robust. The results of this cost analysis complement the known clinical benefits of RAL , 3. FurtS1 Tablea The Dirichlet distribution is the multivariate generalization of the beta distribution and can be used when there are more than two categories that must sum to 100%.PSA, probabilistic sensitivity analysis. (DOCX)Click here for additional data file.S2 TableATV/r, atazanavir + ritonavir; DRV/r, darunavir + ritonavir; RAL, raltegravir.(DOCX)Click here for additional data file.


Multi-substance use is accompanied by increased morbidity and mortality and responsible for a large number of emergency department (ED) consultations. To improve the treatment for this vulnerable group of patients, it is important to quantify and break down in detail the ED resources used during the ED treatment of multi-substance users.This retrospective single centre case-control study included all ED consultations of multi-substance users over a three-year study period at a university hospital in Switzerland. Resource consumption of these patients was compared to an age-matched control group of non-multi-substance users.The analysis includes 867 ED consultations of multi-substance users compared to 4,335 age-matched controls (5:1). Multi-substance users needed more total resources : 762 (459–1226) vs. 462 (196–833), p<0.001), especially physician, radiology, and laboratory resources. This difference persisted in multivariable analysis (geometric mean ratio (GMR) 1.2, 95% CI: 1.1–1.3, p = 0.001) adjusted for sociodemographic parameters, consultation characteristics, and patient comorbidity; the GMR was highest in ED laboratory and radiology resource consumption. Among multi-substance user, indirect and non-drug-related consultations had higher ED resource consumption compared to drug-related consultations. Furthermore, leading discipline as well as urgency were predictors of ED resource consumption. Moreover, multi-substance users had more revisits  as well as longer ED and in-hospital stays .ED consultations of multi-substance users are expensive and resource intensive. Multi-substance users visited the ED more often and stayed longer at the ED and in-hospital. The findings of our study underline the importance of this patient group. Additional efforts should be made to improve their ED care. Special interventions should target this patient group in order to decrease the high frequency and costs of emergency consultations caused by multi-substance users. Substance abuse in Western countries is increasing . It causMulti-substance users frequently present to emergency departments (ED) ,5–10 andWe believe that efficient treatment of this vulnerable patient group not only affects ED resources but on the same hand might reduce side effects and discomfort originating from potentially unnecessary examinations. However, whether this widely suspected resource need really exists and where in the process of ED care it occurs is poorly understood as research on this topic is sparse. Yet, such knowledge is required in order to develop targeted interventions with the highest potential to be effective and efficient. Therefore, the aim of this study was i) to compare ED resource consumption of multi-substance users with an age-matched control group of non-multi-substance users, ii) to identify where in the ED process the largest differences in resource consumption originate, and iii) which parameters among multi-substance users predict the ED resource consumption.This is a retrospective single centre case-control study. The study site was the adult ED (level 1) of the university hospital of Bern, the capital of Switzerland. A mean of more than 35,000 patients per year were treated over the study period.In light of the complex and inconsistent use of terminology of multi-substance abuse  we used any abuse of, or addiction to, two or more psychotropic substances, according to WHO ICD-10 criteria of abuse and addiction (ICD-10: F10-F19), including indiscriminate abuse of polyvalent substances (ICD-10: F19).To ensure clinical relevance, patients with simultaneous alcohol- and tobacco abuse only–without concurrent abuse/addiction of any other psychotropic substances–were not included in this study. This pragmatic approach was agreed upon after consultation with the Swiss Federal Office of Public Health.All consultations of adult patients (≥16 years) were eligible for this study when there was a documented diagnosis of multi-substance use on admission to the ED during the three-year study period between May 11, 2012 and May 10, 2015.Pregnant women usually present to the separate gynaecology and obstetrics department. Younger patients (<16 years) are routinely treated in the paediatric ED and are therefore not included in our study population. Consultations of patients with a previous–but no longer active–diagnosis of multi-substance use were excluded, as were consultations of patients who had refused to provide general consent for the anonymous use of their patient data, and consultations with insufficient information on resource consumption. Furthermore, consultations with incomplete information on the potential confounding variables (see below) and consultations in which the primary attending discipline was psychiatry (no comprehensible resource expense documentation) were excluded.The primary outcome was the total ED resource consumption defined as the sum of physician, nurse, laboratory, and radiology resources (see below). Resources were measured in tax points . TP are a measure constructed for billing purposes. For single services (e.g. patient time), the tax points correspond to minutes of work . One TP is about 0.89 CHF, but the exact value depends–among others–on the hospital size. In contrast to the total ED costs, the sum of the billed TP reflects the resource needs of a patient.The following secondary outcomes were analysed:Resource subgroups: physician resources divided in total resources [TP] as well as patient, admin, and medical report time [minutes], total nurse resources, laboratory resources, and radiology resources [TP]; in addition to the total radiology resources, the binary outcome parameter sonography, X-ray, computer tomography (CT) scan, and magnetic resonance tomography (MRT) scan performed [yes/no] were evaluated.Administrative outcomes: the total ED costs [Swiss Francs], length of ED stay [minutes] and length of hospital stay [days].Clinical outcomes: intensive care unit (ICU) admission and in-hospital mortality.A multivariable statistical model was adjusted for the following covariables:Sociodemographic parameters: age, sex, and insurance type ,Consultation acuity: triage category, which is routinely registered by special qualified nurses with the Swiss Emergency triage scale , resuscitation room use , and typConsultation characteristics: night admission (19:00–06:59), weekend admission (Saturday/Sunday), season , revisit, and area of primary problem .Patient comorbidity: the Charlson comorbidity index , includiTo further predict resource consumption between multi-substance users, the following multi-substance user specific parameters were determined: i) drug-related consultation grouped in directly related such as intoxications and abscesses after drug injection, indirectly such as Hepatitis complication after drug-use, and non-related, ii) documented intravenous drug-abuse as well as iii) heavy-ED user consultation defined as more than 3 consultations in one year .Potentially eligible consultations were identified through a full text keyword search (“polytoxicomania” with different semantic combinations) in the comprehensive emergency medical report. The medical report contains patient history, admission procedure as well as established and chronic diagnoses. The ED medical report is routinely electronically generated and stored by the physician in charge in our computerised patient database .The complete, anonymised medical report–including controller data on resource consumption (see below)–was exported to Microsoft Excel  for further analysis. The medical report was analysed in full text by one study investigator (CR) to check for an active diagnosis of multi-substance use and ensure a fulfilling of the eligibility criteria and presented definition.In addition to the potential confounder mentioned above, the clinical outcome parameters, ICU admission and in-hospital mortality, were extracted from our computerised patient database. The acute diagnoses were classified manually as medical, surgical, or psychiatric diagnosis, as shown in Staff members routinely document their work for each patient in the medical database for billing. Regular trainings for every staff member are performed to ensure a valid billing. Variables describing physicians’ work , nurses’ work, radiology diagnostics , laboratory resources, and total costs  were used to analyse resource consumption. All resource variables were measured in TP.For further statistical analysis, the data was imported into Stata® 13.1 .To each consultation, five randomly selected, age-matched consultations with complete data on the potential confounder variables were matched.th - 75th interquartile ranges (IQR). Categorical variables were shown as per cent, accompanied by the absolute number. All continuous variables were ln-transformed to take into account the non-normal distribution of the parameter.As all continuous variables were not normally distributed (Shapiro-Wilk test), the continuous variables were presented as medians with 25Univariable associations between being a multi-substance user (case vs. control) and categorical variables were tested using a chi square test. Differences in continuous variables between cases and controls were analysed using the Wilcoxon rank sum test.Multivariable regression analysis on the ln-transformed continuous outcomes or logistic regression analysis for the binary