Allergic rhinitis is a chronic inflammatory disease of the upper respiratory tract, which is associated with high incidence of anxiety symptom. There is evidence that medial prefrontal cortex modulates anxiety-related behaviors and receives projections from olfactory bulb. Since olfactory dysfunction has been reported in allergic rhinitis, we aimed to evaluate anxiety-like behavior and oscillations of olfactory bulb-medial prefrontal cortex circuit in an animal model of allergic rhinitis. The number of open arm entries in elevated zero maze was significantly reduced in sensitized rats exposed to intranasal ovalbumin compared to the control group, which was indicating the enhancement of anxiety-like behavior in allergic rhinitis animals. Analysis of local field potentials in olfactory bulb and medial prefrontal cortex during immobility and exploration state showed that anxiety-like behavior induced by allergic rhinitis was in association with increased activity of medial prefrontal cortex and enhancement of olfactory bulb-medial prefrontal cortex coupling in delta and theta bands. Moreover, in allergic rhinitis animals, theta strongly coordinates local gamma activity in olfactory bulb and medial prefrontal cortex, which means to have a strong local theta/gamma coupling. We suggested that disruption of olfactory bulb-medial prefrontal cortex circuit due to allergic reactions might have a governing role for inducing anxiety-like behavior in the allergic rhinitis experimental model. Allergic rhinitis (AR) is a chronic inflammatory disorder of the nasal mucosa, which is characterized by the presence of one or some symptoms, including itchiness, sneezing, rhinorrhea, nasal congestion, and daily alterations in sense of olfaction –4. AR isRetrograde and anterograde tracing experiments confirmed anatomical and functional connections between OB and PFC in representing states of emotional reactivity . A humanTaken together, OB-mPFC functional connectivity seems to have a key role in anxiety behaviors, while previous studies in AR reported alteration in each of these regions separately by focusing on cellular and molecular methods. Therefore, we hypothesized that AR-induced anxiety-like behavior was associated with disruption of OB-mPFC functional connectivity. To investigate this hypothesis, we evaluated oscillation alteration in OB-mPFC circuit as well as anxiety like-behavior in a rat model of AR.Sixteen adult (2–4 months old) pathogen-free male Wistar rats weighing 80–100 g were obtained from the Pasteur Institute . Animals were kept at 21 ± 2°C and 12-h light on/light off cycle (7 a.m. -7 p.m.). All animal protocols were reviewed and approved by the “Ethics Committee of Faculty of Medical Sciences, Tarbiat Modares University”.3 (30 mg) in saline (1 ml i.p.) every 2 days for 14 days. Then, 10 μL of 10% OVA was administered during inspiration was administered every day to both nostrils from day 15 to day 21. In the control group, saline was administered to the rats, pending similar days . As described previously , in AR glar days . To examTwenty-four hours after the last intranasal injection, open field and elevated zero maze (EZM) tests were conducted. We applied EZM test to estimate the level of anxiety in animals. The maze was 70 cm above the floor and made of an annular dark plexi . The maze was divided into four equal quadrants, in which two opposite quadrants were open and the rest remained closed; animals were allowed to explore and move freely for 5 minutes. In the open field test, each rat was placed individually into a standard open field box  allowed to explore for 10 minutes. In the both tests, the movement of rats was recorded using a video camera and a graphical interface of MATLAB were applied for analyzing the percentage of spent time in the open quadrants and the number of open entries in the EZM, and the traveling distance for locomotor activity in open field test.Animals were anesthetized with intraperitoneal injections of ketamine (100 mg/kg) and xylazine (10 mg/kg). Periodic injections of ketamine were carried out in order to have constant anesthesia throughout the surgery. Anesthesia induction was verified by the absence of withdrawal reflex followed by hind paw pinching. An intramuscular injection of 0.1 ml of dexamethasone (2.5 mg/ml) was applied to prevent swelling of the brain. Just before the surgery, 0.5 ml of lidocaine chlorhydrate 2% was subcutaneously applied in the scalp for local anesthesia. After anesthetic induction, animals were placed in a stereotaxic frame  in a flat skull position. An incision was made on the scalp along the midline of the skull surface and then a stainless-steel recording electrodes  were implanted unilaterally into the right hemisphere of two brain areas: OB  and the prelimbic of mPFC  . We implOne week after surgery, rats were placed in an arena (50×50×50 cm) and LFPs were recorded. For this purpose, the socket, fixed on the animal’s head, was connected to a miniature buffer headstage with high-input impedance , via cables to a main AC coupled amplifier (1000 amplification) and to the recording system . Spontaneous LFPs simultaneously were recorded from OB and mPFC in immobility and exploration states of the awake rats. The signals were stored for offline processing using by custom-written MATLAB software . We applied a video tracker for recording the movement of animals to detect the different states.For conforming to the location of electrodes, the rats' brain were carefully removed and fixed with 4% paraformaldehyde for 48h. Then a coronal section of 200 mm thickness was prepared and visually compared to the matching slices in the rat's brain atlas of Paxinos and Watson  Fig 1C)Fig 1C). We used Welch’s periodogram for computing power spectral density with MATLAB pwelch function. Coherence spectra between two regions were measured by calculating magnitude-squared coherence using mscohere function in MATLAB. Both power and coherence spectra computing were carried out in 30s segments of data by using 6 ms Hamming windows with 90% overlap. We calculated cross-correlation coefficient values for the delta (< 4 Hz) and theta (4–12 Hz) filtered signals by the mean of MATLAB xcorr function.Phase-amplitude coupling was calculated using the framework which was previously described . We analStatistical analysis was performed by GraphPad Prism software . The normality of the data distribution within each parameter was verified by Kolmogorov-Smirnov Test. The achieved results were compared by t-test. Data are shown as mean ± SEM. In all experiments, statistical significance was considered as the P < 0.05.The number of nose rubbing motions was assessed in order to confirm the induction of AR model in sensitized rats exposed to OVA. AR model was accomplished on day 21 and the number of nose rubbing motions among AR rats was higher than the control group (p < 0.05), while it was not significant on day 14 . EZM tesPower Spectral analysis (PSD) analysis of LFPs during immobility and exploration showed no significant differences in the mean delta (< 4 Hz) and theta (4–12 Hz) power of OB between both groups . HoweverIn both immobility and exploration states, coherence analysis of the signals, recorded from the OB and mPFC simultaneously, showed higher values for AR rats in delta and theta bands .We computed cross-correlation to more vastly explore the synchrony of OB and mPFC signals. In AR rats, mean OB-mPFC correlation coefficient for the theta-filtered signals (4–12 Hz) was increased during both immobility and explorations periods . We alsoTheta oscillations in the brain regions are known to modulate higher local oscillations and are thought to denote a code for neurophysiological processing . Here, wIn addition, we observed significant theta/gamma phase amplitude coupling in the mPFC during exploration state (p < 0.05) . Phase-aTo the best of our knowledge, this is the first report of association between OB-mPFC rhythmic oscillations and anxiety-like behavior in an AR model. Here, we found increased anxiety-like behavior in AR animals accompanied by the increment power of delta and theta in mPFC. In addition, AR-induced anxiety was in association with enhancement of OB-mPFC coupling, as assessed by coherence and cross-correlation analyses. Moreover, depends on the state of activity, phase of theta in OB and mPFC could strongly modulate amplitude of fast gamma (60–120 Hz) in AR animals rather than control group.A meta-analysis study indicated that there were bidirectional relationships between psychosocial factors and allergic disorders . AlthougHowever, most previous studies merely focused on neuroimmune responses of AR to explain behavioral alterations. In the current study LFP analysis was applied to reveal alterations in the pattern of OB and mPFC oscillations in AR animals. We observed that during immobility state, OB of AR animals represented less power of the narrow frequency sub-band (1.3–1.8 Hz) in delta oscillations. In line with our findings, Ozaki et al. showed that AR reduced power spectra value of OB animals in delta band . The posOlfactory sensory neurons not only relay chemical modality, but also mechanical stimulus induced by nasal airflow enhances the activity of these neurons. Notably, retrograde and anterograde tracing experiments confirmed efferent connection arising from the OB to mPFC . ConsistMoreover, in AR animals, theta strongly coordinates local gamma activity in OB and mPFC which means a strong local theta/gamma coupling. Phase-amplitude coupling referred to a synchronization of slow waves (SW) phase with power of fast frequency (FW) waves . SeveralWe have faced some limitations to interpret entire mechanism. First, we did not record the LFP signals at the same time when the animals were traveling through the EZM. In the animal with AR-induced anxiety, simultaneous record during performance of anxiety-like behavior could provide a deeper insight into the changes of brain network in critical time points. Secondly, our study was limited to evaluate single unit recording which could precisely indicate activity of neurons. Undoubtedly, it would be helpful for the future studies that evaluate circuit of OB-mPFC within anxiogenic condition induced by AR in order to clarify underlying mechanisms of this phenomenon.AR can attribute to anxiety-like behavior in association with alterations of LFPs in OB-mPFC circuit. Proposing the role of neuronal pathways between OB and mPFC in presence of AR-induced anxiety opened a door for future studies to realize how these connections might coordinate cognitive and emotional behaviors in allergic conditions. The data can also conclude to make more effective clinical decisions and superior approaches for managing the behavioral impairment of AR as well as other respiratory allergic conditions.S1 DataFolder of minimal data set contains raw data in mat and xls format.(RAR)Click here for additional data file.


