Uric acid is both a pro-oxidant and antioxidant. We investigated serum uric acid's association with mortality and aging biomarkers in older adults with varying levels of grip strength. A total of 5329 community-dwelling adults aged ≥55 years underwent assessments of serum uric acid levels, grip strength, and biomarkers of diverse physiological systems. The primary outcome was all-cause mortality. We observed a significant (P < .001) interaction between uric acid levels and grip strength on all-cause mortality risk. Among participants with low grip strength, a nonlinear association (P for nonlinearity = .006) was observed between serum uric acid levels and mortality risk after multivariate adjustment. Compared with participants with neither extreme uric acid levels nor low grip strength, those with a combination of high serum uric acid and low grip strength exhibited greater risks of mortality  and deviations in biomarkers of specific systems, so did those with a combination of low serum uric acid and low grip strength . In conclusion, there was a J-shaped association between serum uric acid and the risk of all-cause mortality in older adults. This was primarily true for those with low grip strength. Aging is accompanied by increasing levels of reactive oxygen species; when they exceed a threshold, they can be detrimental and accelerate biological aging –6. AlthoPrevious studies indicated the association of high serum uric acid levels with the increased risks of multiple adverse health outcomes –16. DespUnlike fat, skeletal muscle is a water-rich tissue that holds a large proportion of water in the human body . It is wThis study's primary aim was to investigate the relationship between serum uric acid levels and mortality risk across a spectrum of grip strengths. We hypothesized that high and low serum uric acid levels are associated with increased risks of all-cause mortality, particularly in older adults with low grip strength. We also hypothesized that older adults with both low grip strength and high or low serum uric acid levels would display marked deviations in the levels of clinical biomarkers, reflecting age-related changes in physiological systems.The baseline characteristics of the study participants are presented in P for interaction < .001 when grip strength was analyzed as a categorical variable; P for interaction < .001 when grip strength was analyzed as a continuous variable). We conducted subsequent analysis stratified by grip strength.In the Cox proportional-hazards regression models, a significant effect was observed for the interaction between serum uric acid levels and grip strength on the risk of all-cause mortality after adjustment  between serum uric acid levels and mortality risk after adjustment  or high  serum uric acid levels but without low grip strength exhibited similar risks of mortality to those with medium levels of serum uric acid. The mortality risk was increased in those with low grip strength but without low or high serum uric acid levels , and in those with both low grip strength and low  or high serum uric acid levels , suggesting an effect only in the low grip strength group.The study population was divided into 6 groups based on grip strength (high and low) and uric acid . P for interaction < .001 when grip strength was analyzed as a categorical variable; P for interaction < .001 when grip strength was analyzed as a continuous variable). Results of subsequent analyses stratified by grip strength are shown in In the sensitivity analysis, no qualitative change in the results was observed. A significant effect of the interaction between serum uric acid levels and grip strength was observed on the risk of all-cause mortality , metabolic-system biomarkers (increased insulin [P < .001] and triglycerides [P < .001] and decreased HDL cholesterol [P <.001]), liver-system biomarkers , cardiovascular-system biomarkers (decreased DBP [P <.001] and increased ACR [P <.001]), kidney biomarkers (increased Cr [P <.001] and BUN [P <.001]), and lung biomarkers (decreased PEF [P <.001]). Those with a combination of low grip strength and low serum uric acid had similar deviations in lung biomarkers (decreased PEF [P <.001]) but not in the biomarkers of the immune system (decreased hs-CRP [P = .032] and absolute lymphocyte count [P = .001]), metabolic system , liver , cardiovascular system, and kidneys (decreased Cr [P <.001] and BUN [P <.001]). Prominent deviations in hematologic system biomarkers  were particularly observed in these older adults.To explore the accompanying changes in physiological systems, we examined the levels of 32 clinical indicators of biological aging representing diverse physiological systems  among older adults with different serum uric acid levels and grip strengths. Participants with different serum uric acid levels and grip strengths exhibited different change profiles . ParticiP for nonlinearity > .05) between serum uric acid and serum hs-CRP, IL-6, and TNFR1 were observed in older individuals with low grip strength. The levels of serum uric acid were significantly associated with those of serum hs-CRP, IL-6, and TNFR1 (P < .001). The higher the uric acid levels were, the higher the hs-CRP, IL-6, and TNFR1 levels were.In this prospective cohort study, we delineated the relationship between serum uric acid level and all-cause mortality in adults aged 55 years and older with varying grip strength levels. Serum uric acid levels at either end of the spectrum were associated with increased risks of all-cause mortality. Notably, the increased mortality risks were primarily observed in older adults with low grip strength. Moreover, the combination of low grip strength and low or high serum uric acid was associated with substantial deviations in various physiological systems' biomarkers.Previous studies showed that high uric acid levels are associated with increased risks of multiple adverse health outcomes –16. HoweIn the present study, we observed a significant effect of the interaction between serum uric acid levels and grip strength on the risk of death after adjustment for multiple potential confounders and even after considering possible reverse causation. A nonmonotonic relationship between uric acid levels and death's risk was only observed in older adults with low grip strength. This phenomenon implies that grip strength modifies the relationship between uric acid levels and the risk of death. The processes underlying loss of muscular strength might take part in the pathways linking high and low serum uric acid levels with health risks and drive the unique nature of their relationships in older adults.Low grip strength predicts an increased risk of premature death and a lower likelihood of healthy aging. Increases in oxidative stress and inflammation play major roles in the pathogenesis of muscle mass loss and functional decline during aging , 21. DurSkeletal muscle is among the largest tissues in the body and is rich in water and electrolytes . Approxiin vitro experiments of endothelial cells, vascular smooth muscle cells, adipocytes, pancreatic islet cells, hepatocytes, and renal tubular cells ), and nonnormally distributed data are presented as median (interquartile range). Nonnormally distributed data were normalized using the natural log transformation. The differences between continuous variables were analyzed using one-way ANOVA. The differences between categorical variables were analyzed using a chi-square test.P >.05). In these analyses of mortality risk, follow-up time was censored at the end of the follow-up (May 2020) for those who were still alive.Cox proportional-hazards regression models were used to analyze the relationship between serum uric acid and mortality risk, adjusted for confounders. We first examined the effect of grip strength on the relationship between uric acid and mortality risk. We added the interaction term between uric acid levels and grip strength , in addition to their main effects, into the model and tested its significance. Because it was significant, the study population was stratified by grip strength. We then nonparametrically examined the relation between serum uric acid and mortality risk separately in participants with and without low grip strength using restricted cubic splines with adjustment for confounders . Four knWe investigated the robustness of the study results through the following sensitivity analysis. We randomly split the whole cohort in half and repeated the analysis in each of the two sub-cohorts. To explore the possible influence of uric acid–lowering medication on the results, we excluded participants taking uric acid-lowering medication and repeated the analysis. In addition, to examine the possible impact of reverse causation, we excluded the individuals who died within the first year during follow-up. Finally, we conducted an analysis that takes into account the left truncation.We explored the differences in the levels of each of the 32 clinical indicators of biological aging among older adults with different serum uric acid levels and grip strengths by using the general linear model with adjustment for the type I error of multiple comparisons. To further delineate the relationship between uric acid and inflammatory markers of biological aging, we regressed the levels of blood hs-CRP, IL-6, and TNFR1 against serum uric acid levels and other potential confounders through restricted cubic spline regression analyses.P-value of <.05 was considered statistically significant. We used SAS version 9.4 software  for analysis.In this study, a Supplementary Materials and MethodsSupplementary FiguresSupplementary Tables


In patients with mechanical aortic and mitral valves and left ventricular (LV) tachycardia (VT), catheter ablation is technically challenging due to the limited access to the LV. Promising new alternatives to radiofrequency ablation include pulsed-field electroporation, percutaneous or surgical sympathetic neuromodulation, and noninvasive stereotactic radioablation therapy (SBRT). We herein describe the effect of SBRT as a bailout therapy on the management of a challenging VT case in the presence of double left-sided mechanical valves. Several operators have reported on the application of non-conventional techniques for VT ablation, including transventricular septal puncture, transmechanical valve, transcoronary venous, and transapical approaches.. Due to his previous double valve surgery, we planned and performed an epicardial VT ablation via a lateral thoracotomy . Electroanatomic mappings  showed scar regions containing local abnormal ventricular activities (LAVAs) in the inferolateral wall of the LV . Despite epicardial LAVA ablation, after five months, recurrent VT episodes with similar exit sites from previously delineated scar regions recurred under amiodarone, mexiletine, and sotalol therapies. We also transiently switched off the CRT device to exclude the possible lead-related VT, as there are some controversial data concerning the proarrhythmic or antiarrhythmic potential of CRT therapy.10 As all available cardiologic therapeutic strategies failed to free the patient from VT recurrence, we decided to implement SBRT as a therapy of last resort after discussions in our group and with the patient and his relatives. In the next step, positron-emission tomography-computed tomography (PET-CT) showed hypometabolic scar areas in the inferolateral walls corresponding with previous electroanatomic maps . A four-dimensional (4D) CT scan  with 10 respiratory phases was performed for radiotherapy planning using an alpha cradle and a chest board for immobilization after an eight-hour fast. After transferring the CT images to the radiotherapy planning system , an average-phase CT (avgCT) was created to evaluate cardiac and respiratory movements. After the fusion of PET-CT and avgCT images using the RT planning software  , an inferolateral hypometabolic scar region with the guidance of electroanatomic mapping was created as the internal gross target volume (IGTV). To overcome any uncertainties during positioning, motion, and therapy, a 5-mm safety margin was added to the IGTV for obtaining the final planned target volume (PTV) . Before treatment delivery, re-imaging with cone-beam CT was performed for comparison and alignment of images with simulation images. All treatment procedures were handled by a team of electrophysiologists, radiation