outcomes adjusted for the potential confounder were used to quantify the association between being a multi-substance user and the outcomes. While the measure of strength in the logistic regression was odds ratio (OR), the measure of strength in linear regression with ln-transformed outcome was the geometric mean ratio (GMR) of the original outcome (exponentiated coefficients). Both measures are presented with their 95% Confidence Interval (CI).A multivariable linear regression analysis was also used, to identify total ED resource predictors among multi-substance user. To obtain a final model in the linear regression models, parameters with p>0.2 were stepwise removed from the models.For sensitivity analysis, the final model was varied using a conditional linear regression analysis . As subgroup analysis, we restricted the main analysis to the first consultation of an included multi-substance user to take into account that follow-up visits of a multi-substance user might not be independent events.A p-value of less than <0.005 was considered significant to reduce false positive results .Our search resulted in the identification of 1,364 potentially eligible consultations of multi-substance users during the three-year study period . In total, 8.8% (n = 120) of these had to be excluded because i) the patient was sent to the ED by another health care professional but never showed up (n = 7), ii) the patient had denied the general consent for the detailed use of anonymised patient data in clinical trials (n = 82), or iii) there was insufficient information on resource consumption (n = 31); see Consequently, 867 non-psychiatric ED consultations of documented multi-substance users were included in the detailed analysis. To each consultation, five randomly selected, age-matched consultations out of the 106,834 ED consultations with a negative result in key-word search with complete data on the confounder variables were matched. Therefore, the control group consisted out of 4,335 consultations.The median age of the multi-substance user was 43 (IQR 34–49) years. Compared to the age-matched control group, the following significant differences were found  and in further 9.7% heroin consumption was documented, although the form of administration was not specified. In 58.4% of patients (n = 506), there was no explicit documentation of recent intravenous drug use or heroin use.In total, 262 (30.2%) of the multi-substance user consultations were direct drug-related, 83 (9.6%) indirect and 522 (60.2%) were not drug-related.The discharge diagnoses in the multi-substance users were broad and heterogeneous  in multi-substance users  compared to the age-matched control group  . FurtherThe geometric mean of the total ED resource consumption was 1.2  times higher in multi-substance user ED consultations compared to the age-matched control group in multivariable analysis : in the Focussing the analysis on the multi-substance user, three more variables were added to predict the total ED resource consumption: i) heavy ED user, ii) intravenous drug use, and drug-related consultation.In univariable analysis the three studied administrative outcomes  as well as the two studied clinical outcomes  were significantly increased (p≤0.001) in multi-substance user consultations see . After aA matched analysis using a conditional multivariable linear regression analysis did only very slightly change the effect size between total ED resources and multi-substance user consultation presented in Restricting the main analysis Tables  and 4 toCompared to a control group in confounder adjusted regression analysis, ED consultations of multi-substance users generated higher overall costs and needed more overall ED resources, especially high levels of physician and laboratory resources. Despite the high resource consumption, multi-substance users had more revisits, longer ED and in-hospital stays but no increased mortality or ICU admissions when controlled for confounders.ED visits of multi-substance users consumed significantly more resources than non-multi-substance users. Our detailed analyses showed that this is mainly due to use of physicians’ time and laboratory resources. This may be even more pronounced if one considers the lower use of expensive procedures such as MRT in this subgroup.Increased morbidity associated with substance use, particularly the increased risk of immune-deprived status caused by chronic infectious diseases  , is likeIn addition to general increased morbidity, psychiatric comorbidity may be one of the reasons for excessive physicians’ work and time consumption especially in multi-substance users with frequent ED visits ,8,19. DeThis increased number of psychiatric comorbidities might come together with the known difficult treatment of patients with disruptive behaviour, as is often experienced within the care of multi-substance users or patients with additional mental health disorders. Patients with disruptive behaviour are known to be difficult to diagnose and are in danger of receiving incorrect or delayed diagnoses ,22. SensAlthough the ED work up for the group of multi-substance users devours more resources and is more expensive compared to the matched control group, the multi-substance users had more revisits compared to the control group. This may be attributed to the significantly higher morbidity which is shown in the higher Charlson comorbidity index in our study and in line with the literature ,14. AnotPrevious studies have demonstrated that substance use is associated with more frequent ED consultations ,8,24. MuIt has been shown that multi-substance users misuse the ED as a substitute for primary care . SocioecConsequently, ED interventions which identify patients at risk and target those factors might help to facilitate access to primary care and decrease the number of frequent emergency consultations. Reviews about interventions and screening for substance use disorders showed a reduction in alcohol consume even months after a very limited short time intervention at the ED ,26. ImpoCloser collaboration with primary and secondary care services–in particular those also specialised in treatment of comorbid psychiatric and substance use disorders–may be mandatory. While transitional care clinics have given promising results and closer linkage between ED and primary care services may facilitate follow-up and reduce multiple ED presentations , substanFuture research should evaluate the cost effectiveness of any potential intervention and focus on interventional strategies for the early detection of “at-risk” patients and subsequent interdisciplinary and target-oriented management of these individuals, as well as intensified collaboration between EDs and primary care services.The limitations of our study include the missing or unknown real figure for the specific substances the patients were consuming. As previous studies have shown, associated risk of increased morbidity and mortality differs widely between specific substances ,14. We oAnother limitation is the wide variation in the definition of multi-substance user in the research and official use. In our study, we focused on patients with abuse of multi-substances mainly alcohol, illicit drugs, and opioid/benzodiazepine abuse. This is not in line with the definition of the Swiss Federal Office of Public Health, where simultaneous daily tobacco and occasional alcohol use itself already is classified as multi-substance use. Thus, the characteristics of consultations by multi-substance users could not be set into the context of the background population to further identify multi-substance users at risk for ED consultations. Furthermore, we used a key-word search in the first step to identify cases, which might have led to bias.As this was a single centre study in a university hospital, transferability to other settings may be limited and further research is warranted here. As diagnoses were extracted retrospectively from medical reports, there is a risk of missed cases due to incomplete detection or reporting of diagnoses. However, routine medical reports of our university hospital ED must contain detailed documentation, including a comprehensive medical history that covers all previous primary care and the available inpatient medical reports.Additional strengths of our study include the high number of included cases as well as the reasonable observation period of three years, and this suggests that our findings may be more widely applicable.Compared to an age-matched control group, ED consultations of multi-substance users were more expensive and resource intensive, especially the indirectly drug related visits, particularly with respect to physician time adjusted for important confounding variables.Multi-substance users visited the ED more often and stayed longer at the ED and in-hospital. The findings of our study underline the importance of the patient group of multi-substance users. Additional efforts should be made to improve the ED care and follow-up care of those patients. Special interventions should target this patient in order to decrease the high frequency and costs of emergency consultations of multi-substance users.The study was approved by the regional ethics committee of the Canton of Bern, Switzerland (KEK-BE-2018-00359 and 2018–00198). The data was anonymized prior to analysis. The ethics committee waived the requirement for informed consent.S1 File(XLSX)Click here for additional data file.S1 TableTable showing the diagnostic groups used to classify the different disease patterns.(PDF)Click here for additional data file.S2 TableTable showing the established diagnoses of multi-substance users.(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table(PDF)Click here for additional data file.S5 Table(PDF)Click here for additional data file.S6 Table(PDF)Click here for additional data file.