Only overt hyperglycemia  was associated with parenchymal hematoma type 2. Overall hyperglycemia was associated with poor outcomes and infarct growth, whereas overt hyperglycemia was associated with parenchymal hematoma type 2.We evaluated the effects of admission hyperglycemia with different cut-off levels on 3-month outcomes, infarct growth, and hemorrhagic transformation in acute stroke patients with large artery occlusion of anterior circulation who received endovascular treatment (EVT). Between January 2011 and May 2016, patients that underwent EVT with pre-procedural and post-procedural diffusion-weighted imaging were identified from a multicenter registry. Normoglycemia was defined as a glucose level ≤ 110 mg/dL, moderate hyperglycemia as >110 and ≤170 mg/dL, and overt hyperglycemia as >170 mg/dL. Its effects on poor outcomes , infarct growth, and parenchymal hematoma type 2 were analyzed. Of 720 patients encountered, 341 patients were eligible. There was a statistically significant difference in glycated hemoglobin levels between the normoglycemia/moderate hyperglycemia and overt hyperglycemia groups (p < 0.001). Moderate hyperglycemia  and overt hyperglycemia  were associated with poor outcomes. Post-procedural infarct volumes were significantly greater in hyperglycemic patients (p They are also independently associated with early progression of stroke after thrombolysis2 as well as an increased risk of intracerebral hemorrhage (ICH)3. The mechanisms underlying these associations have been investigated mainly in rodent models of ischemia where reperfusion is guaranteed4. In contrast, reperfusion status has not been well validated in previous clinical studies of IV thrombolysis. This discrepancy has limited the generalizability of laboratory research findings to clinical research settings. Recently, major randomized controlled trials using new revascularization devices have established endovascular treatment (EVT) as the standard therapy for patients presenting with intracranial large vessel occlusion causing acute ischemic stroke9. Reported reperfusion rates after EVT range from 59% to 88%9, readdressing the classic ischemia/reperfusion model in real clinical settings.Presenting hyperglycemia and diabetes mellitus (DM) are predictors of a poor outcome after intravenous (IV) thrombolysis in patients with strokeAnother obstacle to discriminating the effects of hyperglycemia is the difficulty in defining the respective effects of hyperglycemia and DM on patient outcomes. Additionally, stress hyperglycemia has been reported in patients with severe stroke or cardiac disease, even in the absence of DM. Although the classifications of normoglycemia, moderate (or non-diabetic) hyperglycemia, and overt (or diabetic) hyperglycemia vary in the literature, we have made an effort to approximate the most appropriate cut-off values using the ASIAN KR registry, which enrolled patients with acute ischemic stroke who received emergent EVT with modern devices and techniques at three Korean comprehensive stroke centers.We hypothesized that moderate and overt hyperglycemia would exclusively affect clinical outcomes, infarct growth, and hemorrhagic transformation in patients with acute large artery occlusion and a high probability of successful reperfusion. To examine this hypothesis, we classified patients into normoglycemic, moderately hyperglycemic, and overtly hyperglycemic groups, and evaluated the effects of admission glucose level on clinical outcomes, infarct growth on diffusion-weighted imaging (DWI), and development of post-procedural parenchymal hematoma type 2 in the acute setting.The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.10. The consecutive patient data were obtained from three comprehensive stroke centers in Korea . De-identification and allocation of study identification numbers was undertaken for all clinical data. The data collection protocol was approved by the Institutional Review Board of each participating hospital and implemented in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments. The need for written informed consent was waived in view of the retrospective nature of the study.The ASIAN KR registry, which includes data on 720 patients, was assembled for an observational study of consecutive patients aged 18 years or older who received EVT for the treatment of acute ischemic stroke caused by intracranial and/or extracranial large vessel occlusionTo evaluate the effect of glucose level on the outcome of EVT, we applied the following inclusion criteria: (1) acute intracranial large artery occlusion in the anterior circulation; (2) onset-to-puncture time < 720 min, and (3) availability of both pre-procedural and post-procedural DWI volumes within 1 week of stroke onset. Pre-procedural brain computed tomography (CT) or magnetic resonance imaging (MRI) with collection of angiographic data was performed upon admission for each patient. Post-procedural CT or MRI of the brain was usually performed within 5 to 7 days of admission.11. Alberta Stroke Program Early CT scores (ASPECTS) were classified on non-contrast CT (SIS). Successful reperfusion was defined as modified Treatment In Cerebral Ischemia (mTICI) grade 2b–3 12. Post-procedural hemorrhagic complications were classified in accordance with the criteria defined by the European Cooperative Acute Stroke Study13. Subarachnoid hemorrhage (SAH) was classified in accordance with the modified Fisher scale (SIS)14. Parenchymal hematoma type 2 and/or grade 3–4 subarachnoid hemorrhage were regarded as serious post-procedural hemorrhagic complications. Pre-procedural and post-procedural DWI stroke volumes were evaluated (by JWC) using NordicICE semi-automated software .Premorbid modified Rankin Scale (mRS) scores, National Institutes of Health Stroke Scale (NIHSS) scores on admission, and mRS scores at 3 months were analyzed. A 3-month mRS score of 0–2 or no change compared with the premorbid mRS score was classified as a good outcome and a 3-month mRS score of 3–6 was classified as a poor outcome. Routine laboratory results were also collected. After de-identification and blinding of the clinical data, stroke neurologists, neuroradiologists, and neurointerventionists with expertise in acute stroke management performed core laboratory imaging analyses to ensure consistent grading and eliminate possible bias. The location of the initial large vessel occlusion was identified on baseline angiography (SJL). Internal carotid artery (ICA) T, ICA I, middle cerebral artery (MCA) M1, and MCA M2 superior and inferior divisions were included in this study. ICA T was defined as an occlusive lesion in both M1 and ICA including or excluding the A1 segments. ICA I was defined as an occlusive intracranial lesion of the ICA sparing M1 and A110. Patients who presented to centers A and B between January 2011 and February 2016, and patients who visited center C between January 2011 and May 2016 were included. All centers used CT and CT angiography for baseline screening. IV tissue plasminogen activator (tPA) was given to patients that presented within 3 to 4.5 hours of onset and were indicated. If a large artery occlusion corresponding to the stroke signs was observed on CT angiography with an expected onset to puncture time <6 hours, EVT was considered in all patients if there were no contraindications. Patients with large core volumes were excluded according to protocols of each hospital. Center A excluded patients with low ASPECTS on non-contrast CT, and DWI were also utilized to rule out large infarct core volume. Center B excluded patients with ischemic lesions in non-contrast CT involving over half of the corresponding territory, or well developed hyperintensities on fluid attenuated inversion recovery imaging. Center C excluded patients with ASPECTS 0 ~3 on CT, and routinely utilized multiphase CT angiography since Aug. 2014 to rule out poor collaterals. When onset to puncture time was expected to be longer than 6 hours or onset time was unclear, further imaging modalities to select appropriate candidates were performed using multimodal MRI in the three hospitals.The study protocols in participated centers were previously reported elsewhere18. Balloon guide catheters, intracranial or extracranial angioplasty, and/or stenting were implemented as needed.The type of EVT procedure was chosen at the discretion of the treating physician. Direct aspiration and stent retrieval were primarily used in most cases1C) was measured according to each respective stroke center’s protocol. Glucose status on admission was trichotomized into normoglycemia (≤110 mg/dL)19, moderate hyperglycemia (>110 mg/dL and ≤170 mg/dL), or overt hyperglycemia (>170 mg/dL)20, as evaluated by literature reviews and our preliminary analyses  was compared between the groups. Second, to evaluate the effect of hyperglycemia on post-procedural infarct volume while controlling for baseline infarct volume, an analysis of covariance was performed comparing post-procedural DWI volumes between normoglycemic and hyperglycemic patients with a cut-off value of >110 mg/dL, adjusted for age, sex, pre-procedural DWI volume, site of occlusion, and final successful reperfusion. Finally, to evaluate the association between glucose status on admission and hemorrhagic complications, a logistic regression analysis was performed to assess the occurrence of parenchymal hematoma type 2 adjusted for age, sex, initial NIHSS score, IV tPA treatment, pre-procedure DWI volume, onset-to-puncture time, and site of occlusion. For subgroup analyses, the variables were evaluated again in the reperfusion (successful) group  and non-reperfusion (unsuccessful) group (mTICI 0–2a) for association between glucose levels and treatment outcomes, post-procedural infarct volume and occurrence of parenchymal hematoma type 2, respectively. The data are presented as the mean ± standard deviation or as the median (interquartile range). A p-value less than 0.05 was considered to be statistically significant. All statistical analyses were performed using IBM SPSS Statistics version 22 software .Comparative analyses of the admission glucose level groups were performed for clinical characteristics, imaging findings, and treatment outcomes. Differences between the three groups were analyzed using the χ1c levels . Initial NIHSS scores were not significantly different between the groups . In terms of laboratory data, white blood cell count, and erythrocyte sedimentation rate on admission increased significantly in hyperglycemia groups.Of the 720 patients in the registry, 341 met the inclusion criteria for this study. One hundred and ten of these patients presented with normoglycemia, 180 presented with moderate hyperglycemia, and 51 presented with overt hyperglycemia. The clinical characteristics, pre-procedural factors, reperfusion treatment, and outcomes according to glucose status on admission are outlined in Table In the pre-procedural imaging data, the initial site of occlusion, ASPECTS, and pre-procedural DWI stroke volumes did not differ significantly between the three groups. Onset to pre-procedural MRI, onset-to-puncture time, procedure time, and onset to post-procedural MRI also did not differ significantly between the three groups.In terms of reperfusion methods and outcomes Table , treatmePoor outcomes at 3 months weres significantly more common in the moderate and overt hyperglycemia groups than in the normoglycemia group . When glucose status on admission was incorporated into a logistic regression