oncologists, nuclear medicine specialists, and radiation physicists. Radiotherapy was given using a linear accelerator device . A total dose of 25 Gy was delivered in a single fraction to the PTV in 7.5 minutes to be targeted by at least 95% of the given dose. Despite rare hemodynamically stable slow VT episodes responding to antitachycardia pacing, a significant reduction in VT episodes was observed within the first eight months after radioablation therapy . No abnormal device parameters nor acute or chronic adverse effects were detected at 10 months. At present, the patient is being followed up with at the outpatient clinic.A 58-year-old man with two mechanical valves in mitral and aortic positions was referred after multiple appropriate implantable cardioverter-defibrillator shocks despite oral amiodarone and mexiletine therapies. He had nonischemic, valvular, dilated cardiomyopathy with an LV ejection fraction of 15% and had undergone implantation of a cardiac resynchronization therapy (CRT) device 10 years prior. His documented monomorphic VT suggested a lateral mid-LV exit 13 potentially keeping ventricular arrhythmias quiescent while awaiting heart transplantation,14 as was done in the current case. Because of its high precision and target conformity, it can deliver a high dose of radiation to a specific area in tissue without significantly affecting the nearby tissues.18 Indeed, the radiobiology of this treatment when applied to noncancer myocytes is limited, but endothelial vacuolization is a well-described effect of radiation.19 There have been studies that have investigated single-fraction whole-heart irradiation in animal models, and these demonstrated dose-dependent myocardial degeneration and fibrosis progressing from the epicardial tissue to full transmurality in the months after irradiation at doses of 20 Gy and higher.21 Histopathologic findings in the human myocardium after SBRT for recalcitrant VT have also provided radiobiological mechanisms of acute cellular injury during SBRT for VT, which may have an antiarrhythmic effect before the onset of fibrosis.22 These data suggest that SBRT can also be used as a relatively acute antiarrhythmic palliation in patients with electrical storm.21 Nonetheless, the optimal dose regimen has yet to be elucidated, and the long-term efficacy and toxicity of SBRT remain unsettled. Before more data on efficacy and safety are obtained, it could be offered as a “bailout” procedure after failed endo- and/or epicardial catheter ablation.23 The current case suggested that the noninvasive SBRT was applicable as a potential salvage treatment option for patients with double mechanical valves with dosage at 25 Gy providing the safest short-term profile. A recent systematic literature review summarized that VT was targeted with reduction in the number of episodes beyond 85% during follow-up, with an encouraging short-term safety profile.24 Nevertheless, the same analysis revealed significant heterogeneity in the available study designs, limiting the clinical evidence on the efficacy and safety of SBRT.24 Moving forward, randomized clinical trials will be essential to establish the safety, efficacy, and comparative effectiveness of this new and promising modality.23The growing burden of ventricular arrhythmias and their significant morbidity and mortality rates demand new effective therapeutic approaches based on a given patient’s triggers, comorbidities, and underlying pathology. Mechanical prosthetic aortic and mitral valves impede either a retrograde aortic or transseptal approach to the LV endocardium. SBRT, delivered in a single dose of 25 Gy, may serve as an alternative or palliative therapy for otherwise untreatable patients with refractory VT and electrical storm who are otherwise ineligible for catheter ablation,


Tumor volume largely determines the success of local control of borderline resectable and locally advanced pancreatic cancer with current therapy. We hypothesized that a tumor-mass normalized dose of magnetic nanoparticle hyperthermia (MNPH) with alternating magnetic fields (AMFs) reduces the effect of tumor volume for treatment.n = 5) and treated groups having small  or large  tumors. We assessed the clinical feasibility of this approach and of pulsed AMF to minimize eddy current heating using a finite-element method to solve a bioheat equation for a human-scale multilayer model.18 female athymic nude mice bearing subcutaneous MiaPaCa02 human xenograft tumors were treated with MNPH following intratumor injections of 5.5 mg Fe/g tumor of an aqueous suspension of magnetic iron-oxide nanoparticles. Mice were randomly divided into control (Compared to the control group, both small and large MiaPaCa02 subcutaneous tumors showed statistically significant growth inhibition. Conversely, there was no significant difference in tumor growth between large and small tumors. Both computational and xenograft models demonstrated higher maximum tumor temperatures for large tumors compared to small tumors. Computational modeling demonstrates that pulsed AMF can minimize nonspecific eddy current heating.MNPH provides an advantage to treat large tumors because the MION dose can be adjusted to increase power. Pulsed AMF, with adjusted treatment time, can enhance MNPH in challenging cases such as low MION dose in the target tissue and/or large patients by minimizing nonspecific eddy current heating without sacrificing thermal dose to the target. Nanoparticle heterogeneity in tumors remains a challenge for continued research. Pancreatic cancer is the fourth leading cause of cancer death in the USA, with a 5-year survival rate of less than 10%, among the lowest for all cancers . TreatmeTumor size is a key prognostic feature for LAPC and BRPC treatment affecting survival –32. LargHyperthermia 40–45 °C) given concurrently with CRT is being reexamined as a combination treatment to improve local control of many solid cancers ,39. Init–45 °C givia magnetic hysteresis loss . We. We67]. database . Homogendatabase . Constandatabase . Pancreareported  for AMF The role of pulsed AMF, that is, duty cycles, to reducing eddy current heating was based on previously reported small animal study . The dutThe goal of this computational study was to understand how to minimize the nonspecific eddy current heating without affecting the thermal dose deposited in the tumor. Clinically challenging scenarios were simulated by using an AMF setting above the permissible limits, that is, p < 0.005) for both treatment groups, relative to controls. Conversely, tumor growth between the small and large tumor MNPH treatment groups was not statistically significant (p = ~0.05).Measured maximum MiaPaCa02 intra-tumor temperatures for a 20 min AMF exposure are shown in 3 of the tumor and fixed AMF conditions Temperature distribution at the end of 20 min heating for a tumor volume normalized MION dose of 5 mg Fe/cm3 of the tumor for 100, 50, 33.3 and 25% duty-cycles are shown in Temperature distributions for a total AMF-on time of 20 min at constant AMF conditions, Clinical approaches to treat BRPC and LAPC are poorly defined . Large tMinimal thermal dose requirements are often difficult to achieve in deep tumors because of challenges to control energy deposition. MNPH offers the potential to address this challenge because the MIONs, embedded within the target, heat from within and the total amount of energy deposited depends on the amount of MIONs embedded in the tumor. AMF power modulation controls the heat produced by the MIONs, thereby providing energy control with appropriate temperature data. Furthermore, multiple MNPH heat treatments can be performed after a single image-guided injection of MIONs, because they tend to remain within the tumor –51,54.H × f). Certainly, there are additional biological and environmental variables, for example, tumor type, size-dependent physical properties of the tumor, injection rate and volume, etc.; however, total heat energy deposited into a tumor ultimately depends on the power and duration of heating. With increased nanoparticle content, there is increased power given all other conditions are fixed. We hypothesized that MNPH reduces the influence of tumor size on treatment outcome by enabling a tumor volume-normalized increase of heating power. While the thermal rationale for such an approach is straightforward, the biological effects may be complex. Further, when scaling to human sizes nonspecific heating from AMF-induced eddy currents becomes a challenge. Therefore, we tested this hypothesis in two separate but related experiments: (a) a pilot mouse study using two different tumor volumes to test effects of volume-normalized MNPH on tumor growth; and, (b) computational studies accounting for human-scale tissues and tumors, with eddy current heating.We sought to ascertain in a pilot mouse study and human-scale computer simulations if MNPH offers the potential to reduce the effect of tumor volume for treatment. The motivating rationale is that for MNPH, the thermal dose deposited in the tumor depends on several interdependent variables – the total MION dose, their heating rate, and AMF parameters (3) and large (0.3 cm3) tumors were 0.83 mg Fe and 1.7 mg Fe, respectively  was limited to <0.5 cmHuman-scale simulations predicted similarly higher temperatures in large tumors with volume-normalized MNPH ,b). ThisWhile computational models provide valuable insight, several model limitations reduce the clinical relevance of the results. Uniform MION distribution in the tumor was assumed instead of a more realistic or non-uniform distribution to reduce the non-linearity of the computational model. The role of various MION distributions based on the histology  to delivIn the computational studies, we considered (constant) blood perfusion due to the microvasculature and small vessel structures, and ignored the heat sink effect from large blood vessels to reduce computational complexity. LAPC tumors generally exhibit low blood flow, thus making MNPH better suited for favorable treatment(s) . Neverth3 of the tumor was tested in human-scale computational models [Nonspecific eddy current heating is a limiting factor for the translation of MNPH to humans to treat deep tissue tumors ,59. Pulsl models –55. Pulsl models . Such teIn summary, we propose modulated power heating of MIONs using temperature feedback to minimize eddy current heating and to address principal challenges of MNPH. Additional studies are required to understand the biological consequences of tumor size in the context of combined MNPH and CRT, taking into account MION spatial heterogeneity in the tumor. Future studies should be directed toward the use of patient image-based geometries with temperature-dependent tissue properties to develop treatment-planning systems for MNPH with multi-point thermometry. In the long-term, wider acceptance of MNPH in a clinical application depends on a clear demonstration that its inclusion significantly enhances treatment response and patient survival.Tumor volume normalized MNPH offers the potential to reduce the adverse effect of tumor size on treatment outcome, as predicted by heat transfer simulations. Results obtained from pilot mouse studies demonstrated modestly higher temperatures were achieved and sustained in larger tumors, however, this did not lead to significant tumor growth inhibition. Inherent limitations of small animal models for such studies and spatial heterogeneity of MIONs in tumors continue to present challenges. From the physics of heat transfer and computational modeling, it is clear that large tumors are candidates for this approach with MNPH due to the high MION dose and low heat conduction mediated loss to the surrounding tissue compared to small tumors. Pulsed AMF presents a promising approach to enhance MNPH in challenging clinical situations by minimizing nonspecific eddy current heating without sacrificing thermal dose to the target, provided accurate spatial thermometry, and treatment duration is adjusted. Further computational studies with human voxel models and experimental studies using tissue-equivalent gel phantoms and large animal models are required to rigorously test the potential for pulsed AMF applications and refine them for the clinic. Successful clinical translation of this approach will facilitate the treatment of challenging locally advanced pancreas cancer.