Under the hood, iris makes use of npstreams, an extensions of numpy to streaming array-processing, for high-throughput parallel data reduction. Finally, we present scikit-ued, a library of reusable routines and data structures for analysis of UES data, including specialized image processing algorithms, simulation routines, and crystal structure manipulation operations. In this paper, some of the features or all three packages are highlighted, such as parallel data reduction, image registration, interactive exploration. The packages are fully tested and documented and are released under permissive licenses.This paper details a software ecosystem comprising three free and open-source Python packages for processing raw ultrafast electron scattering (UES) data and interactively exploring the processed data. The first package,  The advent of ultrafast electron diffraction (UES) has extended crystallography into the temporal dimension. Combining the spatial resolution of electron microscopy and femtosecond time-resolution, this laboratory-scale technique has shed light on a broad spectrum of phenomena, from photoinduced structural phase transitions in inorganic , 32 and scans—are acquired sequentially. This set of equivalent sub-experiments forms the raw experimental data. In order to extract time-dynamics, the data must be distilled, or reduced; the data reduction might involve scattering intensity normalization or alignment, and ends in averaging. A physical picture of dynamics in a sample is built by looking at in scattering intensity over time, in a fixed region of reciprocal space. A conceptual view of the flow from raw data to dynamics is presented in Fig. Ultrafast electron scattering is a stroboscopic technique. Electron scattering patterns are acquired a fixed time-delay after photoexcitation with an ultrafast laser. A full view of the scattering dynamics can be assembled by acquiring electron scattering patterns for sufficient time-delays. To maximize the signal-to-noise ratio, equivalent experiments—hereafter referred to as iris. We also introduce a software package of reusable routines and data structures related to ultrafast electron scattering (scikit-ued) and a streaming array operations package (npstreams), establishing a software foundation on which the community can build. Iris is the first integrated solution for interacting with UES data.The path from data acquisition to scientific insights can never be fully standardized and streamlined. However, one step common to all workflows is data exploration. This is especially important for time-resolved techniques such as UES due to the breadth and depth of information contained in a dataset. This emerging field would benefit greatly from an aggregation of efforts towards free and open-source tools that standardize and simplify analysis and interpretation of complex dynamics. In this work, we present a program built specifically for interactive data exploration, de facto standard numpy package [The software ecosystem presented in this work is written in Python; the language is accessible to non-programmers, with a simple syntax and dynamic nature. The scientific Python community’s dedication to good documentation and focus on free and open-source packages are attractive features that played heavily in the decision to write iris in Python. While pure Python code typically results in poor performance, bottlenecks can easily be rewritten in a more efficient, compiled language, and seamlessly integrated with existing Python code . It shou package  that expiris, first and foremost a graphical user-interface (GUI) program that allows for interactive exploration of ultrafast electron scattering data. From its GUI, users can interact with raw data, process this raw data into a reduced dataset, enabling interactive data exploration. Iris’ second role consists of a library of data structures for handling ultrafast scattering data in external Python scripts and programs. Everything that can be done in the GUI can also be done programmatically.The primary tool presented in this work is iris workflow involves interacting with raw scattering patterns from a variety of possible unique formats. For this purpose, Iris supports plug-ins that act as bridges between arbitrary data formats for raw data and iris’s internal representation.The first step in the typical iris workflow consists of data reduction. During this phase, equivalent scattering patterns acquired with the same time-delay are reduced in parallel. This reduction operation can involve image-alignment, intensity normalization, or any operation specified by a plug-in. Scattering patterns are then concatenated into a three-dimensional array, similar to a video. Experimental metadata, such as sample temperature, photoexcitation conditions, electron energy, and more, are also preserved. Arbirary metadata can be defined by users through the use of plug-ins. The performance optimization of the data reduction pipeline is discussed in depth in “The second step in the typical Iris handles large reduced datasets by storing them using the Hierarchical Data Format version 5 (HDF5), an archival format designed for large n-dimensional numerical datasets [datasets , 13. HDFiris, dynamics in scattering patterns can be explored interactively, in real-time. Further data transformations are also possible, most importantly azimuthal averaging of scattering patterns from polycrystalline samples. Time-series extraction in the GUI is shown in Fig. The final stage of the exploration workflow—time-series extraction—is specific to time-resolved techniques. Thanks to HDF5’s data slicing feature and careful performance optimizations within Iris was designed with compatibility in mind. For input compatibility, iris’s plug-in architecture allows to interface with arbitrary data formats. Writing a plug-in requires writing some Python code: users can then use the full power of the scientific Python stack to introduce extra processing in iris’s data reduction pipeline. In terms of output compatibility, iris datasets can be inspected and manipulated by a large variety of programs, thanks to HDF5’s official and unofficial bindings to programming languages such as C/C++, Fortran77/Fortran90, LabVIEW, MATLAB, Mathematica, R, Julia, Python, and many more. The HDF5 layout is described in the online documentation.numpy arrays, and then reducing—which usually involves scattering pattern alignment, intensity normalization, and finally a weighted average—is a slow process.Raw scattering datasets can reach sizes up to hundreds of gigabytes. The reduction operation of concatenating images into dense npstreams was created. Npstreams extends the core components of the array-oriented numpy package  to work on streams of arrays rather than dense, in-memory arrays. Npstreams can automagically generate streaming functions from numpy universal functions. The streams of arrays can be generated on-demand (such as images being progressively loaded from disk). Stream operations require much less memory, which in turns allows for parallelization. In fact, in the special case of stream operations on arrays of the same size , data reduction can operate in constant-memory.To effectively reduce the raw data, the package iris, a stream of arrays is formed by progressively