model for poor outcome (Table adjusted = 0.003) although pre-procedural volumes were not significantly different . Similar to the clinical outcomes, this difference was significant in the non-reperfusion group , but not for the reperfusion groups . When patients were dichotomized into normoglycemia and hyperglycemia groups , post-procedural DWI stroke volume was significantly greater in the hyperglycemia group  Table . When gl5 Table .1c levels, suggesting that the overt hyperglycemia group could have had sustained hyperglycemia, while the moderate hyperglycemia group might be more representative of hyperglycemia under non-diabetic conditions.The present study demonstrates that high glucose levels on admission are independently associated with poor 3-month outcomes, infarct growth, and significant hemorrhagic complications; however, the glucose level cut-off points for predicting these outcomes varied. Overall, hyperglycemia was associated with a poor functional outcome and infarct growth, which were predominantly seen in the non-reperfusion subgroup. In contrast, overt hyperglycemia was associated with hemorrhagic complications, which were predominant in the reperfusion subgroup. Ten percent of patients in the normoglycemia group had DM, 18% in the moderate hyperglycemia group, and 80% in the overt hyperglycemia group, with a similar trend observed for mean HbA21.The poor outcomes were in parallel with infarct growth in terms of the cut-off level of hyperglycemia on admission, which was relatively low. Post-procedural infarct volumes were significantly larger in the moderate and overt hyperglycemia groups than in the normoglycemia group, and both groups were independently associated with poor outcome. On this basis, infarct growth seems to be a mediator between hyperglycemia and a poor outcome; however, there was no correlation between glucose level on admission and infarct growth nor an interaction between glucose level and infarct growth in terms of poor outcomes (data not shown). This suggests that this association may not be linear, and an approach using cut-off values may better represent the phenomenon, as shown in our study. Regarding the association with poor outcomes or infarct growth, the significance of glucose levels as an independent predictor disappeared in multivariable analysis when only patients with successful reperfusion were analyzed, whereas both significant associations were still present in patients with unsuccessful reperfusion. This finding implies that successful reperfusion may overcome the negative effects of hyperglycemia. This observation is partly supported by a recent randomized controlled trial known as MR CLEAN, which showed no interaction of hyperglycemia and EVT effect when compared with non-endovascular treatment, indicating that hyperglycemia on admission is not a contraindication in candidates for EVT19. In the literature, glucose levels have been shown to increase with increasing stroke severity via activation of the hypothalamic-pituitary-adrenal axis23. Second, the possibility of a direct contribution of hyperglycemia itself to the aggravation of ischemic stroke needs to be considered. Infarct growth can be precipitated by decreased reperfusion and penumbral salvage, both of which are associated with hyperglycemia24. Several studies have reported the deleterious effects of hyperglycemia in patients with non-lacunar focal ischemia and global ischemia. Further, hyperglycemia has been associated with reduced penumbral salvage in patients with perfusion-diffusion mismatch26. A third mechanism for understanding the impact of moderate hyperglycemia on acute stroke that is worth discussing is that presenting hyperglycemia may represent pre-existing abnormalities in glucose metabolism. A large number of patients with ischemic stroke and no history of DM are found to have insulin resistance, impaired glucose metabolism, or DM at follow-up28. While presenting hyperglycemia does not represent overt DM, it may reflect insulin resistance and comprise the metabolic syndrome, which is known to be associated with poor leptomeningeal collateral status in acute ischemic stroke29. This could be an alternative but complementary explanation for predominant infarct growth in the non-reperfusion subgroup seen in our study. Pre-diabetic conditions were not addressed in our study, and further insights are needed to address this issue.Several mechanisms via which hyperglycemia leads to poor outcomes and infarct growth can be postulated, focusing on moderate hyperglycemia. First, the concept of stress hyperglycemia can be applied to our findings. A previous meta-analysis demonstrated a strong correlation between glucose levels > 110 to 126 mg/dL and poor outcomes only in non-diabetic patients with acute ischemic stroke, leading to this concept30. However, IV rt-PA was not a predictor of parenchymal hematoma and was not associated with the clinical outcomes in our endovascular population. An association between sustained hyperglycemia or DM and hemorrhagic transformation has been recently reported in endovascular populations; however, in one study, the endovascular devices and methods used were somewhat outdated31, and in another study using stent retrievers, the significance for hyperglycemia was not shown, but DM was confirmed to be significant32. Exacerbated reperfusion injury in overt hyperglycemia may be explained as follows. Oxidative stress and activation of inflammation are reported to be aggravated, resulting in dysfunction of the blood-brain barrier35. Moreover, severe hyperglycemia significantly worsens cortical intracellular acidosis in the brain and mitochondrial dysfunction in the ischemic penumbra36. Such mechanisms can lead to increases in hemorrhagic transformation and extensive hemorrhage, as revealed in a feline model of MCA occlusion37. An elevated erythrocyte sedimentation rate, which indicates an inflammatory reaction, was seen in patients with overt hyperglycemia in our study.In the present study, overt hyperglycemia, which is more clearly indicative of diabetic comorbidity, was associated with severe intracerebral hemorrhagic complications, especially in the reperfusion subgroup. Our findings suggest that reperfusion injury can be exacerbated by chronic sustained hyperglycemia. The association between DM and ICH in patients with ischemic stroke, especially after IV thrombolysis, is well recognized38. In a subgroup analysis according to history of diabetes, the ORs for mortality and functional dependence were significantly higher for glucose levels > 120 mg/dL in non-diabetic patients, while the values for mortality and functional independence were 181–200 mg/dL and 160 mg/dL, respectively, in diabetic patients. The OR for symptomatic ICH per the SITS-MOST criteria was significantly higher in patients with glucose levels of 181–200 mg/dL compared with that for patients who had lower glucose levels with or without a history of diabetes. The SITS-ISTR results and our present findings both provide dual glucose cut-off values at similar ranges, with the lower value showing an association with poor outcome and the higher value showing an association with hemorrhagic complications. Our present research also reveals that higher glucose cut-off values may be associated with sustained hyperglycemia and comorbidity of DM.A previous large-scale study of patients who received IV tPA yielded results similar to those of the present study in terms of glucose cut-off values. The Safe Implementation of Treatment in Stroke International Stroke Thrombolysis Register (SITS-ISTR), a study involving over 16,000 patients with acute ischemic stroke who were treated with thrombolysis, showed that glucose levels > 120 mg/dL were associated with increased mortality, while levels > 180 mg/dL were associated with symptomatic ICH per the SITS-MOST criteria39. Third, patients were only included when both pre-procedural and post-procedural MRI data were available, allowing for clinical evaluation of infarct growth. However, post-procedural MRI data were not available for patients with severe pathology or for those who died, such that clinical outcomes in our study population may have been positively overestimated. Nevertheless, the analysis used both pre-procedural and short-term post-procedural DWI, which is very rare, so we believe that this study must have a novel value. Finally, the management of hyperglycemia, which can subsequently affect imaging and clinical outcomes, might have differed between hospitals and attending physicians. Management of hyperglycemia is another unresolved issue in acute ischemic stroke that is currently being investigated in therapeutic trials, such as the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial40.The present study has some limitations. First, although our analysis included multicenter data, it was limited by an observational study design. Nonetheless, the population was medium-sized and presented with acceptable revascularization profiles. Second, the retrospective study design precluded the use of symptomatic ICH as an endpoint, which is widely used in EVT trials. However, parenchymal hematoma type 2, which was used in the current study, is known to be strongly associated with neurologic deteriorationIn conclusion, moderate to overt hyperglycemia on admission was associated with a poor outcome and infarct growth in Korean patients with acute intracranial large artery occlusion who underwent EVT but did not achieve successful reperfusion. Additionally, overt hyperglycemia was associated with significant hemorrhagic complications, especially in patients with successful reperfusion. These findings should be confirmed in future large-scale prospective cohorts.Supplementary table 1 and 2


Management of metastatic or advanced prostate cancer has acquired several therapeutic approaches that have drastically changed the course of the disease. In particular due to the high sensitivity of prostate cancer cells to hormone depletion, several agents able to inhibit hormone production or binding to nuclear receptor have been evaluated and adopted in clinical practice. However, despite several hormonal treatments being available nowadays for the management of advanced or metastatic prostate cancer, the natural history of the disease leads inexorably to the development of resistance to hormone inhibition. Findings regarding the mechanisms that drive this process are of particular and increasing interest as these are potentially related to the identification of new targetable pathways and to the development of new drugs able to improve our patients’ clinical outcomes. Prostate Cancer (PCa) is the most common malignancy in men . Early s®) has been approved [One of the most important obstacles in this line of work is the availability of patients’ tumor tissue. As re-biopsy can be difficult, different approaches have been tested to acquire cells and monitor cells genomic expression modification during treatment. In vitro studies could not reflect the exact genomic modification observed in our patients. The research of circulating tumor cells or circulating tumor DNA represent a promising approach, even if to date only one device  contains a N-terminal domain (NTD), encoded by exon 1 and that contributes in regulating the transcription of the AR gene, a DNA-binding domain (DBD), encoded by exon 2 and 3, a hinge region, and a ligand binding domain (LBD), encoded by exons 4–8 and which recognize the hormone with specificity and selectivity [All prostate cells, both normal glandular epithelium and cancer cells, are strictly dependent on androgens, as they express the human androgen receptor (AR). The ectivity ,27.The AR is a ligand-dependent transcription factor activated by androgen hormones: in the absence of ligands (dihydrotestosterone and testosterone) it is located in the cell cytoplasm and translocates into the nucleus once the androgen hormone binds it. In the nucleus, the AR dimerizes creating a homodimer, binds through its DBD to androgen response elements (ARE) in the promoter regions of androgen response genes, recruits coregulatory proteins and epigenetic factors and stimulates downstream expression of genes that promote cell proliferation and survival ,27.The regulatory activity of the AR upon cellular survival makes its persistent activation a fundamental process at the basis of prostate cancer cells’ development and progression.AR’s gene can undergo alternative splicing that generates constitutive active ARs independent from the presence of the ligand. AR splice variants (AR-Vs) can be characterized by the deletion of the LBD, which acts as a repressor for the receptor, or of the NTD, disrupting important regions that interacts with activation function 2 (AF2) in the LBD resulting in enhanced activation of AF2 and AR-mediated gene activation [tivation .AR splice variants have been identified in prostate cancer and have been associated with the development of resistance to ADT, the most widely studied and clinically meaningful being the AR-V7 (or AR3) and the ARv567es (or AR-V12). AR-FL and the main splice variants structures are represented in Many ARv567es lacks the exons 5–7 that encode the LBD but retains the hinge region of exon 4 necessary for nuclear translocation, producing a constitutively active AR isoform with transcriptional activity independent from the ligand. This variant can be expressed in benign and malign prostate tissues, however, its levels increase during ADT creating a state of resistance to castration ,29.AR-V7 is a truncated isoform of the AR derived from aberrant mRNA splicing of AR exons 1, 2, 3, inclusion of the cryptic exon 3 (CE3) and loss of exons 4–8 that encode the LBD of the AR-FL. As a result, AR-V7 lacks the LBD and contains in its cryptic exon the NLS, allowing an intra-nuclear localization independent of the ligand and persistent activation of AR leading to an excess of survival signaling and growth of PCa cells. The independent activity of AR-V7 from the ligand is at the basis of the resistance to anti-androgen therapies and the development of castration resistant disease ,27,30.AR-V7 has been associated with poor prognosis in PCa metastatic to the bones , increasAR alterations have been associated not only with the development of the state of castration resistance but also to resistance to abiraterone and enzalutamide. Many genetic and epigenetic mechanisms lie beneath this state of resistance. Resistance to AR-targeted therapies in CRPC can be attributed to various mechanisms corresponding to different histological, clinical, and molecular profiles: restored AR signaling, AR bypass signaling, and complete AR independence .Restored AR signaling can be due to molecular alterations like AR-activating mutations, AR active splice variants, and intratumoral dihydrotestosterone synthesis from adrenal precursors.In a minority of patients with CRPC, AR activating mutations in the LBD have been found through genomic sequencing studies, the principal four point mutations being L702H, W742C, H875Y, and T878A . AR carrAR splice variants have been implicated in developing of acquired resistance to ADT, abiraterone, and enzalutamide. The structural alterations of AR-Vs confer androgen-independent activity to the AR isoforms that is correlated with nuclear localization independently by the presence of the ligand. AR-V567es and murine mAR-V4 maintain exons 3 and 4 that are responsible for the complete nuclear localization signal, while the other isoforms are truncated after exon 3 and are mostly cytoplasmic. AR-V7 is an exception, because it has constitutive nuclear localization and transcriptional activity without a full nuclear localization signal . The selIn preclinical studies, knockdown of these variants conferred sensitivity to enzalutamide, underlining their role in the development of resistance to enzalutamide by persistently activating the AR-transcriptional program . FurtherRB1, PTEN and TP53 mutations, amplification of MYCN and Aurora kinase A [Another mechanism of resistance to androgen receptor inhibitors can be bypassing AR signaling by activating the downstream hormone receptor pathway through a different hormone receptor like glucocorticoid receptor, thus overcoming AR dependency . Furtherkinase A .Genetic and epigenetic alteration contribute to the clinical behavior of prostate cancer, which ranges from indolent tumors to more aggressive ones. Epigenetic changes include DNA methylation and histone acetylation and deacetylation, which can occur in various genes and may represent a potential therapeutic target.DNA methylation mechanisms associated with prostate cancer development, and progression are: DNA hypermethylation of CpG sites in gene-promoter regions due to DNA-methyltransferases that lead to transcriptional silencing and DNA methylation in the gene body .Many genes have been implicated in DNA methylation changes correlated to prostate carcinogenesis and tumor progression. Among them, hypermethylation of the AR promoter and the consequent loss of AR expression was described in up to 30% of CRPCs .SCGB3A1, HIF3A, AOX1) differently methylated between the two tissues associated with promoter methylation and reduced gene expression.Geybels et al.  investigPI15, ALKBH5, ATP11A, FHAD1, KLHL8) and three intergenic regions that differ in metastatic lethal prostate cancers and non-recurrent ones [FLNC, EFS, ECRG4, PITX2, PDLIM4, and KCNMA1 genes and local and systemic recurrence [Furthermore, a study of epigenome-wide DNA methylation profiling by the same authors found different methylated CpGs in five genes (ent ones . Anothercurrence .DNA-methyltransferase (DNMTs) are a class of enzymes that work in association with the apoptosis-modulating protein DAXX. The latter is a transcription repressor that promotes chromosome stability: it has been found overexpressed in PCa and its expression level has been correlated with the Gleason score and cancer development . DAXX taHistone modifications are another epigenetic mechanism controlling gene expression correlated with development and progression of PCa and consist of posttranslational changes in the N-terminal tails of histones: acetylation/deacetylation, methylation, phosphorylation, deamination, citrullination, ubiquitination, and ADP ribosylation . The enzThe enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase enzyme member of the Polycomb Repressive Complex 2 (PRC2) . EZH2 reAcknowledging the epigenetic mechanisms involved in PCa is important for their potential use as targets for novel therapeutic approaches.As already mentioned, one of the most important hormone-inhibition-escape-strategy adopted by prostate cancer cells is the alternative splicing of the AR which results in the expression of different alternative AR-Vs. In brief, there are two approaches which could be adopted to overcome this alternative splicing: one consists on the adoption of agents able to modulate AR-Vs transcription, while the other is the development of drugs able to target these specific alternative variants .Regarding the first approach, several strategies targeting different pathways are currently under investigation.The bromodomain and extra-terminal (BET) family proteins and the bromodomain-containing proteins (BRD) are able to recognize and bind acetylated lysine residues in histones and other proteins through their bromodomains (BDs), modulating recruitment of other proteins and regulating DNA transcription D. Differ1/S cyclins, S cyclins, M cyclins and G1 cyclins. In prostate cancer, there are evidences that seem to correlate cyclins expression to AR expression, radio-resistance and hormone inhibition resistance [Increasing interest in the development of cyclin inhibitors is mainly due to the important results obtained in metastatic breast cancer. Cyclins are a heterogeneous group of proteins which acts in different point of cell cycle. Thus, we recognized four types of cyclin according to the different phase of cell division: Gsistance ,64,65. OThe non-selective histone deacetylase inhibitor panobinostat D and theAs already discussed, inhibition of the histone methyltransferase EZH2 could restore sensitivity to hormone therapy. Currently, there are two ongoing phase I/II studies evaluating the EZH2 inhibitor CPI-1205 D in assoOther approaches have been considered to overcome acquired resistance to hormonal inhibition. As already described, specific agents able to target altered splicing ARVs are under evaluation as well as drugs with higher antagonistic power against AR. However, several other altered pathways seem to be implicated in the development of AR inhibition resistance; thus, the adoption of combined treatment between these pathways and AR could be a winning strategy.Through the regulation of an extraordinary number of effectors able to modulate phosphorylation, transcription or translation of several target points the phosphoinositide-3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway modulate cellular process able to promote protein synthesis, proliferation, survival, differentiation, and metabolism. Not surprising, due to the large number of functions regulated by this pathway alteration in PI3K-AKT-mTOR are quite frequent in several tumor types . About pThe SRC gene encodes the proto-oncogene tyrosine protein kinase Src which plays an important role during embryogenic development and cell-growth. Evidences about its correlation with Androgen Receptor pathways and development of castration resistant status are further increasing. Szafran et al. performed an AR high content analysis to characterize the effects of specific compounds including Akt, Abl, and Src inhibitor on AR-V7 expression demonstrating that all these drugs were able to reduce the expression of this splice variant . MoreoveSeveral compounds able to directly inhibit the AR are under investigation. Of these, TAS3681 C,D is anOther AR inhibitor and antagonist with higher AR affinity are also under investigation in different setting of the disease, alone or in association with other compounds . ODM-208 A is a smAnother approach is represented by the administration of drugs able to antagonise the glucocorticoid receptor and so acting as antiglucocorticoid. Relacorilant C, an antManagement of patients progressed to standard androgen deprivation therapy have included agents able to improve hormone inhibition and are also active in castration-resistant prostate cancer. It is probable that combination strategies and development of new drugs will extend the benefit of these drugs and improve survival and clinical benefit of our patients. This goal is possible thanks to the increasing knowledge about genetic mechanisms related to acquisition of castration resistant status and this highlights the need of genomic assessment of tumor cells in different times of the disease. In this line of thought, a parallel evolution that should be considered is the adoption of techniques able to assess circulating tumor cells and DNA more and more effectively.


