These results suggest a role of patient-clinician concordance of the insula, a social-mirroring and salience-processing brain node, in mediating directional dynamics of pain-directed facial communication during therapeutic encounters.Patient–clinician concordance in behavior and brain activity has been proposed as a potential key mediator of mutual empathy and clinical rapport in the therapeutic encounter. However, the specific elements of patient–clinician communication that may support brain-to-brain concordance and therapeutic alliance are unknown. Here, we investigated how pain-related, directional facial communication between patients and clinicians is associated with brain-to-brain concordance. Patient–clinician dyads interacted in a pain-treatment context, during synchronous assessment of brain activity (fMRI hyperscanning) and online video transfer, enabling face-to-face social interaction. In-scanner videos were used for automated individual facial action unit (AU) time-series extraction. First, an interpretable machine-learning classifier of patients’ facial expressions, from an independent fMRI experiment, significantly distinguished moderately painful leg pressure from innocuous pressure stimuli. Next, we estimated neural-network causality of patient-to-clinician directional information flow of facial expressions during clinician-initiated treatment of patients’ evoked pain. We identified a leader–follower relationship in which patients predominantly led the facial communication while clinicians responded to patients’ expressions. Finally, analyses of dynamic brain-to-brain concordance showed that patients’ mid/posterior insular concordance with the clinicians’ anterior insula cortex, a region identified in previously published data from this study The patient–clinician relationship can have a powerful impact on patient outcomes, across disorders , 2 and aNonverbal behavior such as facial expressions have been identified as central in clinical interactions, and better clinician accuracy in perceiving patient emotions is associated with a range of positive outcomes, including greater patient satisfaction, better treatment adherence, and improved comprehension and retention of medical information . In factUsing two-person functional MRI (fMRI hyperscanning), we recently identified patient–clinician concordance in brain activity as a potentially key mechanism supporting therapeutic alliance in pain treatment . SpecifiHere, we investigated the causal dynamics in patient–clinician facial communication in the context of pain treatment, using neural-network-based causality modeling of the dynamics of facial action units (AU). These AUs were algorithmically identified from videos of patients’ and clinicians’ faces during their interaction. Furthermore, we investigated whether these dynamics were associated with concordance in brain activity, using simultaneously recorded fMRI , who were positioned in separate MRI scanners with nonverbal  communication enabled via online video connection  and 22 licensed acupuncture practitioners (“clinicians”) to participate in an interactive pain-treatment experiment during fMRI hyperscanning. Participants were matched to form patient–clinician dyads  for evoking moderate pain . Painful deep-pressure stimuli were applied to the patients’ left lower leg using the Hokanson Rapid Cuff Inflator .During the MRI visits, patients were first positioned in the MRI scanner. The clinician then entered and led the patient through the process of acupuncture needling, in which two needles were inserted above the patient’s left knee, proximal to the cuff, with MRI-safe electrodes attached to each needle. Following needle insertion, the clinician was positioned in the other MRI scanner, on the same floor in the same building. We applied a customized head-coil configuration, using a 64-channel head-coil bottom in combination with a small (4-channel) flex coil positioned over each subject’s forehead, in order to enable full facial coverage for video transfer. MRI-compatible video cameras enabled the participants to communicate nonverbally  during the experimental hyperscanning runs. Each dyad completed two experiments, one in which the patient experienced moderately painful and nonpainful cuff-pressure stimulation while the clinician observed  questionnaire  was fillPatients filled out the Berkeley Expressivity Scale , as an aWe recorded in-scanner videos from both scanners continuously during fMRI scan runs at a sampling rate of 20 frames per second, and used automated facial-feature extraction  to obtain individual action-unit (AU) values for each video frame. Affectiva software extracts the extent of activation/movement of 20 facial AUs, such as brow raise/furrow, nose wrinkle, lip movement , mouth open, chin raise, smirk, eye closure/widen, and jaw drop. A full list of AUs is available in Supplementary Table The time courses of facial AUs extracted from patients’ facial video data during the pain MRI were used to train a nonlinear classifier, using the extreme gradient-boosting (XGBoost) algorithm , in ordeVideo streams from patients and clinicians in the pain/treatment MRI were used to assess “information flow”  betweenGranger causality was independently assessed during anticipation of pain and treatment/no treatment, which preceded pressure stimulus, consisting of 12 nonconsecutive data blocks for each dyad . Pain-related anticipation and expectancy constitute a key factor shaping pain outcomes –38 and ap < 0.05) lower than the median GC strength across “real dyads” (Mann–Whitney U-test) , in order to minimize the presence of “pseudo-concordance” due to the shared structure of the experimental protocol. GC-estimate distributions for “real dyads” were contrasted with these null distributions using nonparametric statistics. Specifically, the causal link between any two signals was considered statistically significant if the median GC strength in the null distribution was significantly (st) Fig. . All thez = 2.3, and cluster significance threshold of P = 0.05 [z = 2.3 has been shown to be relatively conservative compared with other parametric approaches such as Ordinary Least Squares, especially for paradigms using moderate block lengths similar to our study, and yields a false error rate of approximately 5% [See Supplementary Methods for details on MRI acquisition and preprocessing. To investigate whether dynamic brain-to-brain concordance in social-mirroring circuitry would be associated with patient–clinician facial expression communication related to pain, we calculated dynamic fMRI signal concordance for each patient–clinician dyad as previously reported . After pP = 0.05 , 43. Thiately 5% .Ratings of therapeutic alliance (CARE) showed relatively high scores for both patients  and clinicians (mean ± SD: 35.69 ± 4.08), as previously reported . Since wThe XGBoost model distinguished moderate pain from innocuous pressure conditions by employing the patient’s AU data yielding an AUC of 0.75, a precision of 72%, and a recall of 70% Fig. . This isα = 0.05) correction for multiple comparisons of patient-to-clinician directed causality, while there were no significant causal links for clinician-to-patient directed causality after FDR correction. Notably, the dynamics in patients’ AU28 (lip sucking), which was also identified as the feature that best discriminated between moderate pain and innocuous pressure, exerted a significant causal influence on the dynamics of the largest number of clinician AUs. Conversely, clinicians’ AU43 (eye closure), which was the second most discriminative feature of patients’ perceived pain, was the facial feature most influenced by the patients’ facial expressions . The corresponding exploratory analyses of Granger causality during the pain phase showed a similar pattern, with a strong unidirectional effect of patient-to-clinician causality for a wide range of AUs, but no significant causal links in the opposite direction  by patients’ AU28 dynamics, greater dynamic brain concordance was also noted between clinicians’ aIns activity and patients’ fMRI activity in middle/posterior insula (m/pIns), dorsomedial (dmPFC) and ventrolateral prefrontal cortex (vlPFC), supramarginal gyrus (SMG)/anterior temporoparietal junction (aTPJ), and hippocampus (HC) Fig. .Fig. 4Asr = 0.64, p = 0.01), suggesting that dyads with higher therapeutic alliance showed stronger insular dynamic concordance during pain-treatment anticipation  was significantly associated with therapeutic alliance , as intact fMRI and questionnaire data existed for more dyads than those with intact facial video data. However, the same analysis shows a corresponding effect when performed only on dyads with intact facial data for both participants .Next, we investigated whether dynamic brain concordance was also associated with personality factors—i.e., patients’ trait expressivity of negative affect. A Pearson correlation coefficient indicated that dynamic concordance between clinicians’ aINS and patients’ m/pIns was significantly associated with patients’ negative expressivity, assessed by the Berkeley Expressivity Scale  with facial expression recording and neural-network-based Granger causality analyses to investigate the causal dynamics of facial expressions in a therapeutic interaction, and how these dynamics are supported by patient–clinician concordance in brain activity. Using automated extraction of facial action units (AUs) from video time series of patients’ and clinicians’ faces during social interaction, we first applied a nonlinear machine-learning classifier, which predicted whether or not patients were experiencing pain based on AU data alone. Next, Granger causality analyses indicated that patients’ facial expressions caused a range of facial responses by clinicians, but not vice versa, suggesting a leader–follower relationship in which patients led the facial communication while clinicians responded. We then demonstrated that the most salient causal relationship—clinicians’ global facial expression response to patients’ AU28, which exerted the highest relative influence on the machine learning classifier outcomes—was also associated with patient–clinician dynamic brain concordance in circuitry implicated in social mirroring and theory-of-mind. Specifically, the strength of patient-to-clinician directed causality was positively associated with patients’ vlPFC, SMG/aTPJ, and mid/posterior insula concordance with clinicians’ fMRI response in the anterior insula. Finally, insula-to-insula concordance in particular was associated with self-reported therapeutic alliance and patients’ trait expressivity, suggesting that patients with a higher tendency to express negative emotions also showed stronger insula-to-insula concordance with their clinician.Expression of pain is highly dependent on social context and the state of the individual . For exaOur pain-expression model, using the state-of-the art method to assign univocal importance values to features influencing classification (SHAP), identified several facial AUs consistent with previous reports of pain-related expressions, such as eye closure (AU43), lid tighten (AU7), brow furrow/lowerer (AU4), and mouth open (AU52) , 47, 48.Interestingly, the AU that had the strongest influence on