loading scattering patterns at same time-delay (but from different scans). Therefore, the reduction of a dataset of many time-delays and many scans to a dataset of many time-delays and a single scan can be done in parallel. In the limiting case where data processing performance is not bound by data loading time, the performance increase due to npstreams alone is linear in the number of processing units. Thus, an 8-core computer would experience an 8x performance increase by using npstreams in parallel.In the case of data reduction in npstreams, or concatenated into a dense ndarray which is in turns averaged using numpy. The results of running this benchmark on sequence of varying lengths and arrays of varying sizes is presented in Fig. Single-core performance is also improved. To measure single-core performance, benchmarks set up a sequence of npstreams is concerned with autogenerating streaming functions from basic universal numpy functions, some more complex streaming functions are implemented, with the aim of providing real-world examples. For instance, a streaming weighted average and streaming weighted standard deviation routines are included, based on West [While the core of  on West .Npstreams also includes benchmarking functionality, where users can generate benchmark results on their machine with a simple command, as shown in Fig. npstreams extends beyond the requirements of iris and scikit-ued. Streaming array operations can deal with an infinite stream of arrays. For example, an operation can be applied until certain criteria are met, or a pipeline can be assembled which can run forever, in constant (low) memory.The functionality of scikits, extensions of the general-purpose SciPy package [scikit-image [scikit-learn [scikit-spectra), bio-informatics (scikit-bio), and much more. In the tradition of these scikits, we introduce scikit-ued, a collection of algorithms, routines, and data structures commonly needed for ultrafast electron scattering data interactions. Most operations iris performs on datasets are offloaded to scikit-ued.The scientific Python community has access to over 50 research-oriented packages called  package . These sit-image ), perforit-learn ), interaScikit-ued provides a repository of reusable components in many domains, such as image analysis, crystal structure manipulation, baseline-removal, simulation, common utilities, and more. Some of its features are described in the following sections.scikit-ued is the evolution of the approach previously published by the authors. Readers interested in the details are referred to [The baseline-removal functionality provided by erred to . Some exerred to . This apscikit-image can be used. Specific tasks not widely available elsewhere have been included in scikit-ued.Scattering patterns analysis intersects with general image processing in many ways. In most cases, other libraries such as iris, is scattering pattern alignment to a reference. During the course of data acquisition, scattering patterns can drift across the detector due to fluctuations in the electron beam alignment, while other image components  will appear static. Therefore, cross-correlation techniques used in image registration generally fail at scattering pattern alignment. Scikit-ued includes an advanced image-alignment algorithm, known as the masked normalized cross-correlation image registration [A common data processing task, implemented in the data reduction pipeline of stration . By maskscikit-ued. One such operation is azimuthal averaging, a procedure during which polycrystalline scattering patterns are reduced to one radial dimension. Scikit-ued includes discrete symmetry-based operations as well, most importantly discrete rotational averaging. Scattering patterns exhibiting n-fold rotational symmetry can be transformed to yield a higher signal-to-noise ratio. This approach has recently been used to extract small ultrafast diffuse scattering signals from graphite [Symmetry-based operations are also implemented in graphite . An examScikit-ued includes data structures that make it easy to read and manipulate crystallographic information. The Crystal class is the primary data structure giving access to atomic positions, chemical composition, lattice information, and more. It can be generated from a few types of sources, with the most convenient type involving the ubiquitous Crystal Information File (CIF) format [) format , 15. Str) format , 10, as ) format . A numbe) format . An examOnce a Crystal instance has been created, space-group information and symmetry operations can be determined through the library spglib , 27. UsiScikit-ued has built-in support for calculation of crystal potentials, based on the parametrization of Kirkland [Kirkland . The exaScikit-ued exports a routine for simulating electron diffraction patterns for polycrystalline samples based on the atomic positions of Crystal objects. Examples of simulated diffraction patterns from built-in scikit-ued structures are presented in Fig. From the parametrization of atomic potentials, the atomic form factors can also be calculated—and from them static structure factors. Scikit-ued provides routines to read exotic image file formats. Scikit-ued can read Merlin Image Binary files (*.mib)—both single image and multi-images files—as well as Gatan’s proprietary DM3 and DM4 formats . Scikit-ued can also read all images supported by scikit-image, notably images encoded in the Tagged Image File Format (*.tiff).scikit-ued. Fast computation of pseudo-voigt profiles is included and integrated with the polycrystalline diffraction simulation routine, based on the work by Ida et al. [Many small utilities are included in a et al. . Calculaa et al. . Finallya et al. . AdditioAll three libraries presented herein benefit from some common features and development tools.First and foremost, all three packages are documented online . Reference documentation is automatically generated from the source code, which limits the possibility of documentation being out-of-date with respect to the source code . The dociris GUI through a help menu. Bugs and issues raised through GitHub are publicly visible and provide a place to discuss potential solutions.The repositories are hosted on GitHub, a web-based code hosting service with built-in version control through Git. As the packages are free and open-source, GitHub can be used to browse source code. It also provides features not available through Git itself, most importantly an issue tracker. This issue tracker is also directly accessible from the After changes are committed to one of the repositories, the updated package is automatically installed and tested in a remote environment—a practice known as continuous integration. Committed changes also trigger the automatic generation of a new documentation version, which is then posted online within minutes.Finally, stable versions of all three packages are uploaded to the Python Packaging Index (PyPI), where they can be inspected and downloaded. For users of the Anaconda Python distribution, the three packages are also available for install within the conda environment, which provides pre-compiled packages.iris involves data exploration along different dimensions beyond time: diffracted intensity along dimensions of fluence, temperature, doping