Based on guidelines for cardiovascular risk assessment among non-cancer populations, depression and anxiety can be seen as risk factors for CVD, on top of cardiotoxic cancer treatment and traditional CVD risk factors among cancer survivors. Increased inflammation can be a shared potential pathophysiological mechanism, as higher levels of inflammation  are known associates of depression and anxiety. In turn, increased inflammation is involved in the pathogenesis of CVDs. Furthermore, both cancer and cancer treatment including chemotherapy and radiation can lead to elevated levels of inflammation. We will therefore examine whether the relation between depression and anxiety with inflammatory markers among patients with either CVD or cancer is different from those with both conditions.The TweeSteden Mild Stenosis (TWIST) study among patients with non-obstructive coronary artery disease , a type of ischemic heart disease, previously reported a significant association between depressive symptoms and increased inflammation (measured by high-sensitive (hs)CRP). Of the included NOCAD-patients, 6% had a history of cancer. The TWIST patient sample was therefore used to explore whether the association between depression and elevated inflammation (hsCRP) was similar for NOCAD-patients with and without a history of cancer.The association between depressive symptoms and increased hsCRP levels is stronger among NOCAD-patients with a history of cancer than among NOCAD-patients without a history of cancer. Furthermore, whereas this relation is mediated by lifestyle factors among NOCAD-patients without cancer, the association remained significant after adjusting for BMI, smoking, and physical activity among NOCAD-patients with a history of cancer.The stronger association between depression and hsCRP among NOCAD-patients with a history of cancer indicates that there may be an additive or synergistic effect of having NOCAD and cancer for general inflammation and possibly depression. •Depression and anxiety as potential risk factors for CVD among cancer patients.•Depressive symptoms are related to increased hsCRP levels among patients ischemic disease.•Depressive symptoms are stronger related to increased hsCRP among patients with ischemic disease and cancer.•Among ischemic patients with cancer, the association is not mediated by lifestyle factors. A multiCurrent clinical guidelines for cardiovascular risk assessment among non-cancer populations highlight the importance of depression and anxiety as risk factors, with estimates at the same level as traditional CVD risk factors such as hypertension, due to consistent findings that these psychological factors increase the risk for incident CVD . ResearcThe TweeSteden Mild Stenosis (TWIST) study among patients with non-obstructive coronary artery disease , a type of ischemic heart disease, previously reported a significant association between depressive symptoms and increased inflammation (measured by high-sensitive (hs)CRP) . The aut2ClinicalTrials.gov (NCT01788241).Details on data collection have been published elsewhere . In shor2.1Depressive symptoms  and anxiety (HADS-A) were measured with the two 7-item subscales of the Hospital Anxiety and Depression Questionnaire, with scores ranging from 0 to 21. Blood was collected in 10ml vacutainers for routine clinical assessment of hsCRP in serum using the Cobas c502 analyzer. CAD-disease severity was categorized as number of vessels with wall irregularities indicative of stenosis. Diagnostic source was dichotomized into patients being included via CAG or CT. Information on comorbid conditions were extracted from medical records. Those with a previous cancer diagnosis were categorized as NOCAD-patient with a history of cancer versus those without. Additionally the number of co-morbidities (not including cancer) were coded as none, one or two, or more co-morbidities. Cardiac medication was categorized and recoded into a medication count variable (0–7). Self-report and medical records were used to determine BMI and current smoking status. Physical activity was measured with one item and recoded into being ‘active’ or ‘inactive’.2.2HsCRP data were ln-transformed. Patient characteristics stratified by NOCAD-patients with versus without cancer were compared using chi-square or t-tests. To examine whether the association between depression or anxiety with hsCRP was similar for NOCAD-patients with and without a history of cancer hierarchical multivariable regression analyses were run with the interaction term cancer∗depression/anxiety and its main effects. Covariates were added to the model in four additive blocks . First, 3In total, 547 NOCAD-patients were included . Thirty-three patients (6%) had a history of cancer. NOCAD-patients with compared to those without a history of cancer were on average older (66 years vs 61 years). With respect to the other covariates  groups did not differ. Moreover, scores on hsCRP, depression and anxiety were not different between both groups.Multivariable analyses showed a significant interaction for depression with cancer in all four models . RelatinExploratory stratified analyses were performed repeating multivariable hierarchical analyses for those with and without a history of cancer separately . Given t4and cancer for general inflammation and possibly depression. This could be due to cancer (treatment) increasing inflammatory levels (The association between depressive symptoms and increased hsCRP levels is stronger among NOCAD-patients with a history of cancer than among NOCAD-patients without a history of cancer. Furthermore, whereas this relation is mediated by lifestyle factors among NOCAD-patients without cancer, the association remained significant after adjusting for BMI, smoking, and physical activity among NOCAD-patients with a history of cancer. The stronger association between depression and hsCRP among NOCAD-patients with a history of cancer indicates that there may be an additive or synergistic effect of having NOCAD y levels  or elevay levels . It can Results of this study should be interpreted in light of the following limitations. First, only 33 patients had a history of cancer. Nevertheless, different associations for both subsamples were reported. Furthermore, no clinical cancer characteristics were available like type of cancer diagnosis, years since cancer diagnosis, and received cancer treatment, whereas we know that these factors increase levels of inflammation . Third, None.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Behavioural medicine is characterised by findings for the effectiveness and efficacy of complex behaviour change interventions. Comparatively, scant attention has been paid to key intervention components or mechanisms of action. Evaluating relationships between process variables (fidelity) and intervention effects is central to addressing this imbalance. Accordingly, in the current study, we sought to explore the magnitude and direction of effect between fidelity predictors (dietitian adherence and competence) and intervention effects  during the intervention phase of a real-world, stepped-wedge evaluation of ‘EAT: Eating As Treatment’.n=194) conducted after dietitians (n=18) were trained in EAT. Sessions were coded by trained, independent, coders using a study checklist, the Behaviour Change Counselling Index (BECCI) and items from the Cognitive Therapy Scale-Revised (CTS-R). Patient nutritional status was measured using the Patient-Generated Subjective Global Assessment (PGSGA).The EAT clinical trial was conducted within five major Australian hospitals located in Queensland, Western Australia, Victoria and South Australia between 2013 and 2016. EAT is a dietitian-delivered health behaviour change intervention designed to reduce malnutrition in head and neck cancer (HNC) patients undergoing radiotherapy. Dietitian adherence and competence ratings were derived from a 20% random sample of audio-recorded dietetic consultations , dietitian adherence to behaviour change counselling  and competence in delivering behaviour change counselling  were significant predictors of patient nutritional status. Dietitian adherence and competence ratings were higher during consultations with intervention patients at greater risk of malnutrition.Dietitian adherence to a written nutrition plan .This study is a process analysis of a stepped-wedge randomised controlled trial prospectively registered on the Australian New Zealand Clinical Trials Registry (The online version contains supplementary material available at 10.1186/s13012-021-01118-y. Contributions to the literatureA central limitation of the complex behaviour change literature is that evaluations tend to focus on effectiveness and/or efficacy with comparatively less attention paid to key process variables including intervention fidelity.Within a real-world evaluation of a complex behaviour change intervention, we found evidence that dietitian adherence and competence is greater when working with more challenging patients.By addressing a longstanding limitation within the literature, this study makes an important contribution to the science of fidelity, including how dietitian adherence and competence may influence intervention outcomes within real-world clinical settings.Fidelity is a multi-component and multidimensional construct  that is Cognitive behaviour therapy (CBT)  and/or mIntuitively, it may be reasonable to hypothesise that the more faithful a clinician is to delivering an intervention ‘as intended’ (i.e. greater levels of adherence and/or competence) the more beneficial the intervention will be. However, evidence regarding the relationship between fidelity and outcome is limited and complex , 28. Forβ = −1.53; confidence interval = −2.93 to −0.13 [Accordingly, we recently applied published recommendations –4 to theto −0.13 ). Furtheto −0.13  confirmeto −0.13 , and (b)to −0.13 . In lighto −0.13  in the eadherence to the EAT intervention and the nutritional status of intervention patients.Examine the magnitude and direction of association between objective ratings of dietitian competence in delivering the EAT intervention and the nutritional status of intervention patients.Examine the magnitude and direction of association between objective ratings of dietitian In the current paper, we explore the potential functional elements of EAT by examining the relationship between dietitian adherence and competence ratings and patient nutritional status in a randomly selected sample of intervention participants. Given the limited, and often contradictory nature of the literature, we make no predictions regarding the potential direction of effect. Rather, the current analysis is exploratory and aims to:The current paper is derived from data collected during the intervention phase of the EAT clinical trial , conducted between 2013 and 2016 within five major Australian hospitals located in Queensland, Western Australia, Victoria and South Australia. This research was conducted in accordance with the National Statement on Ethical conduct in Human Research . FurtherInclusion criteria , 35 for n=9) had completed postgraduate level training in nutrition and dietetics (including masters or postgraduate diploma in nutrition/dietetics). Experience