classifying pain from innocuous pressure in our machine-learning model was lip sucking AU28). Moreover, lip sucking, when expressed by the patient, was also the AU that exerted significant causal influence on the highest number of clinician AUs during the pain/treatment MRI, suggesting that this patient expression most readily influenced clinicians’ facial expression. Although not necessarily included as part of a “canonical” pain expression, some studies have indeed associated AU28 with pain . Moreove. FurtherGranger causality analyses of facial-expression time series , showed a robust asymmetry in which patient expressions caused a wide range of facial responses by the clinician, but not vice versa. One possibility is that clinicians, in response to patients’ expressions, were attempting to use nonverbal communication as a means for consolation or expressing support for their patient, even though patients were less responsive to expressions by the clinician. Importantly, we applied causality-estimation modeling based on nonlinear neural networks, which has been shown to be superior to traditional Granger causality methods in estimating highly nonlinear, directed coupling in complex networks such as an ensemble of facial AUs from distinct individuals.We previously found that treatment-related change in mirroring of facial expressions was associated with therapeutic alliance and patient analgesia . This raUsing hyperscanning fMRI, we tested whether patient-to-clinician-directed information flow in facial expressions was associated with dynamic brain-to-brain concordance. For dyads showing stronger causal influence of patients’ AU28 (lip sucking) on clinicians’  facial expressions, patients showed stronger dynamic concordance with the clinician’s anterior insula (aIns). The anterior and mid-sections of the insula, a key hub of the salience network, play a fundamental role in integrating sensory signals with cognitive and affective information in order to guide behavioral decisions . FurtherPrevious studies have also linked activation of this circuitry with pain expressions directly. One study found that pain expressions in response to experimental pain were associated with activation of anterior and posterior insula along with somatosensory areas and midline circuitry  . AnotherNotably, in our study, concordance between clinicians’ aIns and patients’ m/pIns fMRI response also showed a significant association with scores on the CARE questionnaire, such that patient–clinician dyads with higher insula cortex concordance reported higher therapeutic alliance. Furthermore, patients that showed stronger insula-to-insula dynamic concordance with the clinician also reported higher trait tendency to express negative affect, as assessed by the Berkeley Expressivity Questionnaire . Both evolutionary theoretical frameworks  and compOur study has several limitations. First, due to the limited sample of intact facial-expression data, our study was likely underpowered, which increases the risk of type-II errors. Thus, the observed classification accuracy (72%) for pain relative to nonpain states, based on facial AU time courses, may be improved with additional training data. Indeed, a recent study, using a deep-learning approach with a larger training data set of static images of facial expressions associated with shoulder pain, reported higher accuracy , suggestIn conclusion, we found that patients’ facial expressions during pain treatment had a strong dynamically causal effect on the clinicians’ facial expressions, but not vice versa. Furthermore, we found that patient–clinician concordance in insula-cortex activity was positively associated with larger causal influence of patients’ pain-related expressions on clinicians’ facial responses. Our findings specify brain-behavioral dynamics that may be central to successful patient–clinician interactions.Supplementary information


Purpose: To investigate the efficacy of intense pulsed light (IPL) combined with deproteinized calf blood extract (DCBE) eye drops for dry eye disease (DED) patients with nociceptive ocular pain. Methods: In this prospective, one-center, interventional study, 23 subjects with DED and ocular pain were treated with a combination of IPL and DCBE eye drops for four sessions at a four-week interval. Subjective and objective assessments on nociceptive pain and dry eye were examined and analyzed. Results: The visual analog scale (VAS), ocular surface disease index, ocular pain assessment survey (OPAS), patient health questionnaire-9 items, generalized anxiety disorder (GAD-7), Athens insomnia scale, corneal fluorescein staining score, meibomian gland secretion quality, and expressibility scores were significantly reduced after the treatment. Tear break-up time and Schirmer I test increased significantly. The brand density of corneal nerves and neuropeptide substance P also significantly increased. OPAS, GAD-7, meibomian gland secretion quality, and expressibility scores were essential factors affecting the VAS changes. Conclusions: IPL combined with DCBE drop therapy was effective for DED patients with ocular pain. With such treatment, both DED symptoms and the sensation of ocular pain may be improved. Dry eye disease (DED) is considered a complicated and multifactorial disorder of the ocular surface, with the prevalence ranging from 5 to 50% in individuals worldwide . AccordiOcular pain is the third most critical symptom that needs attention at clinics . GeneralDED has a variety of effective treatments, such as artificial tears, hot compresses, anti-inflammatory and immunosuppressant eye drops, autologous serum tears (AST), intense pulsed light (IPL), and vectored thermal pulsation . AlthougIn recent studies, AST was investigated to be a highly effective management for severe corneal pain without obvious clinical signs. AST can increase corneal nerve density, restore injured neurons and contribute to the growth of sensory and sympathetic neurons. In our previous study, deproteinized calf blood extract (DCBE) was an effective topical treatment for relieving ocular pain raised by DED . DCBE isConcerning the potential function of repairing tear film and corneal nerve, reducing neuroreceptors irritation and ameliorating corneal pain, we combined IPL therapy and DCBE eye drops in this study to investigate whether this application is an effective treatment for patients diagnosed with DED with specific ocular pain.We recruited 23 patients aged 22–75 years, including five males and 18 females. This prospective study was conducted at the Second Affiliated Hospital of Zhejiang University School of Medicine between September 2019 and July 2020. The tenets of the Declaration of Helsinki were followed in this study, and it was approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine. Written informed consent was obtained from each participant after the nature, and the possible results of the study were explained . Patients with tear break-up time (TBUT) under 10 s and obvious dry-eye-related hyperesthesia symptoms (light sensitivity or ocular pain) which can be relieved after surface anesthesia were diagnosed as DED patients with ocular pain and were recruited for the study. The exclusion criteria included: (1) eye allergies, (2) infectious conjunctivitis, (3) corneal ulcer, (4) eyelid infection, (5) severe blepharitis, (6) palsy, (7) valgus or other ocular lesions, (8) severe systemic disease, and (9) history of wearing contact lenses in the preceding 30 days.The patients were treated with IPL four times at a four-week interval. Patients were also asked to use DCBE eye drops  four times a day after each consecutive IPL treatment for 16 weeks. All patients were followed up every four weeks after each IPL treatment.The subjects were asked to score their own general ocular pain perceptions on a visual analog scale scored from 0 to 10. Self-reported ocular pain was scored as no pain (0) up to the severest pain (10) ever suffered.The OSDI is recommended by TFO DEWS II for diagnosing DED, and its reliability and efficacy have been confirmed. The OSDI contains 12 different questions and scores 0–4, representing the slight to a severe degree. After aggregating the scores, the total score was 0–100. An OSDI score over 13 was diagnosed as symptomatic DED .OPAS was designed as an initial 32-question, 8-domain, ocular pain questionnaire using numerical rating scales to assess eye pain intensity (worse eye) in the past 24 h and two weeks , frequency of eye and non-eye pain (past 24 h and two weeks), non-eye pain intensity (past 24 h and two weeks), impact on quality of life (QoL), pre-occupation with eye and non-eye pain, aggravating factors, associated factors, and symptomatic relief. Questions on the frequency of pain were included to assess the discriminant validity of the OPAS since, hypothetically, any observable relationship with the frequency of ocular pain should not be demonstrated by the intensity of ocular pain. Each test question was scored on a scale of 0–10, or 0–100%, with increments of 1% or 10% units, respectively. The questions were divided into sections for analysis: questions 4–9 pertained to the intensity of ocular pain; questions 10–12, non-ocular pain; questions 13–19, QoL; questions 20–21, aggravating factors; and questions 22–25, associated factors. After excluding the section on symptomatic relief, only questions 4–25 were analyzed in this study [In this survey of nine questions, patients were asked about their frequency of being bothered by problems  over the past two weeks. A cumulative score from 0 to 27 was assigned, with scores related to depression severity . For this study, we conservatively dichotomized depression scores into those with the lowest total scores  as “not depressed,” while those with higher total scores  were categorized as “depressed” .The 7-item generalized anxiety disorder (GAD-7) scale is a validated, reliable, and efficient measurement tool for GAD screening and assessing its severity in clinical practice and research. In the GAD-7 scale, four levels of anxiety severity are classified: none (0–4), mild (5–9), moderate (10–14), and severe (15–21) .The AIS is a self-assessment psychometric instrument designed for quantifying sleep difficulty based on the ICD-10 criteria. It consists of eight items: the first five pertain to sleep induction, awakenings during the night, final awakening, total sleep duration, and sleep quality. The last three are related to well-being, functioning capacity, and sleepiness during the day. They are based on a 0–3 scale, in which three designates adverse outcomes. Total AIS scores range from 0 to 24 points. A minimum total score of six points is an indication of an insomnia diagnosis .The cornea was divided equally into four quadrants. The scoring was recorded after staining as follows: (0) no dye point, (1) 1–30 points, (2) more than 30 dye spots but no fusion, and (3) entirely stained with fusion. A total score in each eye ranges from 0 to 12. Scores over 1 point is regarded as defects of corneal epithelium.Tear film instability was assessed using TBUT measurements. First, fluorescein was added to the tear film, and the patients were asked to blink entirely several times to ensure that it was uniformly distributed across the ocular surface. The time