concentration, and more.The natural progression for npstreams has largely been implemented. The obvious key improvement concerns performance, which could be increased by rewriting the core functionality in C, while exploiting numpy’s C interface.The target functionality of scikit-ued concern the simulation subpackage. Simulation of polycrystalline scattering pattern is indispensable as a tool to test methods and validate hypotheses; simulation of single-crystal scattering patterns is a natural evolution of scikit-ued’s capabilities. While the basic parametrizations of atomic properties are already implemented, as well as the computation of real-space electrostatic potential of arbitrary crystal structures (see Fig. scikit-ued could bind.Future developments of see Fig. , wave-prnpstreams, a streaming array-processing library that allows for constant-memory data reduction. Scikit-ued, a scipy extension that contains algorithms and data structures for the analysis of UES data, was also presented. Finally, the ecosystem culminates in the iris package, the first integrated data exploration interface specifically tailored to the data-rich nature of UES. Iris’ plug-in functionality as well as real-time, interactive capabilities pushes the limits of what is possible in field of ultrafast electron scattering.An ecosystem of three free and open-source Python packages for exploring ultrafast electron scattering data was presented. This ecosystem, governed by permissive licenses, was created with collaboration in mind, while adhering to sane software development practice. We introduced


Recent advances in nonlinear analytic methods for electroencephalography have clarified the reduced complexity of spatiotemporal dynamics in brain activity observed in Alzheimer’s disease (AD). However, there are far fewer studies exploring temporal scale dependent fractal properties in AD, despite the importance of studying the dynamics of brain activity within physiologically relevant frequency ranges. Higuchi’s fractal dimension is a widely used index for evaluating fractality in brain activity, but temporal-scale-specific characteristics are lost due to its requirement of averaging over the entire range of temporal scales. In this study, we adapted Higuchi’s fractal algorithm into a method for investigating temporal-scale-specific fractal properties. We then compared the values of the temporal-scale-specific fractal dimension between healthy control (HC) and AD patient groups. Our data indicate that relative to the HC group, the AD group demonstrated reduced fractality at both slow and fast temporal scales. Moreover, we confirmed that the fractality at fast temporal scales correlates with cognitive decline. These properties might serve as a basis for a useful approach to characterizing temporal neural dynamics in AD or other neurodegenerative disorders. The pathological progression leads to cortical disconnection, which reportedly alters the complex nonlinear behavior of the brain Stam . A varieA chaos/fractal-based approach  were avoided, because they might have disrupted the intrinsic dynamics of the data. Epochs without artifacts were selected by visual inspection. To provide adequate information for analysis of long-range temporal dynamics, we initially prepared a single continuous artifact-free 60-s  epoch during the eyes-closed resting condition. From this dataset, 1000 data points at the beginning and end were removed to avoid interference by the 1.5–60 Hz bandpass filter. Finally, Higuchi’s fractal dimension was calculated on the continuous 50-s  epoch.k, the EEG data X(t) has the fractal dimension D, m) obeysD value in the range of D can be derived as the slope of For the fractal analysis of EEG data, we used Higuchi’s fractal algorithm Higuchi . If the Along with the analysis for temporal-scale-specific fractal dimension, we also performed power spectral analysis as in conventional EEG analyses. The power spectrum density (PSD) (dB/Hz) was estimated using a fast Fourier transform. A Hanning window was applied to the 60 s time-series for the calculation.t tests. Because the temporal-scale-specific fractal dimension values were found to have a skewed distribution, we log-transformed them to obtain an approximately normal distribution. Associations between temporal-scale-specific fractal dimensions and cognitive function estimated by MMSE score were evaluated using Pearson’s correlation coefficient. The Benjamini–Hochberg false discovery rate (FDR) correction was applied for multiple comparisons. For sensor-wise group comparisons, p values), for temporal-scale-specific fractal dimensions , and for PSD , with group (HC vs. AD) as between-subjects factor and node (16 nodes of Fp1-O2) as within-subjects factor, was performed to test for group differences at each frequency band. The Greenhouse-Geisser adjustment was applied to the degrees of freedom, and a two-tailed To observe the differences in power spectrum between EEG signals of HC and AD, as shown in Fig. k to derive temporal-scale-specific fractal dimension. Figure k for D on We evaluated the range of entclass1pt{minimaentclass1pt{minimat tests, the t values for nine nodes  met the FDR criterion . Moreover, by evaluating the relationship between cognitive function measured by MMSE and the temporal-scale-specific fractal dimensions, we confirmed that the fractality at faster temporal scales correlates with cognitive decline. This reduced fractality can be detected even when the length of the time-series is small.Reduced fractality is associated with reduced complexity, which is consistent with the well-established hypothesis Stam  that EEGStam et al. used a graph-theoretical analysis to argue that the decreasing functional connectivity in beta bands is related to cognitive function , alpha band, and fast band (beta/gamma). However, these ranges might need to be optimized for specific brain functions and diseases. This type of optimization should be considered in future work. Regarding cognitive functions, we evaluated the relationship between the temporal-scale-specific dimension and MMSE score in AD. However, due to the ceiling effect for the MMSE, a wide range of cognitive functions cannot be dealt with. Therefore, in future work, we should consider the relationship with other cognitive tests, while expanding the pool of healthy subjects. It is also important to evaluate the temporal-scale-specific fractal dimension in subjects performing cognitive tasks (rather than resting).Several limitations of this study must be considered. Higuchi’s fractal dimension characterizes variation as a function of the In conclusion, the AD group showed temporal-scale-specific reduced fractality and this reduced fractality was associated with cognitive decline. These findings highlight the potential utility of examining temporal-scale-specic fractality of EEG signals in diagnosing AD and evaluating disease severity. Additionally, the possible diagnostic utility of our method was confirmed even with short data sets, which is advantageous in a clinical setting. Although several limitations need to be clarified, characterizing temporal-scale specific fractal properties in neurophysiological data may serve as a powerful complementary approach for diagnosing neurodegenerative diseases.