Atmospheric rivers (ARs) cause heavy precipitation and flooding in the coastal areas of many mid-latitude continents, and thus the atmospheric processes associated with the AR have been intensively studied in recent years. However, AR-associated ocean variability and air-sea fluxes have received little attention because of the lack of high-resolution ocean data until recently. Here we demonstrate that typical ARs can generate strong upper ocean response and substantial air-sea fluxes using a high-resolution (1/12°) ocean reanalysis. AR events observed during the CalWater 2015 field campaign generate large-scale on-shore currents that hit the coast, generating strong narrow northward jets along the west coast of North America, in association with a substantial rise of sea level at the coast. In the open ocean, the AR generates prominent changes of mixed layer depth, especially south of 30°N due to the strong surface winds and air-sea heat fluxes. The prominent cooling of SST is observed only in the vicinity of AR upstream areas primarily due to the large latent heat flux. Using a long-term AR dataset, composite structure and variations of upper ocean and air-sea fluxes are presented, which are consistent with those found in the events during CalWater 2015. ARs are often connected to the warm sector of extratropical cyclones, and are associated with strong low-level winds.Atmospheric rivers (ARs) are narrow elongated regions of strong water vapor transport which typically extend from the (sub)tropics to the mid-latitude12.When strong ARs make landfall, they have substantial impacts on precipitation, floods and snowpack along the coast of many continents including the west coast of US and northern Europe. ARs also influence inland and tropical/polar areas significantly. Because of such an important role of ARs in the global water cycle as well as societal impacts caused by extreme weather events in many coastal areas, atmospheric processes associated with ARs have been studied intensively in the last one and half decades13. The analysis of global AR datasets indicates that they are associated with a doubling or more of the typical wind speed compared to all storm conditions, and a 50–100% increase in the wind speed for extreme events13. The AR-induced strong winds are often associated with large pressure gradients between an extratropical cyclone and anticyclone located on the eastward and equatorward sides of the cyclone14. Given that such strong winds often produce large air-sea fluxes of momentum, heat, and moisture, it is likely that ARs could generate substantial ocean responses. The upper ocean variability produced by ARs could then in turn feedback on the ARs through sea surface temperature (SST) changes and air-sea fluxes. However, ocean response to ARs has not been emphasized in previous studies partly because of the lack of high-resolution upper ocean data which can resolve narrow coastal areas as well as open oceans. This study investigates upper ocean variability and air-sea fluxes produced by ARs using a high-resolution ocean reanalysis along with air-sea flux data sets based on satellite and reanalysis products.Because of the extreme rainfall produced by ARs, previous studies mostly focused on hydrological components such as large moisture transport, heavy precipitation, flooding, and snowpack. Yet a recent study emphasizes the importance of extreme wind events produced by ARs16. In addition to a variety of aircraft and ground-based observations, ship-based observations were also conducted, which include cloud and precipitation radar, wind profiler, and measurements of air-sea fluxes, ocean mixed layer structure and currents. These data provide useful information for the model-based analysis for the ocean variability including the model validation.While making landfall ARs have been routinely monitored by observational networks in many locations , but their behavior over the oceans is much less observed until recently. For the purpose of better understanding the evolution and structure of ARs including those over the open ocean, a new campaign, CalWater 2015, was designed and conducted for the period January-March, 2015in-situ data collected during the field campaign. Then the composite evolution of ocean variability and air-sea fluxes are examined and compared with the CalWater 2015 case study.In this study, we examine the ocean response to ARs such as the evolution of the mixed layer, SST and sea level and the generation of upper ocean currents by surface forcing fields generated by ARs using a high-resolution ocean reanalysis product as well as other data sets based on satellite observations. The ocean variability produced by ARs observed during CalWater 2015 is first described and compared with some of the 17. The system is comprised of the 0.08° HYbrid Coordinate Ocean Model (HYCOM18) and the Navy Coupled Ocean Data Assimilation (NCODA19). Since the detailed description of HYCOM, NCODA, and data assimilation method are presented in other papers21, only aspects relevant to this study is briefly described in the following.The ocean reanalysis product used in this study is similar to the US Navy’s operational Global Ocean Nowcast/Forecast System22. The data assimilated by NCODA include remotely sensed sea surface height (SSH), sea surface temperature (SST) and sea ice concentration as well as in-situ surface and subsurface observations of temperature and salinity. These include synthetic temperature profiles computed using the Improved Synthetic Ocean Profile (ISOP21), in which the vertical profile at a given location is constructed by projecting remotely observed SSH and SST downward from the surface using a global database of statistical relationships. It should be noted that the use of ISOP substantially improved the subsurface temperature profile in comparison to the previous version of the reanalysis that uses the Modular Ocean Data Assimilation System (MODAS)24.HYCOM uses the hybrid coordinate that is isopycnal in the open, stratified ocean, but smoothly reverts to a terrain-following coordinate in shallow coastal regions, and to z-level coordinates in the mixed layer and/or unstratified seas. The surface fluxes of momentum, heat and freshwater are derived from the 1-hourly Climate Forecast System Reanalysis (CFSR) products provided by National Centers for Environmental Prediction (NCEP)https://www.ncdc.noaa.gov/data-access/model-data/model-datasets/climate-forecast-system-version2-cfsv2) from 2011 with an accompanying horizontal resolution increase to 0.205° (from 0.3125°). Note that the time period of 5 years (2011–2015), which includes many AR events in the northeast Pacific, is sufficiently long for the present study.While the HYCOM reanalysis is available for 1993–2015, output for the period of 2011–2015 are used in this study since the surface atmospheric forcing fields are changed from CFSRV1 to Climate Forecast System Version 2 .Latent and sensible heat fluxes and evaporation derived from the Objectively Analyzed air-sea Fluxes (OAFlux) products15. In this study, upper ocean currents measured by shipboard acoustic doppler current profiler (ADCP) and air-sea fluxes calculated using meteorological variables measured on board are used. During the field campaign, R/V Ron Brown stayed at 37°N, 127.2°W when strong AR events passed through this location. ADCP and surface flux data are primarily used for the validation of the HYCOM reanalysis and OAFlux data. Surface fluxes and ADCP data collected during CalWater 2015 are available at ftp://ftp1.esrl.noaa.gov/psd3/cruises/CalWater2015.CalWater 2015 was conducted during January-March 2015Daily mean sea level data measured by tide gauges from the two stations, Neah Bay, Washington 48°22′N, 124°37′W and South Beach, Oregon 44°38′N, 123°03′W, located at the west coast of North America are used to monitor sea level variation associated with ARs. The data are obtained from the University of Hawaii Sea Level Center.et al.14 constructed composites of atmospheric variables associated with ARs using the long-term global AR data set created by Guan and Waliser31. Here a similar method is used to construct composites of ocean variability and air-sea fluxes associated with ARs. ARs are identified based on the characteristics of the integrated water vapor transport (IVT) at 6 hourly intervals31. The AR data set includes the time and location of the AR centroid and IVT at the AR center. The AR events detected in the northeast Pacific domain, 15°N-60°N, 180°E-100°W, are used for the analysis. Then daily variables relevant to upper ocean variability and air-sea fluxes are composited over a 60° longitude by 40° latitude domain centered at the centroid of ARs, using AR events for the 5-year period of 2011–2015. Since the AR data are 6 hourly, ARs are often identified multiple times within a day. In this case, the same daily values are used multiple times for the composite. To exclude weak events, only AR events in which IVT at the center exceeds 500 kg m−1 s−1 are used.Guo Two strong landfalling AR events were observed during CalWater 2015 Fig. . The secA prominent sea level rise is evident during the two landfalling AR events in mid-January and early February Fig. . In partThe sea level rise associated with AR events is also evident in the high-resolution ocean (HYCOM) reanalysis Fig. . The timIn association with sea level rise near the coast, a strong northward jet with the maximum velocity of about 1 m/s is generated Fig. . The cur14. As the AR makes landfall on February 6, the strong southwesterlies reach the west coast of North America. The response of ocean surface currents to these surface winds is detected in the high-resolution (the eddy-resolving) HYCOM ocean reanalysis. Despite the noisy fields of surface currents due to active mesoscale eddies, eastward movement of the areas of strong zonal current associated with the strong southwesterlies are clearly found. When the AR makes landfall, strong currents against the west coast of North America hit the boundary, generating strong northward along-shore currents  and specific humidity at 2 m (qa) is shown in Fig. qs-qa is quite similar to that of surface evaporation. qs-qa in the AR downstream areas are close to zero or even negative, which results in very small evaporation even though winds are strong. Such small values of qs-qa is due to a combination of cold SST , and thus effectively generating the rapid sea level rise.In summary, the results of the composite analysis shown in Figs Ocean variability and air-sea fluxes produced by ARs are investigated using the high-resolution (1/12°) ocean reanalysis and other reanalysis and air-sea flux products. During the recent field campaign: CalWater 2015, two strong ARs made landfall along the coast of North America. In this study, ocean variability and air-sea fluxes generated by the AR events during CalWater 2015 are examined first and they are compared with the composite evolution based on a long record of AR data set. The upper ocean and air-sea fluxes observed during the CalWater 2015 are consistent with those from the high-resolution ocean reanalysis and air-sea flux product. The analysis demonstrates that ARs can generate a strong upper ocean response and substantial air-sea fluxes.AR events observed during the CalWater 2015 field campaign produce large-scale on-shore currents toward the west coast of North America, generating strong narrow northward jets along the coast, in association with a substantial rise of sea level at the coast. In the open ocean in the northeast Pacific, prominent changes of mixed layer depth are evident, especially south of 30°N due to the strong surface winds and air-sea heat fluxes. In contrast, the significant cooling of SST is observed only in the vicinity (northwest side) of AR upstream areas primarily due to the large latent heat flux. The difference in evaporation between downstream and upstream areas is primarily attributed to the difference in vertical humidity gradient near the surface. The vertical humidity gradient is very small or close to zero in the downstream area because of a combination of cold SST and advection of near surface moisture by AR-induced winds.Using a long-term AR data set, composite structure and variations of ocean and air-sea fluxes associated with ARs are presented. The results indicate that the composite structure and evolution are all consistent with those found in the case study for the events during CalWater 2015. This suggests that oceanic processes and air-sea fluxes associated with ARs identified during the CalWater 2015 are commonly found in most AR events.While this study mostly focuses on upper ocean variability and the role of air-sea fluxes in affecting the ocean variability, the results also suggest the importance of air-sea fluxes for the atmospheric processes. The comparison of the spatial distribution of evaporation, surface winds, and TCWV indicates that the strong winds blow from the region of large evaporation to the area of a large amount of moisture associated with ARs. This suggests that the advection of moisture by AR-induced strong surface winds provides a significant amount of evaporated water vapor to the center of the AR. Accordingly, the moisture budget associated with ARs may substantially vary from the AR upstream to downstream regions. Hence moisture budget calculations in different areas of ARs are necessary for fully establishing the hydrological cycle associated with ARs.The comparison of the spatial pattern of latent heat flux and SST tendency suggests that the substantial SST cooling in the vicinity of AR upstream areas are primarily generated by evaporative cooling produced by AR-induced surface winds. However, there are some differences in