between the last blink and the first dry spot on the tear film was measured. TBUT under 10 s was a golden diagnostic criteria for DED.A filter paper strip (35 mm × 5 mm) was put into the lower eyelid conjunctival sac after applying topical anesthesia, and the lengths of the wet parts were recorded after 5 min. Lengths shorter than 10 mm were considered abnormal.2) on the lower eyelid of the participant, similar to the pressure of an average blink, and then the meibomian gland orifices and secretions were observed through a slit-lamp microscope. Three parts of the upper and lower eyelids were evaluated using the meibomian glands expressibility score in the temporal, central, and nasal parts of the lower eyelid. Each part contained five glands. If the five glands in the center of the meibomian glands were normal, zero points were assigned. One point was assigned if either one or two glands without secretions were mildly abnormal. Two points were assigned if only three or four glands discharged secretions with moderate abnormalities. Finally, three points were assigned if there were five glands without secretions for severe abnormalities. The meibomian gland expressibility score for moderate and severe abnormalities suggested the possibility of dry eye, with a total score of 18 points.The meibomian gland evaluator  was used to simulate the constant gentle pressure , inspissated secretion (grade 2), cloudy secretion (grade 1), and clear secretion (grade 0), with total scores of 45 points. IVCM evaluation of the central cornea was performed using Heidelberg retinal tomography (HRT) III with an anterior segment module . This was followed by the installation of a drop of proparacaine hydrochloride eye drops (s.a. ALCON-COUVREUR n.v.) into the conjunctival fornix. The objective lens was covered with a disposable polymethacrylate sterile cap, and Viscotears was applied as the coupling agent. Participants were requested to fix their gaze on a central target to allow for full-thickness scanning of the central cornea in 2 μm increments using the section mode setting of the tomograph. Parameters of corneal nerve fiber length (CNFL), fiber density (CNFL), brand nerve density (CNBD), fiber tortuosity (CNFT), abnormal corneal nerve fiber, and dendritic cells were evaluated.All study participants had tear secretion collected at about 14:00 in a quiet room with weak light without surface anesthetic. Tear samples were collected for each eye with 200 μL normal saline and immediately placed in an EP tube and stored in a deep cryogenic refrigerator at −80 °C to avoid repeated freezing and thawing.The cytokine levels of the tear samples were performed in triplicate. The cytokines included TNF-α, IL-6, and IL-8. The concentration values were obtained from the mean fluorescent intensity (MFI) using Luminex200 IS V2.1 software. Standard curves were generated from the reference cytokine gradient concentrations. The concentrations of these cytokines in the tear samples were calculated from standard curves. The CGRP and substance P levels in the tear samples were determined using the ELISA assay. Analyses were performed in triplicate according to the manufacturer’s instructions for each ELISA kit.p-value of < 0.05 was considered statistically significant. In the raw analyses, t-tests were performed for normally distributed continuous variables, including the OSDI, TBUT, SIT, meibomian gland expressibility, secretion quality scores, CNFL, and the concentration of cytokines and neuropeptides in tear samples. Kruskal–Wallis tests were conducted for ordinal outcomes, including VAS, OPAS, PHQ-9, GAD-7, AIS, and CFS scale. The analysis was double-sided, and a p-value of <0.05 was considered statistically significant.All statistical analyses were performed using SPSS software . The Kolmogorov–Smirnov test was used to identify the normal distribution of continuous variables. A All patients were diagnosed with DED with ocular pain in both eyes. Fourteen of them announced a bilateral headache of facial pain, while eight patients reported no headache or facial pain. Only one patient had a headache or facial pain on his right side. Regarding the psychological assessments, 10 patients had insomnia, five had depression, and five had anxiety. Nine patients had a history of ocular trauma or surgery, and nine patients had systemic diseases. Complete demographic information is shown in Changes in subjective symptoms after every therapy session are shown in Improvements in dry eye examinations that occurred after four IPL treatment sessions combined with DCBE eye drops are shown in The ocular pain sensation could be directly affected by corneal nerve characteristics. The observed changes are displayed in Topical inflammation and pain may be caused by the accumulation of related inflammatory cytokines. We examined five relevant cytokines before the treatment, after the second treatment in the eighth week, and after the fourth treatment in the sixteenth week. The results are shown in The VAS is considered one of the simplest and most sensitive tools for reporting degrees of pain and discomfort. In our study, we divided patients into two groups to find which factors affected the changes in VAS scores. The groups considered were the normal-response group, in which VAS scores decreased less than 50%, and the sensitive-response group, in which VAS scores decreased at least 50%. The comparative results are shown in Multiple studies have been designed to investigate effective treatments for DED. However, few studies have systematically focused on the efficacy of these treatments specifically for the ocular pain symptoms of DED. Our study was the first to investigate the effectiveness of a combination treatment of IPL and DCBE eye drops on DED accompanied by ocular pain. In our prospective study, we found that IPL combined with DCBE eye drops for four sessions was an effective treatment to relieve ocular pain in DED patients. Subjective symptoms, DED signs, and laboratory markers improved after the novel therapy. The VAS, OSDI, OPAS, PHQ-9, GAD-7, and AIS scores decreased significantly during the research. The CFS, TBUT, Schirmer I test, meibum expressibility, and secretion quality improved. Furthermore, the corneal nerve brand density was repaired by the combined treatment of IPL with DCBE eye drops, with which the levels of substance P were also improved, according to our results.The homeostasis of the tear film is broken by DED, inducing ocular hyperosmolarity and inflammation . TopicalIn our study, we showed that after four treatment sessions, the CFS scores were significantly reduced. Meanwhile, TBUT and Schirmer I test results were significantly elevated in all therapy stages. These results are indications that, with the combined treatment of IPL with DCBE eye drops, the tear film could be stabilized, building a healthy ocular micro-environment. TBUT increased an average of 3.65 times (2.03–7.40 s), and there was an average of 62.81% (8.04–13.09 mm) in the Schirmer I test results compared with the baseline. This represents a meaningful clinical improvement and a statistically significant improvement in tear film stability and tear volume. In our study, we found that meibum expressibility and secretion quality were improved by IPL combined with DCBE eye drops, especially during the last two visits. The meibum in the glands may be melted by a high IPL temperature, accelerating its discharge and circulation. These results are in accordance with several previous studies ,18,31,32With the IVCM examination, the brand density of the corneal nerves was enhanced after treatment. At the same time, the length, tortuosity, and relevant cells had no differences. Time and frequency may result in this effect. We presumed that if the treatment sessions were prolonged in our study, the response of the corneal nerves might have been significantly increased. For inflammatory cytokines, only substance P was found to be significantly increased. Although CGRP, IL-6, IL-8, and TNF-α had a decreasing tendency, the analytical results were not different. This was in accordance with the study by Liu et al. . SubstanAfter four combined treatment sessions, the subjective and sensory responses seemed more sensitive and evident. Regarding topical eye sensation, the VAS and OSDI scores decreased at every stage of the treatment and were reduced to nearly one third of the baseline. Six OPAS assessment items decreased after the final therapy, which indicated that treatment with IPL combined with DCBE eye drops could alleviate the lasting time and degree of ocular pain and promote non-ocular feelings and QoL. Psychological improvements were also demonstrated by the PHQ-9, GAD-7, and AIS reduced scores, implying that the systematic feelings of anxiety, depression, and insomnia were alleviated by the combined IPL and DCBE eye drops treatments.We next divided the patients into two groups based on the results of the VAS changes. The overall therapeutic effects of the combined treatment were represented by the VAS. The two groups did not differ in all parameters before treatment. However, after four combined therapy sessions, the OPAS-24H and non-eye pain, GAD-7, meibomian gland expressibility, and secretion quality scores decreased significantly. This is an indication that therapeutic effects might be affected by the degree of pain, systemic anxiety, and meibomian gland function. Apparent relief in anxiety control and improvement of meibomian glands can be expected to produce better curative outcomes.There are several potential mechanisms for alleviating subjective ocular symptoms and objective signs by combining IPL and DCBE eye drops in DED patients with ocular pain. IPL has been widely reported to impact MGD positively , and theIn previous studies, AST was proven to be beneficial to patients with corneal neuropathy-induced photoallodynia or severe corneal pain by promoting nerve regeneration and repairing nerve topography . NeverthCompared to traditional treatments for DED patients with apparent ocular pain, IPL combined with DCBE eye drops has several advantages. To relieve nociceptive pain induced by eye dryness, anti-inflammatory and anti-depressant drugs are adopted ,40. HoweOur study has some limitations. First, the number of enrolled subjects may not be sufficient to determine guidelines for the combined treatment of IPL with DCBE. Furthermore, we need a more significant number of participants to validate the efficacy and conclusion of the current study. Second, our study failed to involve a control group in this experiment, and a randomized and controlled, long-term, multi-center study is essential for further research. The IVCM examination and cytokines did not have apparent changes, and long-term research might be more helpful. Third, due to the apparatus limits, our study failed to evaluate the possible changes of ocular osmolarity, as hyperosmolarity is considered as an essential cause of DED and ocular pain . IPL wasIn conclusion, our study revealed that IPL combined with DCBE eye drops is an effective and reliable treatment for managing DED patients with ocular pain. The combined treatment had positive effects on both dry eye symptoms and the sensation of ocular pain. This may provide a novel guideline for clinical DED treatment.