Creatine kinase-muscle (CK-MM) and aldolase A (AldoA) levels are proven to be realistic biochemical markers to detect muscular dystrophy during osteoarthritic disorders (MD-OADs). The aim of this study is to normalize the MD-OADs characterized by muscle weakness, atrophy, inflammatory disorders, pain with chronic arthropathy by specialized topical phytotherapeutic treatment.Cissus quadrangularis, Calotropis gigantea, Zingiber officinalis, Rosemarinus officinale, Boswellia serratia, Curcuma longa andWithata somnifera mixed with sesame oil and beehives wax for six-week.Baseline data were collected and evaluated from 153 patients, aged 59.89±11.37years, and suffering with MD-OADs for 7.89±1.90 years. Serum CK-MM and aldoA levels were measured at baseline and after a six- week treatment using the appropriate kits. All patients underwent standardized physical, radiographic examinations and completed a questionnaire. All the patients were treated with topical application of phytoconstituents from the extracts of seven Indian medicinal plants namely The elevated levels of biomarkers, CK-MM and aldoA, were reduced to their mean±SEM values 82.77±1.32 and 4.94±1.30U/L, respectively at the end of six-week treatment and the improvements of deranged anatomical features, Pearson’s correlation coefficients, international-approved pain related abnormalities  and reduction of weight at the end of treatment were all highly significant (p<0.0001).It is firmly confirmed that MD-OADs resulted with the elevated levels of CK-MM, and AldoA, along with deranged anatomical features  and pain related parameters  can be successfully normalized by topical phytotherapeutic treatment protocol. According to Newman , musculaResearches have been well-documented with regard to the impairment of different muscles during MD-OADs -10 and aThere are several types of MD such as Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) which are very common. But none of DMD or BMD is involved in MD-OAD as it does not occur relating to their phenomenon . The norMoreover, the author has already developed a unique deranged anatomical measuring protocol to identify quantum of damage of muscles and tissues and also other biomarkers such as calcium, phosphorus, ratio of calcium and phosphorus and level of parathyroid hormone to identify the condition of damage bone during MD in OAD patients , 34-35. The present study was attempted for normalization of MD-OADs by analyzing the decreasing serum levels of CK-MM and aldoA in the patients before and after the treatment using phytoconstiuents extracted from the abovementioned seven plants mixed with sesame oil and beehive wax by specialized treatment protocol which have not been studied yet. Recruitment of patients: From nine center of OPTM Health Care (P) Ltd 315 Indian patients , aged 40 to 70 years old were selected for the study from July 2017 to December 2017, based on the sign and symptoms as described in earlier studies  levels were quantitatively assessed using a Creatine Kinase- MM kit (CK-MM/CPK-MM/CK-3) and an immunoassay . The kit was developed based on the methods reported by Walker  and their mean differences (MDs), 95% confidence intervals (CIs), and p-values of the two biomarkers such as CK-MM and aldoA and their ratios were evaluated at the baseline and at the end of the six-week treatment. Their percentages of mprovements after the treatment were graphically evaluated.Evaluation of pain under Visual analogue scale (VAS): Visual analogue scale (VAS) for pain is a one-dimensional measure of pain intensity  as per method followed by previous researchers  score: Karnofsky performance status (KPS) score is used to determine a patient’s prognosis to carry out daily activities. A higher score indicates the patient is better able to carry out daily activities and its range from 0 to 100 : The Knee-injury Osteoarthritis Outcomes Scale (KOOS) developed by Ewa Roos and co-authors in the 1990s : Body weight in kilogram was measured without shoes or heavy clothing using an electronic scale. Height in meter was measured without shoes using a wall-mounted stadiometer (2) was calculated for all the patients based on measured weights and heights at pre- and post-treatment. The percentage of improvements was evaluated at the end of treatment for all the patients separately. Their mean, SD and p-values overall and separately by gender were also graphically evaluated.diometer . Body maEvaluation of Pearson’s correlation coefficients between two biomarkers: The Pearson’s correlation coefficients between two biochemical markers such as CK-MM at the baseline (CK-MMb) and CK-MM after the treatment (CK-MMt), aldoA at the baseline (Aldo Ab ) and aldoA after the treatment , the ratio of  and  along with their respective p-values were evaluated..Evaluation of radiological images with the Kellgren and Lawrance system: Radiological images for both knee joints and lumbo-sacral spine of 153 combined-sex patients, were collected, both anterior-posterior (AP) and lateral views, at pre- and post-treatment evaluations. The AP views of the knee joints of 153 patients are assessed by K-L grading scale , Calotropis gigantea (root and leaves), Zingiber officinale (rhizome), Rosemarinus officinalis (leaves and flowers), Boswellia serrata (resin), Curcuma longa (rhizome) and Withania somnifera (root) mixed with virgin sesame oil (extracted from seeds at room temperature) and beeswax to make viscous phyto-based oil without using any preservatives or chemicals to preserve the phytochemical properties of plants intact , frequency tables, or ratios for discrete variables, and 95% confidence intervals. Statistical analyses were done using software  with repeated measures for student-t test to determine the significant values at p<0.05 level along with r (Pearson’s correlation coefficient) values to determine strong and weak correlation among two variables for measuring different improvement parameters of combined-sex, female and male patients separately. An alpha level of 5% was established i.e., a p-value less than 0.05 was considered statistically significant.Enrolment and baseline characteristics of patients: A total of 153 patients aged 59.89±11.37 years (71% women) were included in the study. All the patients were suffering from MD-OAD for 7.89±1.90 years having massive muscle wasting specially in the thigh and calf regions, bone erosion and skeletal muscle damaged confirmed by the serum tests of CK-MM and aldoA and radiological images. The baseline demographic characteristics of all patients are shown in Biochemical parameters: b: aldoAb) and at the end of six-week treatment  were highly significant (p<0.0001) when compared to the baseline for both overall and separately by gender.b) and at the end of treatment (CK-MMt), were not significant  for combined-sex patients, female-only and male-only patients. b) and at the end of treatment (Aldo At) and the ratio of CK-MM and Aldo A at the baseline (CK-MMb : AldoAb) and at the end of 6-week of treatment  were all highly significant (P=0.000) both overall and separately by gender. The correlation coefficients between aldoA at the baseline  and aldoA at the baseline  were all highly significant (p<0.05). The correlation coefficients between CK-MM at baseline (CK-MMb) and aldoA at end of treatment  were not significant  for combined-sex patients, female-only patients and male-only patients. The correlation coefficients between CK-MM at baseline  both overall and separately by gender and shown in Pain, stiffness, performance parameters and BMI: The percentage of improvements: on pain under VAS; on pain, stiffness and physical functions under WOMAC index; on performance on daily activities under KPS; of the five separately scored subscales under KOOS knee survey and reduction of body weight confirmed by BMI after the treatment for combined-sex, female-only and male-only patients were all highly significant (p<0.05) both overall and separately by gender depicted in Anatomical parameters: The overall measurements of KGB, DAP and DBP all reduced and DCM and DTM were all increased and observed to be symmetrical for both the legs at the end of the 6-week treatment and were also highly significant (p<0.0001) when compared to the baseline [data not shown]. Improvement on muscular strength during MD-OAD as per radiological image assessed by K-L grading scale: All the anterior-posterior (AP) views of the x-ray reports of 153 patients with OAD at the baseline exhibited