working with HNC patients ranged from a few months to more than 20 years .Eighteen oncology dietitians employed by the study sites were identified (via self and/or head of department selection) to undergo training in the EAT intervention. All intervention dietitians had attained bachelor level qualifications. Half  and a follow-up ‘booster’ workshop . EAT training was delivered by the same facilitators  as part of an overall package designed to support systems level change .To support flexible integration throughout dietetic consultations , EAT is informed by motivational and behavioural principles Fig. .Fig. 1EMI is used throughout consultations to elicit and reinforce patient reason(s) for maintaining adequate nutrition, the performance of helpful nutrition-related behaviours and to collaboratively identify pertinent nutrition-related goals. A written nutrition planner is used to simplify, document, review and reinforce patient goals. An objective measure of nutritional status is provided via the conduct of a standardised nutrition assessment.The “EAT to LIVE” conversation see Fig.  integratn=196) and after (n=194) training in EAT [n=47). Inter-rater reliability was, on average, ‘substantial’ [Fidelity assessment in the EAT clinical trial was conducted using a randomly selected 20% sample of audio-recorded dietetic consultations conducted before , tantial’  , we used the ‘interpersonal effectiveness’ item from the CTS-R . This itDue to the paucity of brief, validated tools available at study inception to assess competence in behaviour change counselling, the CBT competence item from the CTS-R  was modiParticipant nutritional status was measured on four occasions  using the Patient-Generated Subjective Global Assessment (PGSGA ). This iData analysis was conducted using the IBM Statistical Package for the Social Sciences (SPSS) for windows, version 26.0 (2019).To allow for evaluation of within-dietitian, between-patients effects of fidelity on treatment outcome; adherence and competence scores assigned to each consultation were used to generate average adherence and competence ratings for each dietitian sampled during the intervention phase. For the study checklist, dietitian adherence scores for each item were generated by calculating the proportion of their consultations coded ‘yes’ for that skill. The total BECCI scores assigned to each consultation were averaged to generate a mean BECCI adherence score for each dietitian. Average scores for the CTS-R interpersonal effectiveness item and CTS-R competence item were also produced to generate mean ratings of interpersonal effectiveness and competence, respectively, for each dietitian. For each predictor variable, intervention participants were assigned the score of the dietitian they saw in the sampled consultation(s). When an individual participant had sessions sampled from multiple dietitians, individual dietitian scores were averaged to produce an overall score for each of the predictors.n=156) with at least one dietetic consultation randomly selected for inclusion in the fidelity sample (n=107) were compared to intervention participants not included in the fidelity sample (n=49) using independent samples t tests, chi-square or Fisher’s exact test, as appropriate. Linear mixed model regressions were used to analyse associations between the nine fidelity predictors and the dependent variable of patient nutritional status. Predictors were analysed separately to avoid interactions between them. The model utilised unstructured covariance and included the following: cluster level variable of site , individual level variables of baseline PGSGA , tumour site and stage , calendar time  and assessment interval . The model included a random individual level intercept to account for the repeated measures on individuals over assessment moments and a random coefficient for assessment moment to allow for heterogeneity in subject specific trends. The alpha level was set to p=0.05.Baseline characteristics of intervention participants . 107 intervention participants (68%) were represented in the fidelity sample. The average number of coded sessions per participant was 2 (range = 1–6). The demographic and clinical characteristics of patients included in the fidelity sample were largely comparable to those who were not sampled, with the exception of fewer radiotherapy fractions received and poorer baseline nutritional status . Dietitian adherence to behaviour change counselling  and dietitian competence  were also found to be significant predictors. Amongst intervention patients , participants whose dietitians used either the nutrition planner or behaviour change counselling skills more frequently than other dietitians, or who had a dietitian who was more skilful in intervention delivery, demonstrated higher PGSGA scores .Of the nine fidelity predictors , three were found to be significantly related to the nutritional status of intervention participants Table . From thWe found evidence that dietitian adherence and competence were inversely related to patient nutritional status in a sample of HNC patients enrolled in the intervention phase of the EAT clinical trial. Aligned with published differentiation outcomes , signifiHow then, do we interpret these results within the context of the intervention being effective compared to randomised controls, and clinician adherence and competence being significantly higher amongst intervention dietitians? Taken together with evidence for null , 30, 31 Two hypotheses have been proposed regarding the direction of this effect . FirstlyConsistent with this second hypothesis, an evaluation of motivational enhancement therapy (MET)  demonstrWithin the current analysis, two of the EAT intervention features previously shown to differentiate intervention from control sessions   Randomly Selected for Inclusion in the Fidelity Sample.Additional file 2: Table 2. Inter- and Intra-Rater Reliability for Intervention Recordings.


Leontopithecus chrysomelas), an endangered primate inhabiting the Atlantic Forest ofsouth Bahia, is only known to use shaded cacao (Theobroma cacao)agroforests within thematrix. We report on the use of a rubber plantation by a group ofgolden-headed lion tamarins between August 2013 and January 2014. Thegroup used the rubber plantation on 16 of the 22 observation days (73 %),and we recorded behaviours such as eating, grooming and sleeping, consistentwith the use of the area as a home range. We also observed associations withWied's marmosets . The locations of group sightings were notuniformly spread across the entire area of the rubber plantation, suggestingpreferred use of certain areas. The presence of resources such as jackfruits(Artocarpus heterophyllus) and epiphytic bromeliads may be attracting both species to theseplantations. In addition to shaded cacao plantations, rubber plantationswith the appropriate structure may be a viable option for increasing forestconnectivity for both species in south Bahia, reconciling economic rubberproduction with primate conservation.In a landscape fragmented by agriculture, the extent towhich forest-dwelling primates can use the matrix between fragments can becritical for their long-term survival. So far, the golden-headed liontamarin ( The resulting landscapeof smaller forest fragments embedded within a generally inhospitable matrixrepresents particular challenges to animals, especially renderingmatrix-intolerant species more vulnerable to extinction . Matrix permeability critically determines dispersal betweenfragments, which in turn is essential for maintaining a sufficient level ofgene flow and genetic diversity among small fragmented populations .Forest-dwelling primates are particularly sensitive to the effects ofanthropogenic forest fragmentation, with many species experiencingpopulation decline or extinction . Loss ofhabitat due to agricultural expansion is the principal threat to primatepopulations worldwide, with livestock farming and ranching constituting thesecond most important threat in the Neotropics . Yethigh human population growth and poverty rates in primate-range countries,as well as global market economics, increase the likelihood of continuedland-cover changes, forest loss and degradation . Documenting the ability of primates to use the matrix betweenfragments and identifying agricultural land-use practices compatible withprimate survival, reproduction and/or dispersal across the landscape isimperative for developing guidelines for landscape management that reconcileprimate conservation with subsistence of local communities .Leontopithecus chrysomelas) are frugivorous group-living primates of theAtlantic Forest of south Bahia (Brazil) that are classified as endangered and underthreat from habitat loss, fragmentation and degradation . The landscape in south Bahia (Brazil) is a mosaic of Atlantic Forestremnants embedded within an agricultural matrix dominated by shaded cacao(Theobroma cacao) agroforests, locally known as cabruca . Other economically important crops arepresent within the matrix, namely bananas (Musa paradisiaca)and rubber (Hevea brasiliensis), in addition tolesser quantities of coconut palm trees (Cocos nucifera) and manioc (Manihot esculenta) .Golden-headed lion tamarin home ranges can encompass mature and degradedforests, in addition to cabruca . To date, no studies havereported the species using any other type of vegetation within the matrix,although the use of non-monoculture rubber plantations is suspected byformer researchers in the area . Given that thelong-term survival of this species may depend on its ability to use thematrix between fragments across its geographic range, this study aimed toinvestigate this potential use of rubber plantations.Golden-headed lion tamarins ,soursop (Annona muricata), pepper (Piper nigrum),bananas and ephemeral crops such as manioc and garden vegetables.The farm alsoincludes a 30-year-old rubber plantation of approximately 2.5 ha surroundedby secondary forest patches, agricultural plantations and open fields. Manyof the older rubber trees bear epiphytic bromeliads of various sizes.Additional trees, such as cacao, banana, jackfruit (Artocarpus heterophyllus) and guava (Psidium guajava), areinterspersed with the rubber trees .The fieldwork was conducted on a 29.4 ha privately owned farm, Fazenda SantoAntônio , we employed a trained field assistant to start searching daily forgroups of golden-headed lion tamarins on the farm. We recorded theirbehaviour using the following categories: travelling, remaining stationary,foraging for fruit, eating fruit, foraging for flowers, eating flowers, foraging foranimals, eating animals, socialising, resting and “other”, as describedin the ethogram in Raboy and Dietz (2004). From August 2013 through January2014, we conducted ad libitum observations to identify groups ofgolden-headed lion tamarins. To facilitate habituation and monitoring, wecaptured a group of three golden-headed lion tamarins on 28 September 2013in a degraded forest patch adjacent to the rubber plantation, usingplatforms armed with Tomahawk live traps .We recorded the following information at 20 min intervals: GPS location ofthe group (using a handheld GPS 92Xs unit); habitat type (rubber plantation);advanced, medium