This cohort study investigates the use of neural machine translation software to assess postoperative pain and nausea among patients with limited English proficiency. We hypothesized that the application’s translate conversation mode may facilitate assessment of postoperative pain and nausea.STROBE) reporting guideline. Written informed consent was obtained from eligible patients by research personnel fluent in Spanish . The study took place from July 6 to October 16, 2021, including 1-day follow-ups. The primary end point was the feasibility of using the Google Translate translation application conversation mode to assess postoperative pain and nausea among Spanish-speaking patients in the postanesthesia care unit (PACU). Patients were introduced to the application during the preoperative interview, with Spanish-speaking research personnel  explaining study goals and how the study would be conducted in the PACU. Preformulated questions were played for patients in the PACU through the application using an iPad tablet (Apple) held by the research coordinator  at set intervals when nurses would typically evaluate symptoms. Patients responded with yes or no and gave numbers for pain and nausea ratings. Patient ethnicity was self-reported per institutional standard of care.Institutional review board approval was granted for this cohort study by MD Anderson Cancer Center. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  who were enrolled, all spoke only Spanish and self-identified as Hispanic . The sucMost patients (73.3%) were satisfied or very satisfied with standard human translation services. Most patients (93.1%) were also satisfied or very satisfied with their pain and nausea management in the PACU, and 96.6% of patients were satisfied or very satisfied with the ability of the translation application to assess their symptoms . One patMost nurses (96.7%) were satisfied or very satisfied with the quality and immediate availability of current institutional human translation services. Additionally, 83.3% and 86.7% of nurses were satisfied or very satisfied with the speed and ability that the translation application could be used for patient assessment, respectively .2 and can be associated with poor clinical outcomes. In this cohort study, we report the successful use of a web-based electronic translating tool for assessment of postoperative symptoms among Spanish-speaking patients. Although Patil et al3 found that this translation application was suboptimal for comprehensive medical communication, the authors also found that the application was a useful adjunct tool when human translation services were unavailable. Other brief reports have documented the application as a potential perioperative communication tool.6 Limitations of our study included a small sample size and conduct of assessments in 1 language.Disparities owing to race and ethnicity exist in postoperative symptom management across various settingsWe observed that more than 90.0% of patients were able to communicate their pain and nausea using the translation application. Use of this technology could potentially be associated with decreased disparities in postoperative symptom assessment via improved patient-nursing communication.


IntroductionWith the recent increase in popularity of cannabinoids in the management of chronic pain, the inquisitiveness among our patients and health care professionals are probably now at its peak. Many treating health care professionals in their clinical practice come across patients who either use cannabinoids or are interested in their efficacy and side effects. As there is paucity of data and research about their use in rheumatology, patient's self-reported responses and experience of primary care physicians  can guide in expanding our knowledge.MethodsOurs was an observational, cross-sectional study among rheumatology patients and GPs in the Leicestershire area. Initial questionnaire was designed by authors addressing demographics, knowledge, experience and perception. This was piloted among patients and GPs and improvised, redesigned and used for the study. The study design consisted of two arms: first arm including GPs and second arm rheumatology patients.ResultsArm 1 consisted of 100 GPs with median age group of 30-40 years. 34% GPs experienced their patients inquiring about cannabinoids. 78% did not believe cannabinoids benefited the patients. On a scale of 0-10, the mean benefit in managing pain 3.2 + 2.5. Arm 2 consisted of 102 patients. 16% reported using cannabinoids for managing their chronic pain. The users reported significant improvement in pain compared to non-users (p=0.002). On comparing the perception of cannabinoids between GPs and patients, there was a statistically significant difference regarding awareness and effectiveness (p<0.001).ConclusionWith the paucity of data and research about the use of cannabinoids in rheumatology, the patient self-reported responses provided an estimate as to their efficacy. This was significantly different from the GP perception. Disease and drug-focused research is need of the hour. To our knowledge, this is the First Single Centre study in the UK evaluating GP and rheumatology patient perception on cannabinoids. Recently, there has been a lot of interest among patients, general public and clinicians regarding the use of cannabinoids for the management of chronic pain. Certain forms like cannabidiol (CBD) oils are being legitimately sold in high street. Cannabinoids have gained popularity among rheumatology patients and many treating clinicians frequently come across patients who are curious about it, are using it or even asking for a prescription. They are available both legally and through alternative sources in several forms such as oil, tablets, cake and coffee among others. While research on their therapeutic indications particularly in rheumatological conditions are limited, their popularity cannot be ignored.Cannabis plants (C. sativa) are made up of more than 100 different cannabinoids, having different effects on the body. The most common forms known are CBD and tetrahydrocannabinol (THC). THC is the component responsible for psychoactive effects while CBD is devoid of this effect [The endocannabinoid signalling system encompasses cannabinoid receptors, endocannabinoids and enzymes regulating the biosynthesis and inactivation of endocannabinoids. Cannabinoids are found in three settings: endogenous ligands or endocannabinoids (arachidonic acid derivatives); exogenous plant-derived phyto-cannabinoids and synthetic tricyclic terpenes .There are two primary receptors CB1 and CB2 having very different and sometimes opposite actions. CB1 is primarily expressed in frontal cortex, basal ganglia and cerebellum and is responsible for the psychotropic effects of cannabis. Overall, CB1 activation exerts an inhibitory effect on the presynaptic cell. CB2 receptors are located peripherally on immunologic and musculoskeletal cells. it’s the fine balance of effect of cannabis substance on these CB1 and CB2 receptors, that ultimately result in psychoactive or immunomodulatory effects [There are several studies on the use of cannabinoids in rheumatic diseases. JWH133, a selective CB2 agonist, inhibited in-vitro production of cytokines in synoviocytes and reduced in-vivo arthritis score and bone destruction in collagen-induced arthritis (CIA) rat model [Cannabis is currently a controlled drug as classified by the Misuse of Drugs Act 1971. Specific forms of cannabis are licensed for use in spasticity in adults with multiple sclerosis (MS), treatment-resistant epilepsy (Dravet and Lennox-Gastaut syndromes) and refractory vomiting secondary to chemotherapy. They require an initial prescription by a specialist medical practitioner and subsequent prescriptions may be issued by another prescriber  as part of a shared care agreement . On the Management of pain is an integral part of rheumatic diseases. Research on alternative therapies that can modulate pain and improve quality of life is essential. Paucity of data and RCT led to rejection of cannabinoids for management of chronic pain by NICE NG144) guidelines [4 guideliSelf-reported patient responses can assist healthcare providers and regulatory authorities in decision-making. These self-reported responses are unique indicators of impact of disease on the patient, helping in patient empowerment and necessary for determination of efficacy of the treatment. They can also be useful in the interpretation of clinical outcomes and treatment decision-making . The NICIn a self-administered questionnaire study conducted in the UK between 1998 and 2002, medicinal cannabis use was reported by patients with chronic pain (25%), multiple sclerosis and depression (22% each), arthritis (21%) and neuropathy (19%) . In anotDespite frequent discussions in the media on the use of cannabinoids as an alternative therapeutic for chronic pain, physician’s perspective and knowledge on using such therapies is still lacking in the UK. A Colorado-based survey of 114 healthcare providers concluded that though the providers frequently assess patients’ marijuana use, they are uncomfortable and inconsistent in talking to patients about specific health effects .In the absence of any consistent evidence-based guidelines and recommendations for cannabinoid use in rheumatology patients, we conducted a cross-sectional study comparing self-reported responses of rheumatology patients and GPs exploring their knowledge, experience and awareness of cannabinoids use in rheumatology.While rheumatology patients are under specialist care for their specific illness, they are ultimately under the care of their GPs who were the initial port of call by the rheumatology patients for holistic health care requirements. Therefore in our study, we chose GPs as comparative arm for more comprehensive evaluation.This was an observational, cross-sectional study among rheumatology patients and GPs in the Leicestershire area. Initial questionnaire was designed by authors addressing demographics, knowledge, experience and perception. This was piloted among rheumatology patients and GPs which was followed by improvisation and redesigned for the use in the study.Our study design consisted of two arms with first arm including GPs and GP trainees while second arm had rheumatology patients attending general rheumatology clinics in Leicester Royal Infirmary Figure .Questionnaires were distributed from August 2019 to February 2020. Arm 1: The form with 20 questions was divided into four sections covering demography, knowledge, experience and perception of cannabinoid usage for rheumatological conditions. The response was collected through web-based portal (Monkey Survey) which was sent through email. A reminder email was sent