degenerative changes, particularly in the medial tibio-femoral compartment, with marked joint space narrowing and bilateral varus/valgus deformities. Some cases exhibited near-complete medial compartment joint space obliteration and also degenerative changes with osteophytes in the lumbar vertebrae. The AP view of x-ray for bilateral knee joints and lumbar vertebrae of patients after six-week treatment indicated no such degenerative changes and assessment under K-L grading scale shown in table-6. x-ray images of two such patients suffering from pain in the knee joint and lumbar region before and after the treatment are depicted in The present results indicated that MD-OADs can easily be recognized by elevated biomarkers such as CK-MM and aldoA and their ratio. Major research works have been reported that elevation of two biochemical markers such as CK-MM and aldoA are important to detect the muscular dystrophy and skeletal muscle damage , 36-38. Simultaneously, the declining level of these two biomarkers along with improved deranged anatomical features, pain parameter under VAS, improvement of physical functional abilities and quality of life under WOMAC index, KPS scale, KOOS and lowering obesity under BMI by topical phytotherapeutic treatment protocol for a period of 6 weeks, was an endeavour in the present study. Generally, phytomedicines from medicinal plants derived compounds are well-established for the prevention of arthritis, obesity, oxidative stress, inflammation, neuro-degenerative diseases, etc. , 53-55 IThe percentage improvement for the study of pain and related parameters were substantially achieved under the well-known guidelines for the standard clinical outcomes such as VAS, WOMAC Index, KPS, and KOOS and there is a reduction of body weight as assessed by BMI at the end of the six-week phytotherapy treatment for all the studied subjects. The result from the deranged anatomical parameters shows that there are substantially increasing and decreasing phenomenon of the group of muscles connected with various joints and both legs were symmetrical in respect of the measurements of KGB, DAP, DBP, DCM, DTM, SLR, KFS and KES at six weeks post-treatment which indicate the improvement of muscle wasting, muscle weakness and degeneration that occurred during MD-OAD at the baseline. Several researchers have emphasized the normalization of the above-mentioned parameters along with the prevention of osteoarthritis in human -39 but tMoreover, the few research works have been emphasized on structural and functional abnormalities of dystrophin protein located within sarcolemma and causative factor of MD  but the Limitation of the study: The patients suffering from chronic disorders are restricted to this present study such as Duchenne muscular dystrophy (DMD); Becker muscular dystrophy (BMD); rheumatic diseases; osteochondritis diseases; congenital dysplasia; radicular syndrome; joint symptoms caused by malignant tumors; dermatomyositis and polymyositis diseases; iliopectineal or trochanteric bursitis; ischemic bone necrosis; bone and joint infectious diseases; cuts, wounds or any type of chronic skin and infectious diseases; parallel multiple drug dependence for concomitant diseases or risk conditions requiring drug treatment including psychiatric diseases; a history of cancer, including caranomatosis and granulocytic leukemia; a history of severe neurological diseases; a history of chronic liver, kidney and heart diseases and also patients who did not agree to give blood sample, may be due to drugs/alcohol addiction, pregnancy and such other reasons.


This article reviews mechanically-tunable photonic devices with on-chip integrated MEMS/NEMS actuators. With related reports mostly published within the last decade, this review focuses on the tuning mechanisms of various passive silicon photonic devices, including tunable waveguides, couplers, ring/disk resonators, and photonic crystal cavities, and their results are selectively elaborated upon and compared. Applications of the mechanisms are also discussed. Future development of mechanically-tunable photonics is considered and one possible approach is based on plasmonics, which can confine light energy in the nano-scale space. Optomechanics is another innovation, derived from the strong coupling of optical and mechanical degrees of freedom. State-of-the-art studies of mechanically-tunable plasmonics and on-chip optomechanics are also selectively reviewed. Semiconductor technology has grown rapidly in recent decades and nowadays, semiconductor devices are widely integrated with many modern equipment, from radios to satellites. However, the development of electronic devices has reached a bottleneck in terms of the operating speed due to factors such as parasitic capacitance. As a result, there is intensive research—both industrial and academic—on alternative and new technologies as alternatives to semiconductors . One poti.e., to realize tunable photonics. Current on-chip tuning mechanisms can be generally classified as thermo-optic [Numerous studies have been carried out to develop methods to dynamically control photonic devices, mo-optic , electromo-optic ,13 or memo-optic . Electromo-optic . Moreovemo-optic .i.e., by mechanically moving or deforming structures, is a natural way to tune photonic devices and has many advantages over other methods such as a small footprint and compatibility of fabrication process with semiconductors. One widely-used group of mechanical tuning methods is based on micro/nano-electro-mechanical systems (MEMS/NEMS). The history of MEMS dates back to the 1960s and nowadays, MEMS devices are widely commercialized, e.g., MEMS actuators are utilized to drive the micro cameras on cell phones. With the development of micro/nano fabrication, the footprint of MEMS devices can shrink even further as more NEMS devices emerge. MEMS/NEMS devices benefit not only from a size advantage but they also have greatly enhanced performance. Many NEMS devices are currently being rapidly developed and some are employed for various state-of-the-art studies, e.g., nano-scale radiation heat transfer where ultra-precise and reversible mechanical control is required [Mechanical tuning, required . Since iStandard micro fabrication processes have been established for released MEMS microstructures and they generally can be categorized as bulk micromachining or surface micromachining. Bulk micromachining forms structures by selectively etching inside the material substrate, in which case anisotropic etching is commonly used. Unlike bulk micromachining, surface micromachining builds structures by depositing and etching of different layers on top of the substrate. Bulk micromachined devices are space consuming and are usually limited to anisotropic materials. By comparison, surface micromachining permits flexibility in materials selection and enable high-resolution patterns and thus is widely used for the fabrication of MEMS/NEMS and photonic circuits. etc. [Traditional photolithography is a common method to define the patterns in micro fabrication and has a resolution in the micron- and submicron-scale. Improved methods, including electron beam lithography (EBL), focused ion beam (FIB), optical projection lithography, extreme UV lithography, X-ray lithography, etc. , are freetc.  and reacetc. . Whilst etc. . Conventetc.  and wideetc. . 