or initial secondary forest; open or regenerating fields; and agricultural areas; inaddition to ad libitum observations on behaviour. We did not calculate thetotal time the group spent in each vegetation type because of a possiblebias as a result of the process of habituation.Group locations were subsequently entered into ArcGIS 10.4.2 and plotted ona georeferenced image of the study area downloaded from Google Earth Pro(image date: 27 May 2010). We further added layers with additionalinformation on the location of property borders as obtained from theowner's legal registration documents, and the location ofdifferent natural vegetation types and agricultural areas as identified onthe ground.3Between August 2013 and January 2014, we spent 103.5 h in the field, 69.28 hof which were in the presence of the group . Wesaw the group in the rubber plantation on 16 of 22 observation days (73 %)during which we were able to establish visual contact .Additional vegetation types used were initial, medium and advanced secondaryforest, and a regenerating field.Syagrus sp., Family Arecaceae) at thenorthern edge of the rubber plantation, bordering a passion fruit plantation.On 17 occasions (77 % of observation days), we were able to determine thegroup's sleeping site in the morning or evening. In 16 of these 17 occasions(94 %), the group used one particular individual palm tree locally knownas “catulé”  together with the group in the rubberplantation on 10 of 16 sightings (63 %), occurring either in the rubberplantation or in the small patch of degraded forest located to the north ofthe rubber plantation . We observed the group ofgolden-headed lion tamarins using both this northern edge of the rubberplantation, where the palm tree sleeping site is located, and the area alonga central line running north to south through the rubber plantation. We alsoobserved the group in a patch of advanced secondary forest to the southeastof the rubber plantation encountering another group of golden-headed liontamarins just across the border on the neighbouring property. We recordedthe group eating in a jackfruit tree in the centre of the plantation. Weadditionally observed allogrooming, feeding and scent-marking behaviourduring waking hours in the rubber plantation, in addition to hiding andtravelling.We saw Wied's marmosets , further investigation is needed to confirm thispattern. We are currently following this and two more groups to study howthey use rubber plantations spatially  and to obtain detailed information on their resource use andbehaviour.cabruca agroforests . Being predominantly a frugivore, the species' diet variesbetween areas, reflecting differences in floristic composition and plantdensity; this indicates that the species adapts easily to changes in fruitavailability . The extent to which the availabilityof sufficient sleeping sites and/or foraging sites limits its capacity forexploring altered habitats is as of yet undocumented. Therefore, maintaining aforest mosaic that includes patches of forest providing these resources isconsidered important . The rubber plantation in thisstudy is relatively old (approx. 30 years) and infrequently managed throughannual removal of undergrowth. With respect to potential resources forgolden-headed lion tamarins, several of the older rubber trees bearepiphytic bromeliads, providing potential microhabitats for insect foraging. Bromeliads are listed as principal foraging sitesat all study areas where golden-headed lion tamarins have been observed. Although we did not record our study group foraging inbromeliads in the rubber plantation during the observation period describedhere, we observed this behaviour at a later time. We suspect the lack ofbromeliad foraging during the study period to be due to the habituationprocess, which frequently caused the group to hide, usually in bromeliads,and made the visualisation of feeding and foraging behaviour more difficult.Golden-headed lion tamarins have long been thought to depend on matureforests for survival, due to their requirement of resources such as epiphyticbromeliads for foraging and tree holes for sleeping . Morerecent studies have reported the species being able to survive and reproduce insecondary forests, including Tapirira guianensis; Oliveira et al.,2010) and jackfruit trees. Jackfruit, an exotic species introduced inBrazil in the 18th century, is widely distributed along the Brazilian coast. Many animal species consume its fruits, includingLeontopithecus chrysomelas; the consumption of jackfruit has been observed at all sites inthe ombrophyllous forest where this primate has been studied .In addition to bromeliads, the rubber plantation contains some native fruittrees from plants included in the species' diet . The present study demonstrates that such systems may also beused by golden-headed lion tamarins in the fragmented forests ofsouth Bahia. Cacao is the main economic product of Bahia, particularly so inthe municipalities within the species' distribution range(with 547 722 ha destined for production), followed by bananas. However,rubber constitutes the third-ranking crop in terms of area reserved forharvesting , with 33 521 ha of land destined for rubberproduction in Bahia, approximately one third of which is located within thedistribution range of the golden-headed lion tamarin . Ineconomic terms, rubber offers the additional benefit of guaranteeing asteady monthly income for farmers, since the trees provide a dailyharvestable flow of latex in contrast to cacao which is harvestedseasonally, thus providing an income during only a few months of the year. Rubber can be an important additional crop,particularly for farms too small to produce enough cacao to generate incomefor an entire year. In addition to shaded cacao plantations, rubberplantations with a structure that facilitates use by groups of golden-headedlion tamarins, either as a corridor or an extension of their home range, mayconstitute a land-use type that ensures functional connectivity betweenforest fragments for golden-headed lion tamarins, reconciling localdevelopment and conservation while adding value to rubber production andincreasing the available habitat for these endangered primates.


Hepatitis B surface antigen (HBsAg) clearance is regarded as the ideal endpoint for antiviral treatment in terms of drug withdrawal safety and improvements in prognosis. However, the overall rate of HBsAg clearance is low and differs based on treatment method and course. The recent application of combined and extended treatment strategies have improved the HBsAg clearance rate, and several patients achieved HBsAg clearance in clinical treatment. In addition, the durability of and clinical outcomes after HBsAg clearance have become the focus of both researchers and clinicians. This article reviews HBsAg clearance in terms of accessibility, durability, improvements in prognosis and relevant advances. Chronic hepatitis B virus (HBV) infection is a severe public health problem, and it is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) , 2. WithHBsAg clearance occurs spontaneously or via antiviral treatment in CHB patients. The most commonly used drugs are nucleos(t)ide analogue (NA) and pegylated interferon (Peg-IFN). NA drugs include entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). The 2018 AASLD guidelines recommend Peg-IFN, ETV, or TDF as the preferred initial therapy for adults with immune-active CHB. It also suggests that alanine transaminase (ALT) levels be tested at least every 6 months for adults with immune-tolerant CHB to monitor for potential transition to immune-active or immune-inactive CHB . The 201Two large meta-analyses reported spontaneous clearance of HBsAg in 2019. Zhou et al.  analysedThere are few large or conclusive studies on the clearance of HBsAg after NA treatment, and some of these studies are single-centre retrospective studies. Kim et al.  reported10 after delivery. These patients were treated with ADV plus Peg-IFN for 96 weeks. They found that 26.7% (8/30) achieved HBsAg clearance.Various studies showed that the clearance rate of HBsAg ranged from 2.1 to 20% in patients treated with Peg-IFN –19. MostThese controlled studies indicate that extended treatment, combined treatment with NA and Peg-IFN or extended treatment with combined treatment improved the rate of HBsAg clearance. Due to the different characteristics of patients and the different strategies and courses of antiviral treatment in these studies, the clearance rates were different to some extent. Therefore, on the basis of previous studies, we proposed that Peg-IFN treatment should be more individualized and should not be limited to a fixed course. Prolonged treatment with a fixed target and indefinite course of treatment may improve treatment effectiveness. In addition, there was another study of a special population. Cao et al.  evaluateWhen patients with HBeAg-positive CHB achieve a satisfactory antiviral treatment endpoint , the clinical recurrence is 20–40%, and the virological recurrence can be as high as 80–90% after drug withdrawal , 29. BecThere is no unified definition of recurrence after HBsAg clearance or conversion, and most studies defined recurrence as the reappearance of HBsAg or HBV DNA. One study recently  reportedHBeAg status should also receive attention in the pursuit of HBsAg clearance. The clearance of HBsAg in most patients is based on HBV DNA suppression and HBeAg seroconversion, but a few patients exhibit different HBsAg response patterns, such as HBsAg clearance without HBeAg seroconversion. Only HBsAg clearance based on HBV DNA suppression and HBeAg seroconversion is safe for drug withdrawal .HBsAg clearance is the ideal endpoint for antiviral treatment, but the ultimate goal for CHB patients is to reduce the risk of HCC and improve prognosis. Whether the ideal endpoint is associated with significantly favourable clinical outcomes has become a clinical focus. Liu et al.  performeThese related studies provide clear recommendations that patients who achieve HBsAg clearance have favourable clinical outcomes compared to patients who achieve only HBV DNA suppression and HBeAg seroconversion. HBsAg clearance leads to biochemical, virological and liver histological improvements, and it significantly reduces the risk of HCC. However, HCC may occur after HBsAg seroclearance despite it being the ultimate treatment endpoint recommended by current guidelines. The risk factors associated with HCC include the presence of cirrhosis, male sex, and age ≥ 50 years at the time of HBsAg clearance . Closer These high-risk patients should be re-examined in a timely manner even if HBsAg clearance is obtained. These results also suggest that achieving a functional cure early in the absence of cirrhosis results in a better prognosis , 53.In conclusion, HBsAg clearance may be pursued as the ideal treatment goal. Combined treatment with NA and Peg-IFN or Peg-IFN add-on therapy and prolonged treatment lead to a higher rate of HBsAg clearance, especially in special populations, such as postpartum patients and IHCs. The drug may be safely withdrawn by consolidation therapy after HBsAg clearance, and clearance is sustainable, with an overall recurrence rate of approximately 10%. Consolidation treatment and high anti-HBs levels are protective factors against recurrence, but patients with a history of drug resistance and S-region variation must be constantly monitored. Patients who experience HBsAg clearance have a significantly decreased HCC incidence and favourable clinical prognosis, and patients without baseline cirrhosis have a significantly lower HCC incidence and better long-term prognosis than patients with cirrhosis. Therefore, it is feasible to pursue HBsAg clearance, and we emphasize the importance of obtaining HBsAg seroclearance early.Notably, most of the infected individuals had a fairly low chance of a cure with the currently available antiviral drugs. However, novel therapies aimed at functional cure are under active development, including HBV core protein inhibitors, drugs targeting cccDNA, siRNAs targeting viral transcripts, and immune modulators with different modes of action . These d