these spatial patterns. For example, the SST tendency near the AR center is negative (cooling) and the small negative values are evident all the way to the AR downstream areas in the composite, while the latent heat flux anomaly in these areas is close to zero or positive. This suggests that the entrainment cooling produced by the deepening of the mixed layer may contribute to the SST cooling during some of the AR events. The complete upper ocean heat budget calculations using non-assimilative models are necessary to further quantify processes that control SSTs.32. Given such broad areas of anomalous wind stress curl and divergence associated with ARs, they may potentially cause significant mixing in the deep area through generating internal waves. Further study which focuses on the dynamical response to AR wind fields is thus desirable for examining the AR’s impact on the longer time scale climate variability.Because of the presence of an anticyclone on the southeast side of the AR center, AR-induced winds generate significant wind stress curl and divergence in the broad areas around AR  average (January-March) of sea level at Neah Bay in 2015 is about 6 cm lower if the AR-induced rise is excluded. Such a difference is significant for longer term variations, and thus the long-term changes in frequency of ARs could impact the long-term sea level variation along the coast. Accordingly, the results suggest that it may be necessary to consider the influence of short-time scale atmospheric variability such as ARs for identifying the processes that control the long-term sea level variation along the coast.The observed sea level rise produced by ARs during CalWater 2015 is substantial (~50 cm). ARs in the northeast Pacific are generally associated with relatively narrow but very strong southwesterlies that effectively generate strong surface currents against the west coast of North America, which results in the rapid increase of sea level. Strong southwesterlies around the AR center are accompanied by the large pressure gradient between the extratropical cyclone and anticyclone located southeast of the cycloneSupplementary Figures


Despite the success of genome-wide association studies for allergic rhinitis (AR), no definitive causal variants have been identified, and a substantial portion of the heritability of the disease is yet to be discovered.Four families, each with at least 1 parent and one child suffering from dust mite (DM) AR, were recruited, and whole-genome sequencing was performed on samples from 9 eligible individuals from these families. Conjoint analysis was performed for existing gene expression profiling data in the literature and the whole genome sequencing data obtained for these individuals; for presence of family-specific variants segregating with AR and the pathways involved. Similar analyses were also performed with data obtained for 96 sporadic house dust mite (HDM) AR patients and 96 healthy controls.Three rare variants in three genes , which are involved in Focal Adhesion pathway, were identified in affected, but not unaffected, subjects in two families. VEGFB_c.322A > C and/or ITGA2_c.502+1G > A were further detected in all DM AR patients but not in any healthy individuals in 1 family; which was further investigated for members. The 3 identified variants were not found in any of the sporadic DM AR patients or healthy controls.Despite the relatively small sample size, this study has identified several potentially functional rare variants in AR candidate genes, and it provides a platform for future work in larger numbers of families and sporadic individuals for a better understanding of the genetic basis of AR. AR:allergic rhinitisBCAP:B cell adaptor for phosphatidylinositol 3-kinaseC11orf30:chromosome 11 open reading frame 30DEG:differentially expressed geneDM:dust miteFLT1:fms related tyrosine kinase 4GWAS:genome wide association studyHLA-DRB4:major histocompatibility complex, class II, DR beta 4IgE:immunoglobulin EITGA2:integrin subunit alpha 2MRPL4:mitochondrial ribosomal protein L4NEC:nasal epithelia cellNP:nasal polypSNV:single nucleotide variantsVEGFB:vascular endothelial growth factor BAllergic rhinitis (AR) is an inflammatory disease of the nasal mucosa, which is induced by an immunoglobulin E (IgE)-mediated reaction in allergen-sensitized subjects, and it has increased in prevalence over the last decade.19Allergic diseases, including AR, are complex genetic diseases resulting from the effect of both multiple genetic and interacting environmental factors on their pathophysiology.Four AR families and 96 AR sporadic subjects suffering from DM-induced AR, as well as 96 healthy controls, were recruited from the outpatient clinic of the Allergy Department in Beijing TongRen Hospital, during the period of February 2012 to February 2016.All subjects had a history of AR for at least 1 year and fulfilled all criteria of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelinesChenopodium album); animal hair (dog and cat); molds  and cockroach. The serum antigen-specific IgE Phadiatop™test was also performed to test for sensitization to common allergens, and subjects were considered to be sensitized to the allergens when the serum IgE was ≥0.35 kU/l. The CAP classification system divides results into 7 categories from 0 to 6; which are scored as follows: class 1: 0.35–0.70 kU/l; class 2: 0.71–3.5 kU/l; class 3: 3.51–7.5 kU/l; class 4: 7.6–17.5 kU/l; class 5: 17.6–50 kU/l, and class 6: 〉50 kU/l. This unit reported by CAP was in accordance with the defined WHO serum standard IRP75/520. Procedural recommendations for total IgE  were followed strictly, and the results were considered positive if a value for total IgE was>100 kU/l.The tested antigens included DM (Der f and Der p); seasonal grass pollens  co-morbid asthma, eczema, or any other allergic disease; ii) hypertension, diabetes or other chronic diseases; or iii) tumor in the nasal cavity or any other inflammatory nasal disease such as sinusitis and nasal polyps. The diagnosis of asthma was confirmed by a chest physician according to the Global Initiative for Asthma (GINA) guidelines.A total of 96 healthy adult volunteers were also recruited as controls from an ethnically similar local population, to determine background allele frequencies in the population. These control subjects presented no clinical features, local nasal cavity signs or a family history of allergic disease, and they showed negative serum antigen-specific IgE by Phadiatop™testing.All subjects were of Han Chinese ethnic origin from the Beijing region, China, and they provided written informed consent prior to entry in the study. The study protocol was approved by the Ethics Committee of Beijing TongRen Hospital and performed in accordance with the guidelines of the World Medical Association's Declaration of Helsinki.The genomic DNA was assessed in samples from nine individuals from the four families affected by AR, using whole genome sequencing. Library preparation and genome capture were done with Illumina TruSeq DNA Sample Preparation Kit , and whole genome sequencing was performed on illumina HiSeq2000 platform . Initial alignment was performed with Burrows-Wheeler Aligner (BWA) according to the reference human genome build hg19. single nucleotide variants (SNVs), and insertions/deletions (Indels) were determined using the Genome Analysis Toolkit (GATK). Annotation of all variants was performed using SnpEff.Variants were filtered and low quality variants were excluded using the following criteria: 3 or more variants detected within 10 bp; coverage depth less than 5 folds; mapping quality score less than 30; genotype quality less than 30.Taking into consideration the likely pathogenicity, we also filtered out heterozygous variants , which were detected in both the affected parent and the child and were absent from dbSNP143 and 1000 Genomes Project.The pathogenicity risk of nonsynonymous variants was estimated using Sort Intolerant from Tolerant (SIFT), Polymorphism Phenotyping v2 (PolyPhen2), PhyloP and mutation taster. The prediction of new splice site was tested with four different tools: namely, Human Splicing Finder, MaxEntScan, Spliceman and NetGene2. Potentially deleterious variants were reviewed in the Exome Aggregation Consortium (ExAC).Three-dimensional (3D) modelling of wild type and missense variants was performed using the SWISS-MODEL. Data obtained by the homology models were visualized using Swiss-PdbViewer 4.1.P < 0.05 were considered to be statistically significant.Data from a previous global gene expression study of nasal mucosa from 7 AR patients and 5 non-allergic control subjects (GSE43523) were used to analyze the distinct expression gene shared with whole genome sequencing data. Gene Ontology (GO) function enrichment was generated by DAVID Bioinformatics Resources. KEGG and Reactome pathway databases were used to obtain canonical pathway and disease and bio functions. Values of After filtering against multiple databases, Sanger sequencing was used to confirm that mutations were more likely to be responsible for AR. Direct polymerase chain reaction (PCR) products were sequenced using Bigdye terminator v3.1 cycle sequencing kits  and analyzed using the ABI 3700XL Genetic Analyzer.P = 0.034)  to identify “family-specific” rare variants or pathways in at least 2 families. Microarray data for nasal mucosa from 7AR patients and 5 non-allergic control subjects enrolled in the present study demonstrated a total of 1117 differentially expressed genes (DEGs) between the two groups of subjects. These DEGs were loaded into DAVID for GO enrichment analysis, employing all significantly enriched GO terms including categories of biological process, molecular function and cellular component A. Pathwa 0.034) B. Gene e 0.034) .Fig. 2GeD2), which is important for VEGF binding.8-109), a homodimeric hormone that induces proliferation of endothelial cells.Family 4 was further enlarged and the clinical and demographic data were shown in D2 and VEGF8-109 were previously identified as the most important domains for ligand-receptor binding.D2 with the “poles” of the VEGF dimerTo determine whether the identified 2 rare missense variants in FLT1 and VEGFB affect their binding, the 3D-structural models of FLT1 and VEGFB were predicted with SWISS-MODEL. The crystal structures of FLT1  and VEGFB (2c7w1) were used as the templates, which was determined by X-ray diffraction at a resolution of 4 Å and 2.48 Å, respectively. The residues FLT1_Glu201 and VEGFB_Ser108 together with nearby residues within 6 Å, were illustrated. Flt-1Sanger sequencing showed that the 3 rare variants demonstrated in the 4 families were absent in both the groups of 96 sporadic HDM AR patients and 96 healthy control subjects. The demographic data were shown in This study identified 3 rare variants: in FLT1_c.603A > T, VEGFB_c.322A > C and ITGA2_c.502+1G > A, which may potentially be important in causing HDM AR. Moreover, the compound heterozygous carrier of c.322A > C in VEGFB and c.502+1G > A in ITGA2 had a more severe clinical phenotype. Indeed, VEGF and its receptors have previously been demonstrated to play an important role in nasal mucosal inflammation during ARA family history of an allergic condition is a well-accepted risk factor for the development of an allergic condition in an individual, particularly for allergic disorders such as asthma, eczema, and AR. However, the question of whether specific allergen sensitization is inherited has been considered to be a complicated matter. Misiak et al.Candidate gene association studies and GWASs have demonstrated the presence of susceptibility loci, which conferred relatively small increments in risk but not the full profile of the genetic characteristics of allergy, thus suggesting restricted ability of these techniques to find rare risk alleles which might contribute to the disease.Assessment of increased numbers of individuals in Family 4, exhibited the presence of intrafamilial heterogeneity and heterozygous variants c.322A > C; p.S108R in VEGFB and c.502+1G > A in ITGA2. It is noteworthy that all the DM AR patients in this family carried either 1 or both of the variants and that the compound heterozygous carrier of both these variants had more severe clinical symptoms and increased serum DM levels. We thus hypothesised that there may exist family-specific mutations, and, further, at least 1 of these mutations was necessary to lead to the development of AR, and in combination the mutations would additionally control the severity of the disease. This could be in accordance with the theory that certain combinations of susceptibility genes are specific for allergic airways disease and/or are associated with severity of disease.Increased vessel number and permeability are important features of the nasal mucosa in AR, and are mediated in part by the cytokine VEGF, a major regulator of angiogenesis and enhancer of vascular permeability. In mammals, the VEGF family consists of VEGFA, VEGFB, VEGFC, VEGFD, and placenta growth factor (PLGF), with each member having a specific site of expression and showing distinct binding pattern to the different VEGF receptors (VEGFRs).Last but not least, even though the greatest effect of studies on genetics of AR has been in increasing our understanding of disease pathogenesis, there are still ways in which the findings regarding genetic basis of AR will improve diagnosis and treatment in the future. To begin with, identification of mutations in the 3 genes can enable more accurate prediction of the likelihood that a subject will develop DM AR and that facilitating lifestyle change to avoid DM allergen exposure will be valuable. Secondly, it has been convincing that genetics might play an important role in prediction