2) is a common final fabrication process step to release and functionalize MEMS/NEMS devices. It is usually done using the HF vapor, instead of liquid, phase to avoid adhesion/stiction of nano structures arising from liquid surface tension [As for deposition, there are diverse techniques of chemical  and phys tension .etc. are a well-developed group of on-chip photonic devices. They have already proven to have strong capability in infrared (IR) light confinement and modulation [Silicon photonic devices built with materials like single crystal silicon, poly-silicon, silicon oxide, silicon nitride, dulation ,29. SiliIn this section, the field of mechanically-tunable photonic devices with on-chip integrated MEMS/NEMS actuators is classified and reviewed based on the configuration of the photonic devices. A dielectric rectangular waveguide is a kind of conventional on-chip wave-guiding structure. The light is confined by total internal reflection when the index of the dielectric waveguide is higher than that of its surrounding. Mechanically-functional waveguides are generally based on configurations of segmented waveguides see a, coupleIntuitively, it can be surmised that the transmission of light along segmented waveguides is roughly proportional to the total effective mode overlap integral of the waveguide cross-sections, which varies with the offset of the centers of the fixed and movable waveguide segments. The relationship between the normalized transmission (output power over input power) and the offset can be simulated using the finite difference time domain (FDTD) method. Typical results are plotted as the curve in One way of building an optical waveguide switch is by mechanically moving the central movable waveguide segment , a confii.e.,A(0) and B(0) are the modes launched into the coupler from two input ports while A(z) and B(z) are the modes emanating from two output ports, z denotes the coupling length, δ is the initial phase mismatch of the two input modes and κ denoting the coupling coefficient between the two waveguides. Mechanically moving one of the dual coupled waveguides changes the coupling strength between them and thus varies the intensity and phase of the output light to realize optical modulation and switching. This mechanism can be applied to coupler switches [The configuration illustrated in switches ,42,43,44The curve at the bottom left of Besides in-plane tuning of the dual-coupled waveguides, out-of-plane tuning is also investigated for on-chip large scale switches , the conFurthermore, not only can the output light intensities be controlled by tuning the coupling between the waveguides, but the output phase information can also be modulated. For example, a phase shifter has been developed based on such a principle , in whicBesides changing the coupling gap, moving one of the waveguides along its length direction while maintaining a constant coupling gap will result in light modulation as a result of variation in the effective optical path length. This method is also known as delay line modulation and is used to control optical phase information . As showQ factor).A combination of optical path length tuning and coupling strength tuning is also possible . As showQ factors of over 108 [Due to the intrinsic light field resonant enhancement, optical resonators are widely used for light control because they are wavelength-selective and usually have relatively high sensitivity to tuning. A well-known family of conventional micro optical resonators is micro ring/disk resonators, also known as whisper-gallery-mode (WGM) resonators. Reported ring/disk resonators fabricated with silicon/silica materials can have over 108 . Generally, a ring resonator system consists of a ring and coupled channel waveguides, as illustrated schematically in A relatively simple way to tune the coupling strength between the channel waveguides and the resonator through deformation of the waveguides has also been reported . As illuBesides in-plane waveguides actuation, out-of-plane waveguides bending b that acBesides static tuning, dynamic modulation based on such devices has also been demonstrated to have a high signal to noise ratio . In the 2O3 [The modes of actuation in the above-mentioned studies are all based on the electrostatic method. Another conventional MEMS driving method that is widely used is thermal actuation using bimorph materials . Thermal2O3 . When thPhotonic crystal ,66, a kiQ factors of over 106 [Q factors of over 106 [et al. developed a wavelength-selective channel drop switch with a 2D PhC in-plane coupled to a movable waveguide with the gap between them controlled by a comb-drive [PhC cavities can be generally grouped into three types: one-dimensional (1D), two-dimensional (2D) and three-dimensional (3D) cavities. Of these, 3D cavities are difficult to fabricate on-chip and characterized, whilst 1D and 2D cavities are the most widely studied. Typical configurations are shown in over 106 . Similarover 106 . MEMS/NEmb-drive . The dromb-drive , controlmb-drive ,74, tunamb-drive  and manymb-drive ,77.et al. studied near-field perturbation to 1D PhC cavities using nano-scale probes driven by monolithic NEMS comb-drive actuators, as shown in Q factor and transmission of the cavity drops significantly, whereas only moderate degradation of the Q factor and transmission is observed with a meniscus-like tip probe. The near-field perturbation tuning method was later further enhanced with a nano-scale multi-tip probe , in which dielectric probes or cantilevers are suspended above 2D PhC cavities ,79 or miip probe d and theradation . It should also be noted that the near-field perturbation mechanism can be applied to other photonic structures as well, e.g., waveguides  and waveQ factor and transmission may result. To address these issues, the coupled-cavity tuning approach has been proposed and developed. When two cavities are coupled together, the resonance frequencies of their coupled supermodes can be adjusted by controlling the coupling coefficient between them, which is determined by the overlap integral of the mode fields of the two resonators. The coupling between two optical resonators could be described by the well-established temporal coupled mode theory (CMT) given below [1a and 2a denote the optical modes on the two resonators, ω0 is the nature resonance frequency of individual resonators  and μ denotes the coupling coefficient between the resonators. The resonance frequency of the coupled system can be given byAs mentioned earlier, the resonance tuning range that is obtained with near-field probe perturbation is generally not very large and moreover, additional energy losses that negatively affect the en below :(2)ddtaFor nanobeam PhC cavities, the resonance with a lower frequency usually has a symmetric mode shape and is named as the even mode, while the resonance with a higher frequency possesses an anti-symmetric mode shape and is hence called the odd mode. Typical mode profiles of even and odd modes are shown as inserts in A number of experimental demonstrations of the coupled-cavity resonance tuning approach have been reported. They are commonly based on 1D (nanobeam) PhC cavities due to their small footprint and ease of mechanical control. For example, when a voltage is applied across two in-plane-coupled 1D cavities, the induced electrostatic force pulls the two cavities together and thus changes the coupling strength between them . A resonQ factor degradation when the coupling gap was changed from 750 to 150 nm [o 150 nm . To furto 150 nm . It is ao 150 nm . Q factors. Due to dielectric discontinuity, the cavity mode is tightly confined and enhanced inside the narrow air gap between the two photonic bandgap structures. A mode volume of 0.14 of a cubic wavelength has been numerically demonstrated [Q factor varied only slightly [Another way to control the cavity resonance is by MEMS/NEMS-controlled reconfigurable or deformable PhC cavities. For 2D cavities, a design referred to as air-slot cavities, which have ultra-small mode volumes , is popunstrated  and suchnstrated ,98. Besislightly .Q factor of the cavity can be widely tuned and yet, the resonance wavelength is barely affected [Q-switched lasers. Longitudinally-split nanobeam cavities can also be mechanically tuned by varying the offset laterally between the two components in-plane ,120119,1In this review, the authors focus on light modulation in the guided mode. As for the field of free-space light modulation, metamaterials have been and are being extensively investigated. Plasmonic metamaterials ,122 utilFor further development of mechanically controlled photonics, actuation using optical forces appears attractive due to its potential to be applied in all-optical systems. Driving photonic structures with optical force has already been experimentally proven ,128,129 A comparison of performance in light modulation of MEMS/NEMS tunable Si photonic devices, plasmonic devices, mechanically-tunable metamaterials, and optomechanic devices is presented in In the present review, recent progress on mechanically-tunable photonic devices with on-chip integrated MEMS/NEMS actuators is reviewed based on publications mostly within the last ten years. Works are classified according to their device configurations. Typical and significant studies are discussed with their tuning mechanisms elaborated and results highlighted and compared. As an outlook of future development of mechanically-tunable photonics, state-of-the-art studies of MEMS/NEMS tunable plasmonics and chip-scale optomechanics are also briefly reviewed.