Venous thromboembolism (VTE) is a common disease amongst hospital patients. Within acute hospitals, there are well established protocols for risk assessment and prevention of VTE via mechanical and pharmacological prophylaxes.In psychiatry, assessment of VTE risk is more commonly overlooked despite many inherent risk factors which are unique to acute psychiatric admissions; including antipsychotic medications, physical restraint, catatonic states, and poor nutritional and hydration status[1]. The risk is compounded in older adult psychiatric patients, in which both patient and admission-related risk factors can act synergistically.Anecdotally, it was reported that VTE assessments were not being completed and documented on the electronic patient record system. Our aim was to introduce a physical VTE risk assessment to attach to paper drug charts, which would act as a prompt for junior doctors, and serve to increase rates of completion.A baseline retrospective audit of all patients admitted to the older adult inpatient ward over an 11-week period (05/08/2019~20/10/2019) was undertaken. The number of completed electronic VTE risk assessments at admission, and at 24 hours post-admission were calculated.Subsequently, a new paper VTE risk assessment proforma was developed, combining the Department of Health VTE risk assessment tool[3] with several VTE risk factors associated with psychiatric patients . Education was provided to the ward doctors, and regular assessments of VTE risk was incorporated into the weekly MDT meetings.A re-audit was completed to assess the completion rates of the new paper VTE proforma. A snapshot style audit of all inpatients on the ward on Thursday 24th February 2020 was performed.The baseline audit included 23 patients admitted during the 11-week period, consisting of 21 men and two women. The mean age was 74 years. Three patients  had their VTE and bleeding risk assessed on admission.Following the implementation of a new VTE risk assessment proforma, the re-audit showed that all 19 inpatients  had a completed assessment. Although none of the patients required mechanical prophylaxis, one patient was receiving ongoing treatment for pulmonary embolism.VTE is a preventable disease, which historically has been under-recognised by psychiatric doctors. The introduction of a paper risk assessment proforma increased completion from 13% to 100%. It also prompted regular review of VTE risk during the weekly MDT meetings. This intervention may reduce the incidence of VTE-related pathology on the ward.


N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is a multi-stage autoimmune-mediated disease associated with a multitude of neuropsychiatric and dysautonomic features. Orofacial dyskinesias are frequently associated with this condition and manifest as abnormal movements of the orofacial musculature. These involuntary movements may result in significant trauma to the oral and maxillofacial complex including the avulsion of the dentition and orofacial lacerations.Anti-We describe the course of two female patients with anti-NMDARE in whom significant involuntary self-inflicted maxillofacial trauma was suffered despite the use of complex parenteral sedation regimens. The application of traditional maxillomandibular wiring techniques and pharmacologic strategies, including botulinum toxin, to immobilize the mandible were initially unsuccessful. These difficulties led to the fabrication and wire-based fixation of a patient-specific acrylic oral appliance that maintained the mandible in a depressed position and mitigated all lateral and protrusive movements.These cases illustrate the first known successful use of an appliance-based therapy for managing orofacial dyskinesias in the anti-NMDARE patient population through an adaptation of traditional maxillomandibular fixation techniques. This approach eliminated further orofacial trauma and afforded physicians with safer means to manage and assess patients afflicted with this condition during their protracted intensive care unit admissions. N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is a multistage autoimmune disorder primarily affecting adolescents and young adults [N-methyl-d-aspartate (NMDA) receptor, composed of NR1 and NR2 subunits that bind glycine and glutamate, respectively, is critical in normal neural network formation and synaptic plasticity [1 (IgG1) antibody crosslinking of the NR1 subunit which leads to the internalization of the receptor and its depletion from the synapse [1 antibodies in cerebrospinal fluid (CSF) or serum [Initially described as the presence of teratomas in a clinical setting of psychiatric syndromes in 2005, anti-g adults . The preg adults . The N-masticity . The mec synapse . In prog synapse . In late synapse . T2-weig synapse , 10. Ele synapse . In some synapse . Ultimator serum , 14. UnfDuring protracted hospital admissions in the setting of anti-NMDARE, significant oral and maxillofacial trauma may occur as a result of orofacial dyskinesias. These injuries include complex intraoral and facial lacerations and tooth avulsion which may result in significant hemorrhage and wound infection. To date, there is a scarcity of literature describing an effective and reliable management strategy for orofacial dyskinesias in this patient population. While other dyskinetic manifestations of this process are potentially mitigated with a variety of pharmacologic agents, there is only one case report describing the successful management of orofacial dyskinesias in a single patient with anti-NMDARE using botulinum neurotoxin serotype A (BoNT-A) . UnfortuThis paper describes the use of a novel oral appliance designed to manage and prevent recurrent oral and maxillofacial trauma resulting from uncontrolled orofacial dyskinesias in patients diagnosed with anti-NMDARE. This appliance is rapidly fabricated and can be effectively utilized for extended periods of time during prolonged ICU admissions.To mitigate the need for increasingly complex anesthetic regimens and to prevent further oral and maxillofacial trauma, an oral appliance with several mechanical and functional design features was constructed to manage orofacial dyskinesias secondary to anti-NMDARE Fig. a–c. The We have effectively used this device in five female anti-NMDARE patients ranging from 23 to 34 years of age for between three and  eight months duration who were at risk for significant oral and maxillofacial trauma secondary to orofacial dyskinesias. The described appliance was simple to manufacture and rapidly installed utilizing methods germane to any oral and maxillofacial surgery (OMFS) service. The application of this device affords safer patient management and assessment in conjunction with sedative medications by critical care physicians. Furthermore, its installation mitigates further orofacial trauma thereby decreasing the potential for oral and maxillofacial wound infection and bleeding episodes while eliminating the need for increasingly complex prosthetic rehabilitation following recovery. Below, we discuss two representative examples which chronicle the clinical course of the initial patients affected by anti-NMDARE who were referred to our OMFS service.A 23-year-old nulliparous woman with a past medical history significant for mild asthma initially presented to a peripheral community hospital in an agitated state with manic symptoms. She was treated for a psychiatric disorder with haloperidol, olanzapine and electroconvulsive therapy (ECT) without any improvement. The patient developed fever, rigidity and tongue-biting movements and was intubated and sedated shortly after admission. A lumbar puncture (LP) was performed revealing the presence of anti-NMDA receptor antibodies confirming the diagnosis of anti-NMDARE. MRI as well as computed tomography (CT) and positron emission tomography (PET) of the head demonstrated no discernable abnormalities. Multiple EEG examinations revealed an extreme delta brush pattern. Screening ultrasound (US) in addition to CT and MRI studies of the thorax, abdomen and pelvis failed to reveal the presence of a teratoma. A trial of intravenous immunoglobulin (IVIG) and methylprednisolone did not result in improvement and the patient was transferred to the ICU at the Toronto Western Hospital (TWH) approximately one month following her initial hospital presentation. Seven cycles of plasma exchange (PLEX) and three cycles of rituximab were administered without any change in patient symptomatology or EEG findings. A tracheostomy and percutaneous endoscopic gastrostomy (PEG) were performed in anticipation for prolonged ventilatory support and ICU admission. Due to refractory symptoms, the patient underwent a bilateral laparoscopic salpingo-oophorectomy, revealing the presence of a mature cystic teratoma associated with the right ovary. Several pharmacologic regimens were unsuccessful in suppressing the patient’s severe dyskinetic movements involving the orofacial region and extremities including tetrabenazine, quetiapine, haloperidol, olanzapine, botulinum toxin deposited within the masseter muscles, and deep sedation with propofol and hydromorphone. Multiple complications were encountered during the patient’s admission including a coagulase-negative staphylococcal bacteremia and ventilator-associated pneumonia.One major complication during this admission was an episode of significant oropharyngeal bleeding. This event occurred secondary to uncontrolled orofacial dyskinesia-induced trauma involving the avulsion of the mandibular central and lateral incisors and a significant laceration of the right anterior tongue which required the transfusion of packed red blood cells Fig. a. To preA previously healthy nulliparous 25-year-old woman presented to a peripheral community hospital with new-onset right-sided twitching, generalized tonic–clonic seizures, confusion and hallucinations. CT imaging of the head was negative for structural abnormalities, while US imaging of the pelvis revealed a mass associated with the left ovary. Initial treatment with phenytoin, propofol, valproic acid and clobazam was ineffective and necessitated patient transfer to TWH. Upon arrival, the patient exhibited  irregular movement of all limbs and non-purposeful eye movements as well as lip smacking and chewing motions which