after one week. Paper-based forms were collected from GP trainees.Arm 2: Patients were given a written participant information statement about the study and after taking informed consent and were invited to complete the anonymised questionnaire consisting of 20 questions with four sections on demography, knowledge, experience and perception of cannabinoids in managing their pain.For grading answers, a 10-point Likert scale was used and for qualitative answers, participants were asked to rate in terms of “no help at all”, “somewhat helpful” and “extremely helpful”. All collected information were compiled in the Microsoft excel sheet and then analysed using SPSS Software v23.0 version . Demographic data were analyzed using descriptive statistics including Chi-square test for comparing the percentage. Numerical responses were tabulated and summarized using counts and percentages. To facilitate bivariate comparisons, we collapsed qualitative and Likert scale responses to helpful and not helpful (agree or disagree) and excluded the equivocal (“somewhat”) responses.A comparison between perception of GPs and patients regarding the efficacy of cannabinoids in managing rheumatological pain along with the opinion on availability of CBD via prescription was done. We also compared the experiences of cannabinoid users and non-users to shine more light in to the subject. Arm 1: GP responseThe response rate was 70%. Total of 100 complete responses were analysed.Section 1: Demographics54% were male with 47% GP trainees 51% GP) and two nurses. Most of the responders (51%) had a clinical experience of up to 5 to 10 years while 21% had been practising for >15 years. Median age group was 30-40 years  of the GPs replied that only 10% of their patients use any form of cannabinoids for their pain management while only 11% believed that 20% of their patients use complementary medicine for the management of chronic rheumatic pain. Only one replied 30%-50% of their patients use cannabinoids. Fibromyalgia (FMS) was the most common (41%) reported indication for their patients using cannabinoids, followed by rheumatoid arthritis (RA) (29%) and osteoarthritis (OA) (20%) Table .During routine clinics, 34% GPs experienced their patients inquiring about cannabinoids. When asked about the frequency of these inquiries, 4% GPs reported always, 22% reported sometimes and 8% GPs reported rarely. 15% GPs reported that patients have asked them to prescribe cannabinoids for their pain. Some of the other indications for which they have been asked to prescribe included insomnia and mood disorders. On asking about self-reported side effects by the patients to their GPs, 8% GPs reported adverse events which included constipation and anxiety. Section 3: KnowledgeMost of the GP trainees (85%) accepted that they were unaware of the indications where cannabinoids can be recommended while 57% of experienced GPs (5-10 years’ experience) were aware of the indications where cannabinoids are currently prescribed in NHS practice. Only 21% reported cannabinoids being used for other medical conditions which included MS, epilepsy and malignancy-related pain. Interestingly few also reported chronic pain and depression as being reasons for cannabinoid usage among their patient group.Section 4: PerceptionMost GPs (78%) did not believe that the use of cannabinoids benefited their patients much. 20% believed it did not help at all. On a scale of 0-10, the mean overall benefit they believed was 3.5 + 3.1 (median 2.5). In terms of managing rheumatological pain their response was similar with mean benefit on a scale of 0-10 being 3.2 + 2.5 (median 4.5). Only 14% would willingly recommend CBD usage in their practise; however, 27% agree it should be available as prescription in NHS. Arm 2: Rheumatology patient responseSection 1: DemographicsTotal of 102 responses were analyzed where 60% were females and the majority (45%) had secondary school level education. Median age of patients using cannabinoids was 55 years. Almost half of the users were unemployed and only 33% were in full-time employment. 75% were Caucasians and 18% Asians. Very few Asian patients participated in the study and any stigma or cultural belief need to be explored in a diverse population of Leicestershire. RA (54%) was the most common diagnosis followed by OA (23%) and FMS (19%). In terms of non-rheumatological co-existent mental health diagnosis, 42% reported suffering from depression and anxiety. Most of the respondents (94%) complained about having ongoing pain with the majority rating pain score between 6 and 8 on a Likert scale. While 42% were satisfied with their current therapy, 18% of patients believed it was inadequate.Of those that admitted to using cannabinoids for managing their pain (users), 88% were Caucasians and 38% reported alcohol consumption along with it. They were suffering from chronic illness with a mean duration of 6.25 years. There was no ethnicity difference noted in the use of CBD.Section 2: Knowledge65% of responders are aware of complementary medicine and 16% accepted using cannabinoids for their pain. 60% of the patients who did not report using CBDs were interested to know more about them. None of the responders were aware of any drug interactions or adverse effects of cannabinoids.Section 3: ExperienceMost common form of cannabinoid used was oral preparation (70%) followed by smoking or vaping (25%) with only 5% using topically. 56% reported using them for more than three months and majority used daily. RA was the most common cause of chronic pain (68%) followed by OA and FMS  among users (n=16). All of the users had ongoing pain with a mean intensity of 7 on 0-10 scale compelling cannabinoid usage. Only one reported having experienced any side effects. It was noted that while the conventional therapy was somewhat helpful in managing their pain, cannabinoids were extremely helpful with all users strongly believing that they help in managing their pain almost completely Figure .On comparing self-reported responses of cannabinoid users vs non-users there were no significant differences in terms of demography, duration of illness or nature of disease. There was a significant difference p=0.002) in improvement in pain among those who used cannabinoids along with conventional therapy compared to those on just conventional therapy . While the patients advocated the availability of cannabinoids through NHS, GPs were reluctant about it Table . While GPs believed that the most common indication for usage of cannabinoids was FMS (41%), patients reported RA (54%) (p=0.001).To the best of our knowledge, this is one of the first studies conducted in the UK, assessing the perception of rheumatology patients and primary care physicians regarding cannabinoid usage in rheumatology. Over the last decade use of cannabinoids as complementary medicine has expanded drastically with many countries now legalizing it for various indications including pain. We conducted a narrative literature review and found several studies from Canada, the USA, Australia, Israel and Ireland regarding perception and experience of cannabinoids among primary care physicians and rheumatologist Table .Unlike the UK, some of these states have legalised cannabinoids in pain management. The responses of these studies are in line with our findings, wherein most clinicians still do not advocate the usage of cannabinoids in chronic pain, have inadequate knowledge, less confident and have reservations regarding their legal status. On the contrary, the patient reported response from our study to support the usage of cannabinoids in rheumatic pain. This study raises some important concerns. There is limited confidence and lack of knowledge among GPs regarding cannabinoid usage. Furthermore, in the setting of increase demand by the patients, there is an imbalance between need, advocacy and knowledge. This serious gap covers many aspects of cannabinoids including uncertainty of content, unspecified dosing, lack of clear recommendations or guidelines and drug interactions. This disconnect sometimes results in difficult consultation and puts a strain on the physician-patient relationship.Our group of patients attending regular rheumatology clinics reported using CBD more for pain in RA as compared to OA/FMS. This needs to be explored further particularly in context with possible drug interactions and failure to meet the treat to target concept . We also noted a lack of self-reported adverse effects by the patients which could be due to appropriate safety profile or reduced concentration of THC in the preparation used. There was a difference in the perception of GPs regarding the use and benefits of cannabinoids in their patients compared to actual patient reported data. Possible explanation could be that GPs come across more FMS patients in their daily practice when compared to rheumatology patients. Strength of our study includes a good response rate and two arms comparing GPs and patient responses. The ubiquitous nature of the endocannabinoid system raises questions as to the exact function of this system in health and disease, with limited experience in the clinical arena. The cannabinoid effects are not only confined to the nervous system and pain pathways, but also have roles in inflammation and immune-modulatory effects . Thus thLimitation of our study is the sample size given the popularity and abundant utilisation of cannabinoids by our patients. Although 16% of our patients reported using cannabinoids, we believe this to be under-reported and a larger study can decipher a much superior figure. In a paired survey of primary care providers(PCP) and their patients it was found that PCPs were aware of marijuana use in their patients only 53% of the time . While t In 2016, a Canadian study reported 3.8% of patients using cannabinoids. Most common indication  was OA. They reported users as younger, more likely unemployed or disabled, and having poorer global health . Our stuThus we believe the lack of knowledge among GPs stems from the paucity of clinical information regarding the use of cannabinoids in rheumatology practice. To date, there is not a single controlled clinical study that has examined the efficacy or safety of herbal cannabis in the rheumatic diseases . There iDespite the lack of evidence-based medicine, rheumatology patients have access and use CBD products, sometimes without the knowledge of healthcare professionals. There is a significant difference between patient and physician perception on the use of cannabinoids as a therapeutic agent in rheumatic pain. Quality research and clinical trials are in need of the hour; however, until we have more evidence, health care professionals should currently dissuade rheumatology patients from using cannabinoids.