is in disease severity, and the ability to identify those who are most likely to have severe persistent disease would allow targeting of preventative treatments and be of significant clinical utility. For example, here we reported that the compound heterozygous carrier of both c.322A > C; p.S108R in VEGFB and c.502+1G > A in ITGA2 had more severe clinical symptoms and serum DM levels; thus, more attention should be exerted towards such population. In addition, the further investigation concerning the relationship between asthma phenotype and the identified mutations would shed light on the issue regarding how to predict the potential asthma subtypes in DM AR subjects.In summary, our findings suggest that 3 rare variants in FLT1_c.603A > T, VEGFB_c.322A > C and ITGA2_c.502+1G > A are probably causal variants in DM AR. Although allergy is widely considered to be a complex disorder, our study further suggests that these variants are present within several families, indicating a strong involvement of the genetic components. However, further studies replicating the methodologies employed in present study in a much larger population as well as functional studies are required to determine the relationship among the rare variants found in the 3 genes in patients with AR.Three rare variants in 3 genes , which are involved in Focal Adhesion pathway, were identified in affected AR subjects in DM AR families by whole-genome sequencing and conjoint analysis of gene expression profiling data. Despite the relatively small sample size, this study has identified several potentially functional rare variants in AR candidate genes, and it provides a cutting edge opportunity for future work in larger numbers of families and sporadic individuals for a better understanding of the genetic basis of AR.The ethics review board of the Beijing Tongren hospital, P.R. China, approved the study and, prior to entry into the study, all participants provided written informed consent.Not applicable.The datasets generated during the current study are available from the corresponding author on reasonable request.All authors declare that they have no competing interests.the national key R&D program of China (2016YFC0905200), the program for the Changjiang scholars and innovative research team (IRT13082), the national natural science foundation of China , Beijing Natural Science Foundation (7182034), Beijing municipal administration of hospitals' mission plan (SML20150203), and Beijing advanced innovation center for food nutrition and human health , Beijing Health Bureau Program for High Level Talents (2014-3-018) and Cross-disciplinary Collaborative Program of Beijing Nova program (xxjc201712).This work was supported by grants from All the authors contributed significantly to the study: YZ, JL and YZ collected the data. JL performed statistical analyses. YZ and JL wrote the manuscript. CW and LZ designed and supervised the study.


The World Health Organization (WHO), in its “Rehabilitation 2030 A Call for Action”, identified the need to strengthen rehabilitation in health systems to meet the growing demands of current and future populations. Greater access to rehabilitation services is required to secure the achievement of the United Nation’s third Sustainable Development Goal, “Ensure healthy lives and promote well-being for all at all ages”. To support this mandate, WHO issued a call for non-governmental organizations, associations and institutions to share their rehabilitation-related competency frameworks which will be used to construct a global rehabilitation competency framework. In response to this call, the World Federation of Chiropractic (WFC) developed a chiropractic rehabilitation competency framework. In this article, we present the chiropractic rehabilitation competency framework that will contribute to the development of the global framework in support of WHO’s strategic planning for rehabilitation. The goal of WHO’s strategic planning is to improve the integration and support of multi-disciplinary rehabilitation and establishing opportunities for global networks and partnerships in rehabilitation.The online version of this article (10.1186/s12998-019-0249-8) contains supplementary material, which is available to authorized users. An increasing unmet need for rehabilitation exists globally as a consequence of the rising prevalence of non-communicable diseases and injuries and the ageing population . While hIn February 2017, the World Health Organization (WHO) launched its “Rehabilitation 2030 A Call for Action” to: “1) draw attention to the increasing needs for rehabilitation; 2) highlight the role of rehabilitation in achieving the SDGs; 3) and call for coordinated and concerted global action towards strengthening rehabilitation in health systems” [The objective of this article is to present a chiropractic rehabilitation competency framework developed by the World Federation of Chiropractic Disability and Rehabilitation Committee (WFC DRC). The framework includes a set of core competencies: communication, knowledge, technical skills, clinical reasoning, values, and reflection which taken together will ensure the rights, well-being and safety of patients are protected and that chiropractors will employ evidence-informed practices in the delivery of patient care , 3.The Secretary-General of the World Federation of Chiropractic (WFC) invited the Chair of the WFC DRC to respond to the WHO call for rehabilitation competency frameworks. The WFC DRC Chair formed a subcommittee of individuals representing expertise in rehabilitation and disability, and educational frameworks for a competency-based education for chiropractors, to collaboratively develop the rehabilitation competency framework.The WFC DRC subcommittee reviewed WHO documents and other key resources from chiropractic councils and educational institutions to inform the development of the chiropractic rehabilitation competency framework , Australia (n = 1), Europe (n = 7), North American (n = 9), South American (n = 1)) and professions , psychology (n = 1), medicine (n = 1), chiropractic (n = 13), occupational therapy (n = 1)). An external chiropractic representative from Asia also provided peer review of the draft document in September 2018, to ensure representation across all world regions. Finally, the Chair of the WFC-DRC submitted the final framework to the WFC Secretary-General who submitted it to the WFC council members. WFC council members reviewed the final framework and approved it through consensus. The final framework was submitted to WHO on September 30, 2018.The subcommittee met on six occasions to develop the chiropractic rehabilitation competency framework. Each of the three key domains and associated competencies were discussed and independently reviewed by each member of the subcommittee. A draft framework was approved by the subcommittee through consensus. The final draft framework was then submitted to the WFC-DRC for critical review in September 2018 and comments were integrated in the final framework. WFC-DRC members represent various world regions Additional file 2:Glossary. Alphabetical list and meanings of key terms used in chiropractic rehabilitation framework. (DOCX 22 kb)


Scientific Reports is dedicated to this research.More than two centuries ago Henri de Saint-Simon envisaged physical laws to describe human societies. Driven by advances in statistical physics, network science, data analysis, and information technology, this vision is becoming a reality. Many of the grandest challenges of our time are of a societal nature, and methods of physics are increasingly playing a central role in improving our understanding of these challenges, and helping us to find innovative solutions. The Social physics Collection at  Indeed, many aspects of collective behavior in human societies have turned out to be remarkably predictable, and this fact has paved the way for methods of physics to be applied to many contemporary societal challenges. Examples include traffic2, crime3, epidemic processes4, vaccination5, cooperation6, climate inaction7, as well as antibiotic overuse8 and moral behavior9, to name just some examples.Although we are unique and hardly predictable as individuals, research has shown that in a collective we often behave no differently than particles in matter10. However, similar ideas have been around already in the 17th century, when Thomas Hobbes based his theory of the state on the laws of motion, in particular on the principle of inertia, which was then deduced by his contemporary Galileo Galilei11. The ‘invisible hand’ proposed by Adam Smith in the second half of the 18th century is also eerily similar to the now famous notions of economic and social self-organization13, and at the time was deemed to be as dependable in operation as the law of gravity14. And in the 19th century, the evolving physical theories of matter as a vast collection of atoms and molecules inspired a statistical view of societies and the predictable averages therein. Just as the random movements of molecules in a gas yield the mathematically simple gas laws, it was fathomed that societies may also be predictable in the collective scale. Thus, as Philip Ball argued aptly10, early sociology was indeed constructed according to an unspoken faith that there was a kind of ‘physics of society’.In fact, possible synergies between physical and social sciences have been floating around in the scientific literature for centuries. Over two centuries ago, the French political and economic theorist Henri de Saint-Simon was amongst the first to propose that society could be described by laws similar to those in physics15 and computational social science16, and by the relentless innovations in computer and information technology. The result today is social physics, or the physics of social systems, which is rapidly gaining momentum and developing into a research tour de force for a better tomorrow.But despite the long and fascinating history, it was not before the very end of the 20th century that truly remarkable progress had begun along the interface of physical and social sciences. This progress has been driven by advances in statistical and theoretical physics, by the coming of age of network scienceScientific Reports is dedicated to this line of research, and after only half a year in the making underlines its strong potential. Given the diversity of the topics that are covered by social physics, it is challenging to pull a common thread through, and even to select, contributions that have been published thus far in a brief editorial. Therefore, in what follows, only a few representative examples are highlighted.The Social physics Collection at 17 present a network-based framework to detect cartels – groups of firms that set prices collectively to increase profits at the expense of consumers – based on the interaction patterns between them. They apply their method to a school milk market in the Republic of Georgia that consists of nearly 150,000 public contracts, revealing groups of firms with high cohesion and exclusivity that are significantly more likely to display cartel behavior.Wachs and Kertészet al.18 study the dynamics of recruitment into organized crime and terrorist networks, using evolutionary game theory as the backbone. Their research identifies key factors that influence the growth and decline of such criminal structures, and it reveals the convoluted interplay between agents that associate with illicit groups, criminals that act on their own, and the rest of the civil society.Martinez-Vaquero et al.19 study whether human cognition imposes constraints in the digital space similar to those that we know exist in the physical space, such as keeping the number of friends and favorite places stable over time. Indeed this seems to be the case, with the results painting an intriguing picture that links human behavior in the physical and digital worlds, bridging research across computer science, social physics, and computational social science.De Nadai et al.20 studying the role of reward and punishment in climate change dilemmas, by Johnson et al.21 studying the emergent dynamics of extremes in a population driven by common information sources and new social media algorithms, and by Agarwal et al.22 studying the identification and characterization of teleconnections on different scales through networks. There is no doubt that the Social physics Collection will amass a number of fascinating contributions over time. We encourage the readers to stay tuned, and we cordially invite prospective authors to consider contributing to the Collection.In addition to the three examples above, several other fascinating papers have been published recently, for example by Santos With all the current and upcoming scientific and technological breakthroughs, it is easy to be excited about what the future holds. But there are formidable challenges up ahead as well. Examples include climate inaction, the depletion of natural resources, growing inequality, and perpetual conflicts in some parts of the world. These challenges, although primarily of a societal nature, require insights from different fields of research to be solved successfully. And physics has in recent years emerged as an important piece of this puzzle.In the 20th century, physics gave us, among many other great discoveries, the atomic bomb. And although it would seem that peace and prosperity can sometimes benefit from such a show of strength, the hope is that the physics of the 21st century will give us a better understanding of our societies so that the universal goals of humanity can be achieved without force. If social physics will ultimately stand for that, all goals of this line of research would be achieved.