were initially managed with clonazepam and clonidine. CT and MRI studies of the brain did not reveal structural lesions nor parenchymal, leptomeningeal or dural enhancement. The patient was intubated and, shortly thereafter, luxated the right maxillary and mandibular central and lateral incisors resulting in marked hemorrhage requiring consultation with the OMFS service Fig. a. After Patients diagnosed with anti-NMDARE often suffer from significant involuntary self-inflicted maxillofacial trauma secondary to severe orofacial dyskinesias. We describe the application of a novel oral appliance to manage orofacial dyskinesias in anti-NMDARE patients with several custom mechanical and functional design features. While we demonstrate the efficacy of this appliance in reducing the incidence of oral and maxillofacial trauma, it is not a replacement, but rather, an adjunct for the judicious use of sedative medications to mitigate ataxic movement in this patient population during their hospitalization.Orofacial dyskinesias are regarded as a characteristic clinical presentation of anti-NMDARE that can result in significant morbidity if not adequately controlled , 18. DesDespite the prolonged installation of an oral appliance which drastically altered the vertical dimension of occlusion (VDO), clinical assessment of patients treated in this fashion during their consultation for oral rehabilitation after discharge revealed no evidence of TMJ internal derangement. Currently, there is a dearth of well-designed studies which investigate the effect of large changes in VDO and the development of symptoms suggestive of temporomandibular dysfunction (TMD). More subtle changes in VDO have, however, resulted in only transient and mild discomfort in the TMJ region which was unlikely in these cases as our oral appliance was designed in a manner which promoted maximum occlusal stability through significant coronal contact .Classic wire-based MMF techniques were initially ineffective in establishing occlusal stabilization as they could not completely terminate lateral and protrusive movements in this patient population despite the presence of the majority of their dentition and a stable occlusion. The authors recognize that other methods for occlusal stabilization are available and may have included the use of intermaxillary fixation (IMF) screws or cementation of vacuum-formed splints. Unfortunately, in the setting of maxillofacial trauma, IMF screw failure is generally noted after approximately one month posing a considerable aspiration risk and cement-retained vacuum-formed splints are unable to adequately immobilize unstable mandibular fractures , 25. As While the advent of this appliance in relation to managing orofacial dyskinesias in anti-NMDARE patients may appear extraneous given the myriad of critical medical complications associated with this disease process, its importance cannot be overstated. The placement of our oral appliance eliminated the need for management of ingested or aspirated teeth, infection or sepsis, or bleeding episodes requiring transfusion secondary to involuntary self-inflicted oral and maxillofacial trauma. The use of this appliance also afforded a copacetic clinical appearance, easing the anxiety of visiting family members caused by the otherwise alarming degree of dyskinetic jaw activity, especially in those cases where orofacial trauma had already manifested. Overall, the clinical benefit of the appliance allowed for transient weaning of sedative medications to facilitate patient assessment following both medical and surgical therapy without risk of further oral and maxillofacial trauma during lengthy hospitalizations. Our limited experience with this patient population cannot be directly extrapolated to all patients with oral dyskinesias. However, in conjunction with the support of an ICU and immunotherapy with or without tumor ablation, oral appliance therapy was critical for a positive outcome in these patients with significant orofacial dyskinesias secondary to anti-NMDARE.


The coronavirus disease 2019 (COVID-19) pandemic has disrupted health systems worldwide and threatened the supply of essential medicines. Especially affected are vulnerable patients in low- and middle-income countries who can only afford access to public health systems.Soon after physical distancing and curfew orders began on 15 March 2020 in Kenya, we rapidly implemented three supply-chain strategies to ensure a continuous supply of essential medicines while minimizing patients’ COVID-19 exposure risks. We redistributed central stocks of medicines to peripheral health facilities to ensure local availability for several months. We equipped smaller, remote health facilities with medicine tackle boxes. We also made deliveries of medicines to patients with difficulty reaching facilities.Τo implement these strategies we leveraged our 30-year partnership with local health authorities in rural western Kenya and the existing revolving fund pharmacy scheme serving 85 peripheral health centres.In April 2020, stocks of essential chronic and non-chronic disease medicines redistributed to peripheral health facilities increased to 835 140 units, as compared with 316 330 units in April 2019. We provided medicine tackle boxes to an additional 46 health facilities. Our team successfully delivered medications to 264 out of 311 patients (84.9%) with noncommunicable diseases whom we were able to reach.Our revolving fund pharmacy model has ensured that patients’ access to essential medicines has not been interrupted during the pandemic. Success was built on a community approach to extend pharmaceutical services, adapting our current supply-chain infrastructure and working quickly in partnership with local health authorities. Before this time, the revolving fund pharmacy scheme used a pull-based supply system whereby medicines were supplied to 85 peripheral health facilities throughout western Kenya based on drug order requests from those health facilities. However, after the Kenyan government enacted physical distancing guidelines and curfew requirements, we switched to a push-based supply system to support more rapid availability of medicines during this health crisis. We developed three context-specific strategies to ensure a continuous, timely and secure supply of essential medicines to patients throughout western Kenya. We present the available data on 33 essential medicines in 14 therapeutic categories.The first strategy was the creation of decentralized warehouses in peripheral health facilities. In response to the physical distancing directives, staff of the revolving fund pharmacy scheme worked in partnership with appropriate county health authorities to determine the types and quantities of medications, as well as a delivery plan for essential medicines. Before the COVID-19 pandemic, the majority of the revolving fund pharmacy scheme’s medications were stored in a central pharmacy warehouse. After March 2020, we decentralized the medication supply by redistributing the central stock of essential medications for chronic disease management  and acute ailments (such as infectious diseases) to 11 health facilities throughout western Kenya.The second strategy was to provide patients with safer access to essential medicines. As of 15 March 2020, patients with chronic disease needs were encouraged to limit visits to hospitals. In response, staff of the chronic disease management programme increased the time between follow-up clinical visits. The change in follow-up interval was communicated by the clinicians to patients and the staff of the revolving fund pharmacy, who then modified the quantity of medications provided to each patient. Thus, we could easily refill patients’ long-term medications without unnecessarily exposing patients or clinicians to the risk of COVID-19. We converted many of the health facilities in the chronic disease management network into sites where medicine tackle boxes containing a full complement of chronic disease medications were provided to assist staff with dispensing. These facilities were the smallest ones, located in very rural areas, where chronic disease medications have traditionally not been available. Medicine tackle boxes were stationed at these facilities even on days when there was no chronic disease management clinic, so that patients could come and obtain medication refills at their convenience. The clinicians in our network informed patients about the new system so that patients could correctly refill their medications at facilities equipped with medicine tackle boxes. Patients were reminded to follow all safety measures as per the health ministry guidelines, including wearing of masks and hand-hygiene. By enabling access to chronic disease medicines at the nearest health facility, we avoided the need for patients to travel long distances via public transport to reach higher-level facilities.,The third strategy was community delivery of medications. For patients who faced extra problems in reaching even their nearby health facilities , we developed a system of direct deliveries of medication to patients. Using our point-of-care electronic medical record system,The supply of these medications to facilities surged in April 2020, 1 month after Kenya’s first COVID-19 case was identified . The quaBefore March 2020, we had 11 peripheral health facilities equipped with tackle boxes. In less than 1 month after the first case of COVID-19 in Kenya, we had converted and equipped an additional 46 peripheral and rural health facilities with tackle boxes, so that more patients could easily receive their medications while minimizing COVID-19 exposure risks.As of 19 June 2020, our team has delivered medications to 264 out of 311 patients (84.9%) whom we were able to reach. All patients received a 90-day supply of medicines at each encounter, followed by a follow-up telephone call to ensure the medications were being used correctly. Currently, our team is working closely with health authorities, local COVID-19 rapid-response teams and community strategy focal personnel. The plan is for continuous drug delivery efforts, community-based portable care delivery and community-health volunteer engagement to ensure patients do not miss any treatments for hypertension, diabetes and other noncommunicable diseases.Preserving the supply of essential medicines in low-resource settings is essential to protect patients with and without COVID-19-related complications during this pandemic. Our paper describes a proactive approach to ensuring the continuous, timely and secure supply of essential medicines for public-sector patient populations throughout western Kenya . First, Box 1Community-centric and proactive strategies ensured the continuous, timely and secure supply and availability of essential medicines for public-sector patient populations during the coronavirus disease 2019 pandemic.Adaptability, flexibility and forward thinking allowed us to leverage and convert the current pharmacy network to more local medicine distribution points so that patients continued to have safe access to essential medicines.Local partnership was required to ensure an important pillar of the health system was not interrupted during this health crisis.