Introduction: Deep brain stimulation (DBS) is a treatment option for refractory dystonia's motor symptoms, while its non-motor symptoms (NMS) have been less systematically assessed. We aimed to describe the effects of DBS on NMS in refractory generalized inherited/idiopathic dystonia prospectively.Methods: We evaluated patients before and 1 year after DBS surgery and applied the following scales: Burke–Fahn–Marsden Rating Scale (BFMRS), NMS Scale for Parkinson's Disease (NMSS-PD), Parkinson's Disease Questionnaire-8, short-form Brief Pain Inventory (BPI), Neuropathic Pain Symptom Inventory (NPSI), and short-form McGill Pain Questionnaire (MPQ).Results: Eleven patients (38.35 ± 11.30 years) underwent surgery, all with generalized dystonia. Motor BFMRS subscore was 64.36 ± 22.94 at baseline and 33.55 ± 17.44 1 year after DBS surgery . NMSS-PD had a significant change 12 months after DBS, from 70.91 ± 59.07 to 37.18 ± 55.05 . NMS changes were mainly driven by changes in the gastrointestinal (p = 0.041) and miscellaneous domains (p = 0.012). Seven patients reported chronic pain before DBS and four after it. BPI's severity and interference scores were 4.61 ± 2.84 and 4.12 ± 2.67, respectively, before surgery, and 2.79 ± 2.31 (0.00–6.25) and 1.12 ± 1.32 (0.00–3.00) after, reflecting a significant improvement . NPSI score was 15.29 ± 13.94 before, while it was reduced to 2.29 ± 2.98 afterward (p = 0.028). MPQ's total score was 9.00 ± 3.32 before DBS, achieving 2.71 ± 2.93 after (p = 0.028).Conclusions: DBS improves NMS in generalized inherited/idiopathic dystonia, including chronic pain. Generalctively) –6. The actively) . They usctively) . Patientctively) . GPi-DBSctively) . Howeverctively) –10. Our This study was approved by our Institutional Ethics Review Board (protocol number #48607515.5.0000.0068), and all patients gave written informed consent before being included in the study. Patients were evaluated from December 2015 to July 2019.Patients had generalized dystonia of inherited/idiopathic etiology , and allThis prospective observational study evaluated patients before and 1 year after DBS surgery, in which motor and non-motor signs and symptoms were assessed as described later.After consent to participate, patients were evaluated before and 1 year after DBS surgery with motor scales and a series of non-motor scales that include mood and pain evaluations. For the motor assessment, we registered the motor subscale (0–120) of the Burke–Fahn–Marsden Rating Scale (BFMRS). For mood and general non-motor symptoms, the Hospital Anxiety and Depression Scale (HADS) and the Non-Motor Symptoms Scale for Parkinson's Disease (NMSS-PD) were applied, respectively. The Parkinson's Disease Questionnaire-8 (PDQ8), derived from the Parkinson's Disease Questionnaire-39, was used to assess the quality of life (QoL). The questionnaires used for pain assessment included.i) The Brief Pain Inventory (BPI) short form, which provides two principal scores: a pain severity score , and a pain interference score in daily activities ;ii) Neuropathic Pain Symptom Inventory (NPSI), which also evaluates different clusters of descriptors of neuropathic and varies from 0 to 10  with two additional items related to the duration and frequency of paroxysmal pain;iii) The short-form McGill Pain Questionnaire (MPQ) in which pain descriptors are categorized into three dimensions of pain: sensory (questions 1–8), affective (questions 9–13), and evaluative (questions 14–15). Also, there is an item for pain intensity by the visual analog scale .baseline); (2) these scores of patients with or without pain after 12 months with DBS (p1year); (3) these scores of patients with pain in the baseline and after 12 months with DBS (pwithpain); (4) these scores of patients without pain in the baseline and after 12 months with DBS (pw/opain); (5) the pain scales  scores/subscores in the baseline condition and after 12 months with DBS. Spearman's rank correlation assessments were performed to verify whether changes (Δ = 12 months – baseline) in the different scales scores trended similarly or distinctively.Data were expressed as mean ± SD (min–max). Non-normal data were evaluated using the Wilcoxon signed-rank test for dependent  samples. The primary outcome was the change in BFMRS, HADS, and NMSS-PD scores and subscores 12 months after DBS surgery from the baseline condition. Secondary outcomes included the following: (1) these scores of patients with or without pain in the baseline condition , and statistical significance was set at THAP1, two DYT-PRKRA, and the others did not undergo genetic analysis  years (36.3% women). Four patients had DYT-analysis . Of the p = 0.102). However, the anxiety subscore had a significant decline, from 7.09 ± 6.28 (0.00–20.00) to 3.00 ± 5.40 (0.00–19.00); p = 0.028. QoL had a substantial improvement after DBS with PDQ8's baseline scores being 40.06 ± 17.72% (9.38–62.50%) and improving up to 17.33 ± 15.96% (0.00–43.75%) after 1 year (p = 0.005), an improvement of 56.7%  at baseline to 6.82 ± 9.66 (0.00–35.00) at 1 year with DBS  and miscellaneous domains of the scale (p = 0.012).Total NMSS-PD had a significant change 12 months after DBS, from 70.91 ± 59.07 (0.00–223.00) to 37.18 ± 55.05 (0.00–176.00), rovement . This wap = 0.043 and p = 0.028, respectively).Seven patients (63.6%) reported chronic pain (CP) before surgery , while op = 0.028 at 1 year. Likewise, MPQ total score was 9.00 ± 3.32 (3.00–12.00) before surgery, being reduced to 2.71 ± 2.93 (0.00–7.00), p = 0.028 after surgery. The comparisons of BFMRS, PDQ8, NMSS-PD, and HADS scores between both groups of patients at the baseline and 12 months after DBS did not significantly differ (p = 0.043). The BFMRS motor subscore also significantly improved, up to 48.7% (p = 0.043), in the subset of patients with pain.NPSI total score was 15.29 ± 13.94 (0.00–40.00) before DBS, while it was reduced to 2.29 ± 2.98 (0.00–7.00), y differ . QoL impp = 0.009, The only differential scores that were significantly different from baseline and that had significant correlations were the PDQ8 and the NMSS-PD scales , urinary, sexual function, and miscellaneous symptoms. NMS has significantly improved in our sample; interestingly, mainly driven by the GIT and miscellaneous subscores. Previous reports have shown an improvement in QoL; our cohort used PDQ8 with almost 78% improvements.An important fact is that QoL improvement was mainly driven by NMS's improvement, while the improvement of the motor symptoms did not influence QoL in our correlation.Despite their prevalence and impact on QoL, other NMS have rarely been assessed. The NMSS-PD evaluates different NMS and NMS have significantly improved in our sample. Previous reports have shown an improvement in QoL; our cohort used PDQ8 with almost 78% improvements.PRKRA. There were two particular phenotypes in the original published DYT-PRKRA cases: (1) generalized isolated (pure) dystonia; (2) dystonia–parkinsonism dystonia that was non-responsive to levodopa .Our study has some limitations, such as a small sample size with DBS being performed to different targets. However, generalized dystonia is a relatively rare disease, and most surgical studies reported on small sample sizes as well , 4. Thislevodopa . Therefoinsonism . This exSTN and GPi DBS may globally activate different cortical and subcortical networks in PD and dystonia. However, it may provide similar endpoints on motor symptoms of dystonic patients , 7. Thisa) The activation of a group of common structures/hubs modulated by both approaches that provide a common and similar symptomatic relief by shared mechanisms;b) Other variables. For instance, the percentage of motor improvement may be similarly obtained by both targets in different patients, which are not necessarily overlapping. In addition, analogous to two antidepressants that may provide a 60% response rate each in controlling depression, the patients responding to each of the two drugs may not be necessarily the same, given that these two drugs act by different mechanisms.In support of point (a) above, an interesting study  evaluateConcerning the effects of both DBS target on NMS, it remains widely unknown the exact and detailed effects of DBS in general on NMS, as well as the effects of individual targets on these same symptoms. Such an approach would require a controlled and larger study, which cannot be provided by our current article. Here, based on the assumption that both targets have similar motor symptoms , we have explored the NMS of both approaches in a long-follow-up and prospective design, using a very detailed assessment of NMS, even recurring to still non-validated questionnaires when necessary. In addition, we found original data on NMS control brought about by surgery, which need further exploration in controlled settings.Our findings highlighted the improvement in chronic pain and other NMS, along with the known improvements in motor symptoms and QoL . Also, tIn conclusion, we found that DBS improves NMS in generalized inherited/idiopathic dystonia, including CP, and it correlated with improvements in QoL after surgery.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Comissão de Ética para Análise de Projetos de Pesquisa do HCFMUSP. The patients/participants provided their written informed consent to participate in this study.CL: responsible for data curation, formal analysis, investigation, methodology, writing the first draft, and reviewing it. RC: responsible for conceptualization, project administration, and reviewing draft. SC: data curation and project managing. EL: formal analysis, investigation, and reviewing draft. DA: data curation. NS: data curation and project managing supporting. VD and RG: data curation and methodology. JM and JA: data curation. EB and MT: conceptualization and reviewing the draft. DD: conceptualization, reviewing the draft, and project managing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