Under-appreciation of the importance of rehabilitation within the continuum of care is a major obstacle to achieving universal health coverage. Lynn Eaton reports. Shakya Nishchal remembers the 2015 Nepal earthquake well. “I was at home in Kathmandu with my family when it struck,” he says. “I was thrown against the walls as I ran through to my baby’s room to protect her. It was terrifying.”Once his family was safe, and the ground had stopped shaking, Nishchal  got in touch with colleagues to organize a rehabilitation team. Getting a group of specialists together was not a problem, but getting them into action was. “After the earthquake, despite trying hard at all levels, it was very difficult to set up a service department for physiotherapy, even in the most affected areas,” Nishchal says.What made it difficult for Nishchal and his colleagues to go to work was not a lack of demand, (an estimated 22 000 people were injured in the earthquake) it was a lack of appreciation on the part of the health ministry of the importance of rehabilitation services in an emergency.Sunil Pokhrel, a physiotherapist with the nongovernmental agency Humanity & Inclusion, which played a key role in response efforts, encountered similar issues.“The health ministry had been working on an emergency preparedness plan in collaboration with WHO, so we were not entirely caught off guard, but even so, the clinics and hospitals were quickly overwhelmed with patients,” he says.According to Pokhrel most of the doctors and nurses had an awareness of rehabilitation services because of training given to them during the preparedness planning. However, there were very few staff trained in rehabilitation and they had limited stocks of assistive devices.For Pauline Kleinitz, a physiotherapist working with the World Health Organization (WHO), Nepal’s experience highlights challenges faced by many low-income countries.“Health emergencies such as Nepal’s 2015 earthquake throw into stark relief the problems resource-constrained countries face, notably the tendency to underfund rehabilitation services,” she says.Global atlas of the health workforce, the density of skilled rehabilitation practitioners, in many low- and lower- middle-income countries is below 10 per 1 million people.While there is a lack of robust national studies of unmet rehabilitation need, according to WHO’s Kleinitz believes there is a link between the under-allocation of resources and the way rehabilitation is defined. “The pigeon-holing of rehabilitation as an ‘extra’ or as something that is only needed for people with significant permanent disability often stands in the way of health system planners making the necessary investment in capacity across the system,” she says.The exclusive focus on permanent impairment was something that Nishchal observed during the earthquake response. “Those rehabilitation interventions that were implemented, mainly targeted people with permanent impairments, such as lost limbs,” he says.That a resource-constrained health system under the pressures imposed by an emergency should prioritize the needs of someone who has just lost a leg, first by keeping them alive, and second by helping them adjust to their new reality, is of course understandable. It can also be argued that such a patient, in any circumstances, will always take priority over patients with less pressing needs.However, it is important to recognize that the benefits of rehabilitation extend well beyond such cases and should be taken into account in capacity building and resource allocation.Since 2017 Kleinitz has been assisting countries to develop rehabilitation capacity as part of the WHO Rehabilitation 2030 initiative. Launched in 2017, the initiative identifies areas requiring concerted action to reduce unmet needs for rehabilitation and strengthen health systems to provide rehabilitation services. The second Global Rehabilitation 2030 Meeting took place in July 2019, bringing together representatives from 55 countries.As part of her work Kleinitz has been supporting Botswana, Guyana, Jordan, Myanmar, Nepal, Solomon Islands, and Sri Lanka in their efforts to assess their situation and to develop national plans.In her advocacy and technical support efforts Kleinitz stresses the importance of ensuring rehabilitation services for a wide range of health conditions. “Rehabilitation addresses much more than disability and is in fact needed by anyone with a health condition, impairment or injury, acute or chronic, that limits functioning,” she says.Kleinitz argues that for rehabilitation to realize its full potential it needs to be integrated into the broader health system, from the primary health-care (PHC) level up. “People need to be able to access appropriate rehabilitation services in their own town or village so that they don’t always have to travel to a specialist centre based in a major hospital,” she says, and argues that integrating rehabilitation into PHC is key to advancing the universal health coverage agenda, and progress towards the broader health goal .Kleinitz stresses however, that optimal delivery of rehabilitation services requires them being integrated into and between primary, secondary and tertiary levels of health systems, as well as with social welfare services and long-term care.Needless to say, the integration of rehabilitation services across health systems is predicated on the existence of health systems that can deliver a full range of health services and have effective referral systems.Most of the low- and middle-income countries Kleinitz is working with fall short on both counts.Myanmar is one example. According to a recent WHO assessment of the country, over the past decade, health spending has increased and there has been a corresponding expansion of government health services. However, legacy weaknesses accumulated during several decades of military rule are still very evident.Despite the challenges faced, over the last decade rehabilitation capacity has improved. There are now 23 physical medicine and rehabilitation departments across the country’s 38 tertiary hospitals, while 76% of the secondary level hospitals have at least physiotherapy services.“Rehabilitation is being increasingly integrated into a range of tertiary and secondary healthcare, but there is still progress to be made,” says Kleinitz, citing the limited integration of rehabilitation within primary healthcare as an example. “Very few rehabilitation personnel are located at the primary care level, nor have rehabilitation interventions been built into the provision of primary health care by other health personnel,” she says.“Rehabilitation… needs to be integrated into the broader health system, from the primary health-care level up.”Pauline KleinitzDr Myint Htwe, Myanmar’s health minister, acknowledges the need for increased investment in rehabilitation services, and considers WHO’s assessment of the current state of rehabilitation service provision ‘a wake-up call’.Myint reports that the government plans to train health workers in primary health care centres to provide basic rehabilitation advice, but acknowledges that this may take time. In the short term there are plans to boost capacity by making smart phones available to staff that will support diagnosis and treatment. The government has already circulated 12 000 smart phones and plans to distribute another 14 000 in August.President of the Myanmar Physiotherapy Association, Tin Hlaing Soe believes that bringing in private sector players could also help. “The government should train more physiotherapists and create specialized posts in small towns as well as encouraging private clinics,” he says.In Nepal the resource constraints are just as daunting. Despite various initiatives to support health systems strengthening, dating back to the promulgation of a national health policy in 1991, and despite Nepal’s 2015 constitution guaranteeing basic health care as a fundamental right, to date the development of a robust health system has been more an aspiration than a reality.With specific regard to rehabilitation, it is grass roots efforts that have driven the rehabilitation agenda, notably the community-based rehabilitation schemes, which are now established in each of the country’s 75 districts.“Under the direct control of the local community and disabled persons’ organizations, these schemes have played an important role in promoting inclusion and in collecting basic information related to persons with disabilities,” Kleinitz says, noting that many are now moving beyond rehabilitation to include services and initiatives designed to promote inclusion of persons with disabilities.However, while Kleinitz applauds these initiatives, she is keen to see the governments build on the health system capacity developed in response to the earthquake.Nishchal shares the same desire. “The seven health facilities equipped with rehabilitation services after the quake still continue to provide rehabilitation care to people with injuries and limitations in functioning caused by back pain and osteoarthritis,” he says, adding that they are still actively involved in early detection, assessment and treatment, follow-up through community home visits and outreach programmes. “This has set an example in the country,” he says. “They offer a ray of hope.”