While current therapeutic countermeasures for acute OP intoxication significantly improve the chances of survival when administered promptly, they are insufficient for protecting individuals from chronic neurologic outcomes such as cognitive deficits, affective disorders, and acquired epilepsy. Neuroinflammation is posited to contribute to the pathogenesis of these long-term neurologic sequelae. In this review, we summarize what is currently known regarding the progression of neuroinflammatory responses after acute OP intoxication, drawing parallels to other models of SE. We also discuss studies in which neuroinflammation was targeted following OP-induced SE, and explain possible reasons why such therapeutic interventions have inconsistently and only partially improved long-term outcomes. Finally, we suggest future directions for the development of therapeutic strategies that target neuroinflammation to mitigate the neurologic sequelae of acute OP intoxication.Acute intoxication with organophosphates (OPs) can cause a potentially fatal cholinergic crisis characterized by peripheral parasympathomimetic symptoms and seizures that rapidly progress to  Organophosphates (OPs) are a group of compounds originally synthesized in the 1930s as insecticides. Throughout the 20th century, OPs were widely used to control insects in residential and agricultural settings. While their residential use has been increasingly restricted in the United States and European Union over the past several decades due to human health concerns, they remain the most widely used class of insecticides worldwide with particularly heavy use in developing countries . In the status epilepticus (SE) and death  activity . These sExperimental animal data confirm and expand these human data. SRS have been demonstrated in animals following acute intoxication with OP nerve agents or pesticides . Rats acResearch to identify pathogenic mechanisms underlying the long-term neurologic consequences of acute OP intoxication have historically focused on mechanisms responsible for sustaining seizure activity. Seizure activity has been considered the primary driver of not only immediate, but also long-term neuropathology and neurologic outcomes  because Neuroinflammation has emerged as a potential pathogenic mechanism contributing to the chronic neurologic consequences of acute OP intoxication. Similar to peripheral inflammatory responses, neuroinflammation is often critical to functional recovery . HoweverAn increasing body of experimental evidence indicates that acute OP intoxication triggers robust neuroinflammatory responses that evolve over the course of hours to months following exposure . In rat Microglial responses to acute OP intoxication tend to manifest more slowly than astrocytic responses and differ between animal models. Following acute intoxication with OP nerve agents, microglia progressively adopted the classic ameboid morphology of activated phagocytic microglia within 2–3 days and clustered around regions of severe tissue damage . In a moAcute OP intoxication also elicited pronounced shifts in the expression of inflammatory mediators. Soman upregulated transcription of the proinflammatory cytokines interleukin 1-beta (IL-1β), IL-6 and TNFα, as well as several immune cell adhesion molecules within 6 h of exposure . Some daExperimental investigations of the effects of acute intoxication with OP pesticides on inflammatory mediators have yielded mixed findings. Chemokine mRNA and protein expression was largely upregulated within 1 day after DFP exposure and altered expression patterns persisted through 28 days post-exposure . HoweverLevels of COX-2 mRNA and protein were significantly upregulated within hours of acute OP intoxication and remained elevated up to 1 week following exposure . PGE2 lein vitro , there are data suggesting a similar neuroinflammatory response may happen in humans. For example, expression of proinflammatory genes was upregulated in human astrocytes exposed to the OP pesticide chlorpyrifos in vitro . Patientin vitro , by PET in vitro . These sin vitro . WhetherNeuroinflammation as a Mechanism Contributing to the Neurologic Sequelae of Acute OP Intoxication, there is substantial experimental evidence documenting that acute OP intoxication triggers robust neuroinflammation prior to and/or coincident with the onset of long-term neurologic effects, and increased neuroinflammation can persist for weeks to months. Whether neuroinflammation is a cause of the chronic neurologic consequences associated with acute OP intoxication remains debatable. The strongest support for this hypothesis comes from studies probing a causal role for neuroinflammation in the pathogenesis of cognitive dysfunction and epileptogenesis triggered by factors other than acute OP intoxication. For example, delayed onset of cognitive deficits and SRS are observed in experimental animal models of pilocarpine- and kainate-induced SE  mitigated DFP-induced neuroinflammation, evidenced as significantly decreased activation of microglia and astrocytes, and decreased expression of proinflammatory cytokines coincident with a lower incidence, frequency, and intensity of SRS  following DFP-induced SE significantly reduced neuroinflammation and neurodegeneration in the rat brain . This try of SRS . Howevery of SRS . Adminisy of SRS .There is indirect evidence of a causal association between neuroinflammation and functional deficits downstream of OP-induced SE. Rats administered the anesthetic urethane following acute DFP intoxication had greater reduction in neuroinflammation and development of SRS compared to rats given diazepam after DFP . UrethanWhile it has yet to be definitively demonstrated that neuroinflammation mediates the long-term neurologic effects of acute OP intoxication, current evidence suggests neuroinflammation likely contributes to at least a subset of these neurologic sequelae. Additional research efforts are needed to directly investigate the role of neuroinflammation in OP-associated outcomes. The OP research community can look to analogous studies in non-OP SE models for guidance.The complex relationship between neuroinflammation and the development of long-term outcomes following SE continues to stymie therapeutic advancement. There are sufficient clinical data demonstrating that inflammatory processes exacerbate or perpetuate established epilepsy. Indeed, suppression of inflammatory pathways is efficacious in the treatment of some refractory epilepsies . Yet theThe neuroinflammatory response involves the coordinated function of numerous cellular mediators and soluble molecules. To date, SE research has generally taken a blunt approach to targeting inflammatory processes by providing therapeutics with broad anti-inflammatory activity. While there are instances in which such strategies provide therapeutic benefit , it may Similarly, neuroinflammation encompasses heterogeneous activational states of microglia and astrocytes. Many investigations that measure microglia and astrocyte activation as biomarkers of neuroinflammation equate astrocyte and microglia hypertrophy with neurotoxic outcomes; however, the morphology of microglia and astrocytes is not a reliable indicator of functional status. Activation-associated changes to their morphology have been linked to diverse functional phenotypes , includivia their unique transcriptional profiles (Single-cell transcriptomic approaches can be effectively employed to identify functional subsets of microglia and myeloid cells in the CNS profiles . Microglprofiles . Similarprofiles . The funprofiles  has not profiles , but chaThe inconsistent therapeutic efficacy of approaches that block neuroinflammation following OP-induced SE may be due to the neuroinflammatory response changing with time post-exposure. The role of inflammatory mediators following chemical-induced SE varies across the phases of acute SE, the latent period of epileptogenesis, and chronic epilepsy. In experimental animal models of chemical-induced SE, administration of anti-inflammatory therapeutics prior to SE induction exacerbated both acute seizure activity and subsequent neuroinflammation and did not decrease neurodegeneration . ConversRecent studies also hint to a similar impact of time post-SE with regards to the role of microglia. The depletion of microglia prior to pilocarpine- or kainate-induced SE exacerbated acute seizure activity , demonstThe role of microglia with increasing time after chemical-induced SE is largely undefined. Only one investigation thus far has evaluated the effects of microglial depletion post-SE on the development of SRS . MicroglWhile less frequently considered, a similar role has been proposed for astrocytes following SE in a rat model of acute sarin intoxication . ExperimThe neuroprotective vs. neurotoxic roles of neuroinflammation may continue to evolve in the weeks and months following acute OP intoxication . CollombAs discussed above, there is evidence showing that the functional role of microglia shifts over the course of the neuroinflammatory response following acute brain injury in a variety of neurologic diseases not related to seizures . These dMicroglia are known to regulate astrocytic polarization , suggestWe propose a model of the relationship between neuroinflammation and functional outcomes over time following OP-induced SE  in whichWhile rigorous experimentation is needed to validate our proposed model of the functional role of neuroinflammation following acute OP intoxication, it advocates for the evaluation of current anti-inflammatory therapeutics at more delayed times after SE induced by acute OP intoxication and other triggers. It should be noted that this proposed scheme is compatible with the Collombet framework  in that Research on acute OP intoxication has made significant advances in characterizing the long-term effects of OP-induced SE. Despite these advances, limited progress has been made in developing therapeutics that meaningfully improve long-term neurologic effects. Neuroinflammation is emerging as a potentially critical determinant of SE-associated neurologic consequences. Substantial evidence indicates that the spatiotemporal profile of neuroinflammation is consistent with a proposed role in the various neurologic sequelae linked to acute OP intoxication; however, therapeutic interventions targeting neuroinflammation in experimental animal models of chemical-induced SE have been equivocal. This likely reflects differences in the timing of therapeutic interventions relative to shifts in the functional profile of microglia and astrocytes as a function of time post-exposure. Increased understanding of the spatiotemporal profiles of functional polarization of microglia and astrocytes coupled with increasing availability of biomarkers for distinguishing their different functional states will enable more targeted therapeutic strategies and optimal therapeutic windows that preserve the protective functions and attenuate the neurotoxic effects of microglia and astrocytes.