TNs were fabricated applying ethanol injection method based on D-optimal experiment. TNs were evaluated with regard to entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). Further explorations were conducted on the optimum formulation (F7). F7 showed spherical appearance with EE%, PS, PDI, and ZP of 100.00 ± 1.10%, 358.60 ± 10.76 nm, 0.51 ± 0.004, and −30.00 ± 0.80 mV, respectively. The in silico study revealed the ability of the FTN–cholesterol complex to maintain favorable interactions throughout the molecular dynamics simulation (MDS) study. Moreover, Trichophyton mentagrophytes growth was inhibited effectively by F7 than by FTN suspension applying 2,3-bis(2-methyloxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay. Furthermore, a clinical appraisal on patients with tinea corporis fungal lesions confirmed the superiority of F7 compared to Miconaz® cream in the magnitude of clinical cure of tinea corporis. Thereby, TNs could be considered as promising vesicles for enhancing the antifungal potential of FTN for the topical management of tinea corporis.The current investigation aimed for loading fenticonazole nitrate (FTN), an antifungal agent with low aqueous solubility, into trans-novasomes (TNs) for management of tinea corporis topically. TNs contain Brij Fungal diseases are becoming more common these days. They have greater toxic side effects encountered with traditional systemic therapy . Brij® is composed of polyethylene gylated single-chain penetration enhancer with different acyl chain entities and polyethylene glycol (PEG) chain lengths , oleic acid amount (X2), and Brij® type (X3) were chosen as independent factors, whereas entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP) were chosen as dependent responses. The optimum TNs was investigated in vitro for its antifungal activity in comparison to FTN suspension utilizing 2,3-bis-(2-methyloxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction technique. To investigate the antifungal ability of the optimum TNs compared to Miconaz® cream through evaluating their efficiency on patients suffering from tinea corporis.As far as we can tell, this is the first research to employ TNs as a drug carrier to optimize the antifungal potency of FTN, as well as the first to test FTN loaded TNs clinically on patients suffering from tinea corporis. Hence, the goal of this work was to estimate the potential of TNs to optimize the topical delivery of FTN. To accomplish the preceding target, different factors impacting vesicles properties were attempted by D-optimal design applying the Design Expert® cream (miconazole nitrate 2%) was purchased from Medical Union Pharmaceutical (MUP) Co. .Fenticonazole nitrate was kindly provided by Andalous Pharmaceutical Co. . Span 60, Brij 93, Brij 58, and cholesterol were purchased from Sigma-Aldrich Chemical Co. . Oleic acid, methyl alcohol, and dimethyl sulfoxide (DMSO) were gained via El-Nasr Chemicals Co. . Miconaz® type employing ethanol injection technique  was mixed with distilled water. When sudden turbidity was detected, TNs were produced. The mixture was constantly mixed until all of the ethanol had evaporated for 30 min. The outcome was subsequently subjected to sonication applying a sonicator water bath using a bath-sonicator  for 5 min for reducing the PS. After that, TNs dispersions were maintained at 4 °C  was used to centrifuge 1 mL of each TNs dispersion for 1 h at 4 °C and 20,000 rpm. Following that, methyl alcohol was used to destroy the sediment and FTN concentration was determined at PS, PDI, and ZP were measured for the fabricated TNs by Zetasizer 2000  , oleic acid amount (X2), and Brij® type (X3). As dependent variables, EE%, PS, PDI, and ZP were chosen . Statistically significant p values <.05 were used. The system was optimized to recommend the formulation with the lowest (PS and PDI) and the greatest EE% and ZP values. The recommendation was based on the desirability function which allows all constraints to be examined at the same time. The formulation with the highest desirability outcome was chosen. The recommended optimum formula was fabricated, tested, and compared to the predicted data to ensure that the model performance is accurate.The D-optimal design was utilized to assess the impact of different independent factors in fabricating TNs. Three variables were evaluated: Span 60 amount  software version 2019.0102. All compounds were sketched using ChemDraw 20.1.1 and then converted to 3D structures by MOE  was utilized to detect the optimum TNs morphologically. A negatively stained sample with an aqueous solution of phosphotungstic acid  dissolution apparatus II  at 37 °C for 24 hours. One milliliter from the optimum TNs were placed in tubes with a permeation area of 3.14 cm2 with one end tightly covered with a cellulose membrane and the other end attached to the shaft of the dissolution apparatus instead of the baskets. Fifty milliliters phosphate buffer saline solution was used as the receptor medium (pH 5.5). At 1, 2, 3, 4, 5, 6, 8, and 24 hours, aliquots were removed. A UV spectrophotometer was utilized to examine the samples at λmax 252 nm .The optimum TNs were maintained at 4–8 °C for 45 days to examine its physical stability  growth is fully inhibited. A micro-well dilution technique was employed to estimate MIC applying generated inoculums containing 104 CFU/mL. In a 96-well plate, DMSO was utilized to dilute FTN suspension and optimum TNs. Forty microliters of sabouraud (the growth medium), 10 µL inoculum, and 50 µL of diluted formulae were placed in every well of the microplate. As a negative control, DMSO was employed. The plates were incubated for 24 h at 37 °C before being exposed to 40 µL of XTT and after that incubated in the dark at the same temperature for an hour. The microplate photometer  was employed to calculate any color change caused by XTT decrease at 492 nm. The following is the equation used to determine inhibition % .This clinical appraisal included 40 patients having lesions of tinea corporis. Those patients were picked from the Minia University Hospital (Dermatology Clinic). Before participating in this ongoing study, each patient signed an informed written consent form. Only patients with skin lesions who had not received any topical or systemic treatments for at least one month prior to participation were included. However, patients with skin lesions, showing tinea capitis or onychomycosis, patients with uncontrolled diabetes, pregnant or lactating females; were excluded.All of the patients provided a complete personal history , current history , previous history (previous treatment), and family history of fungal infections. The patients were photographed before treatment and after 4 weeks or complete improvement. The lesions were subjected to dermoscopic examination before treatment and after 4 weeks or complete cure. Skin scrapings were collected from the lesions for mycological diagnosis before treatment and after 4 weeks or complete improvement. Two drops of 20% potassium hydroxide (KOH) were added to the collected skin scrapings on a glass slide prior to its microscopic examination  in the same manner as group A (twice a day for 4 weeks or complete cure). The simultaneous use of any topical, systemic antifungal, systemic antihistamine, or systemic corticosteroid agent other than the received treatment was not permitted. Throughout the study, patients were instructed to record any discomfort. The efficacy of the used treatment was measured using three parameters: clinical cure, dermoscopic cure, and mycological cure  twice daily for 4 weeks or complete cure. In group B, each patient was instructed to apply Miconaz creamErythema, pruritus, and scaling are the measured parameters in each lesion. They were graded into (1) mild, (2) moderate, and (3) severe and were scored at baseline (day 0) and after 4 weeks. The maximum score was 9. Moreover, the global evaluation response  through a light microscope  with a camera . The mycological cure indicates the disappearance of all fungal elements from the skin scrapings. The assessment efficacy was scaled on a two-point scale, with 0 representing the absence of fungal elements and 1 representing the existence of fungal elements.® program 22.0. At p≤ .05, the difference is significant.Mann–Whitney’s test, Wilcoxon’s signed rank test, and Chi-Square test were utilized for clinical experiments via SPSS® program according to D-optimal design. The created design recommended 15 experimental runs to reflect all conceivable combinations of the various levels of the examined factors. The chosen model was a quadratic model for EE% and ZP and was 2FI for PS and PDI. The potential of the model to navigate the design space was confirmed with adequate precision. A ratio of more than four is preferable  values matched adjusted (R2) values in all of the investigated responses. The impact of formulae factors on the explored responses is displayed as 3D plots in Screening experiments were implemented to assess the independent variables that might have an impact on the development of FTN enclosed TNs. The preparation of TNs was done by the use of the Design ExpertX1) significantly (p=.0013) impacted EE% of FTN. The obtained findings indicated that as Span 60 amount was increased, the EE% value augmented. This might be ascribed to the increase in emulsification ability caused by the high Span 60 amount in TNs. Similar outcomes were observed by Mosallam et al. , it was found that increasing oleic acid amount resulted in a significant (p<.0001) decrease in the EE%. Kumar et al. (® type (X3) had a significant (p=.0073) influence on EE%. The observed outcome revealed higher EE% values in TNs containing Brij 93 compared to Brij 58 which could be explained by the difference in HLB values for both Brij 93 (HLB = 4) and Brij 58 (HLB = 15.7)  impacted the PS of the fabricated TNs significantly (p<.0001). The outcomes revealed that the PS of the fabricated TNs increased upon increasing Span 60 amount. This corresponded to the EE% outcomes as Span 60 showed high EE% values at high concentrations. Hathout et al. , a significant (p<.0001) increase in the PS was observed with increasing oleic acid amount. Due to the attractive steric forces, an increase in the chain length of oleic acid reduces the ability of oil molecules to penetrate the interfacial film, resulting in larger particles  had a significant (p<.0001) impact on the PS, where Brij 93 produced larger PS compared to Brij 58. This might be related to the PEG content of both edge activators as Brij 93 contained 2 PEG units and Brij 58 contained 20 PEG units  had a significant (p=.017) impact on the PDI. On the other hand, Span 60 amount (X1) and Brij® type (X3) had no significant effect on the PDI . Regarding oleic acid amount (X2), it was clear that as the amount of oleic acid was increased, the PDI increased. This might be justified by there was a direct correlation found between the PS and the PDI, with the highest PDI value found in TNs with the highest PS. This outcome was in accordance with the previous finding of Kumar et al.  had a significant (p<.0001) influence on the ZP. On the contrary, Span 60 amount (X1) and oleic acid amount (X2) had no significant impact on the ZP . With respect to Brij® type (X3), when comparing Brij 93 with Brij 58, it was found that Brij 93 had a greater negative ZP value. This might be ascribed to the fact that Brij 58 (HLB = 15.7) is more hydrophilic than Brij 93 (HLB = 4) which could result in the negative charge being shielded by adhering to the surface of the bilayers of TNs, disguising its charge. As a result, the ZP value has been significantly reduced . The chosen formulation was fabricated employing 70 mg Span 60, 10 mg oleic acid, and 10 mg Brij 93. The predicted outcomes of F7 were consistent with the actual outcomes  displayed a spherical shape with the development of smooth, non-aggregated, and small vesicles . The PS in vitro release profile of FTN from the optimum TNs (F7) in comparison with FTN suspension is illustrated in the supplementary materials  with a statistically significant difference (p<.001) between the two groups  when the global evaluation response of the two groups was compared  than Miconaz® cream (2% miconazole nitrate) indicates the capability of TNs to improve the antifungal potential of FTN.There was a significant clinical improvement in group A . Furthermore, F7 exhibited favorable characters in terms of EE%, size, charge, vesicular appearance, and stability. After that, the Click here for additional data file.


Background: Depression is a prominent and highly prevalent nonmotor feature in patients with Parkinson’s disease (PD). The neural and pathophysiologic mechanisms of PD with depression (DPD) remain unclear. The current diagnosis of DPD largely depends on clinical evaluation. Methods: We proposed a new family of multinomial tensor regressions that leveraged whole-brain structural magnetic resonance imaging (MRI) data to discriminate among 196 non-depressed PD (NDPD) patients, 84 DPD patients, 200 healthy controls (HC), and to assess the special brain microstructures in NDPD and DPD. The method of maximum likelihood estimation coupled with state-of-art gradient descent algorithms was used to predict the individual diagnosis of PD and the development of DPD in PD patients. Results: The results reveal that the proposed efficient approach not only achieved a high prediction accuracy (0.94) with a multi-class AUC (0.98) for distinguishing between NDPD, DPD, and HC on the testing set but also located the most discriminative regions for NDPD and DPD, including cortical regions, the cerebellum, the brainstem, the bilateral basal ganglia, and the thalamus and limbic regions. Conclusions: The proposed imaging technique based on tensor regression performs well without any prior feature information, facilitates a deeper understanding into the abnormalities in DPD and PD, and plays an essential role in the statistical analysis of high-dimensional complex MRI imaging data to support the radiological diagnosis of comorbidity of depression with PD. Parkinson’s disease (PD) is a major neurodegenerative disease influenced by both genetic and environmental factors . As the Nonmotor features can appear in the earliest phase of the disease even before clinical motor impairment ,5,6. DepAlthough the neural and pathophysiologic mechanisms predicting rates of DPD progression remain unclear and are key research priorities. Understanding the inner working mechanisms and discovering biomarkers of DPD is one of the most intriguing scientific questions. Studies in neuroscience strongly suggest intervention during early therapeutic windows ,17. PD iA variety of neuroimaging technologies, including functional magnetic resonance imaging (fMRI), structure MRI (sMRI), positron emission tomography (PET), and electroencephalography (EEG), have also been adopted for PD diagnosis. The recent Movement Disorders Society Clinical Diagnostic Criteria for PD have included the results of a few of these neuroimaging techniques to serve as single supportive criteria or absolute exclusion criteria for the diagnosis of PD . StructuStructure MRI has received more research focus with better stability and repeatability compared to fMRI, where there were concerns about accuracy due to noise ,27. A brMachine learning and artificial intelligence are recognized as booming and promising methods used to detect connectivity . A studyUp until now, most of the existing methods have focused on either the individual diagnosis of PD or the progression of depression comorbidity without simultaneously inferring the onset as well as the stage of PD. In this study, our goal was to build and validate a multinomial tensor-regression-based framework that leveraged three-dimensional (3D) sMRI data to differentiate between non-depressed PD, depressed PD, and healthy subjects. We used the method of maximum likelihood estimation coupled with state-of-art gradient descent algorithms to predict the individual diagnosis of PD and the development of DPD in PD patients. The proposed method could further identify regions of interest in NDPD and DPD relevant to the disease onset such that physicians could perform an early diagnosis in time for available treatment. More importantly, our method performed well without any prior feature information that restricted analysis to only a few brain regions, demonstrating its ability to be executed by untrained operators and to be applied to unseen patient data for both the diagnosis of PD and the assessment of depression comorbidity.This study was approved by the Medical Research Ethical Committee of Nanjing Brain Hospital  in accordance with the Declaration of Helsinki, and written informed consent was obtained from all subjects. A total of 276 PD patients, including 84 depressed PD (DPD) patients and 192 NDPD subjects, along with 200 healthy controls (HCs) were recruited. All the demographic characteristics and clinical symptom ratings were collected before MRI scanning, and all patients were in the ON state during the MRI scan. All subjects underwent a complete neurological and psychological status assessment and a review of medical history records. Mini-mental state examination (MMSE) was used to evaluate cognition. DPD patients were diagnosed with the Diagnostic and Statistical manual of Mental Disorders, Fifth Edition (DSM-V) criteria by an experienced psychiatrist. Afterwards, the severity of depression was quantified using the Hamilton Depression Scale (HAMD). Unified Parkinson’s Disease Rating Scale-Motor (UPDRS-III) was recorded for motor function, and Parkinson’s disease severity was rated according to Hoehn and Yahr (H & Y). The same metrics listed above except UPDRS-III and H & Y were applied to the control group. The neurocognitive tests were administered to each participant individually by a professional appraiser in the neuropsychological research center. The demographic and clinical data of patients with NDPD, DPD, and HC were compared using a Fisher’s exact test (for sex), multivariate analysis of variance (MANOVA) , and analysis of variance (ANOVA) (for UPDRS-III and H & Y between NDPD and DPD only). The level of significance was set at Images were scanned on Siemens verio 3.0T superconducting MRI system with 8-channel head coil in the department of radiology. The structural scans were acquired using 3D T1-Flair with the following parameters: repeat time (TR) = 2530 ms, echo time (TE) = 3.34 ms, matrix = 256, flip angle(FA) = https://www.fil.ion.ucl.ac.uk/spm/software/spm12/, accessed date: 20 August 2019) on the Matlab platform. The detailed step included spatial normalization to the Montreal Neurological Institute (MNI) space using the transformation parameters estimated via a unified segmentation algorithm [Three-dimensional T1-weighted images from both PD patients and HCs were then normalized using Statistical Parametric Mapping , , 3), we Algorithm 1. Block relaxation algorithm for maximizing  w w3) was We compared the performance of the proposed method with the multinomial logistic regression as well as 3D CNN, where each voxel was treated as a covariate. Note that the multinomial logistic regression could not handle the large dimension of over 500,000. Therefore, we only considered taking the first 1000, 3000, and 10,000 voxels as predictors and built the multinomial logistic regression models under these three cases. The multinomial logistic regression model was implemented in R glmnet, and 3D CNN was built in Python deep learning API keras. The area under the ROC curve (AUC) is a widely used measure of performance of supervised classification rules. However, the simple form is only applicable to the case of two classes. We adopted the AUC calculation for the case of more than two classes by averaging pairwise comparisons , i.e., tThe results were provided in One major advantage of our method was that one could simultaneously reveal the most discriminative structural changes in NDPD and DPD patients. In In this study, we built and validated a multinomial tensor-regression-based framework that leveraged 3D sMRI scans to simultaneously differentiate among NDPD, DPD, and healthy subjects. Other than the tool of tensor regression, interested readers might be aware of another class of machine-learning-based methods to localize PD in the brain . Salvatore et al. , Zhang eThe proposed method certainly has limitations. First, this method was only based on the tensor regression method with structural MRI rather than the previous methods based on network and functional MRI, which would be excellent topics for future studies. Second, the sample size in typical neuroimaging studies, including the current study, is quite small compared to the large image voxel size. Hence, the high-dimensional challenge remains pervasive rather than an exception in neuroimaging analysis. In these cases, regularization becomes essential for stabilizing the coefficient estimates and for minimizing the harm of over-fitting. In the near future, for sample-starved studies, we intend to either use penalty regularization ,48 or imTo the best of our knowledge, this study was the first attempt to construct a tensor-regression-based platform for structurally discriminating among NDPD, DPD, and HC with a high prediction accuracy. In terms of clinical characteristics, significant differences were detected with respect to the HAMD and H & Y scores among three groups of DPD, NDPD, and HC. In terms of regions with abnormal structures, significant differences were found in bilateral the frontotemporal and occipital lobes, basal ganglia, thalamus, corpus callosum, midbrain, and cerebellum between NDPD and HC. Concurrently, structural differences in the corpus callosum, cerebellum, and the right superior temporal gyrus, as well as the bilateral fronto-occipital lobe, left temporal lobe, bilateral basal ganglia, and thalamus were detected between DPD and NDPD.These findings suggest disease-related alterations of structure as the basis for faulty information processing in this disorder. Our findings were in good agreement with the alternative structure and functional features in cortical regions, cerebellum, brainstem, bilateral basal ganglia, thalamus, and limbic regions in previous studies ,29,50,51