Peripheral artery disease (PAD) is caused by atherosclerotic buildup in the lower extremities, leading to obstruction and inadequate perfusion to the peripheral vasculature. Impenetrable plaques initially treated with percutaneous vascular intervention (PVI) have led to worse secondary bypass outcomes and amputation in patients. In this case report, we discuss the importance of using magnetic resonance imaging (MRI) histology in PVI planning in a patient with critical limb ischemia. PVI attempts to recanalize the limb failed because of an impenetrable occlusion in the popliteal artery that was not identified on routine preoperative imaging. Subsequent bypass occluded multiple times eventually requiring an above-knee amputation. An MRI-histology protocol—using ultrashort echo time (UTE) and T2-weighted (T2W) sequences—that was performed prior to the index PVI identified the occlusion as a dense collagen plaque. Histology analysis of the amputated specimen confirmed the MRI finding. This imaging modality offers a novel approach to characterize plaque composition and morphology, thereby identifying lesions at greatest risk of PVI failure and potentially playing an important role in selecting the right candidates for an endovascular-first approach. PVI is mostly performed as a first-line treatment due to its minimally invasive nature and low periprocedural risks.9 To prevent these adverse events, it is imperative to accurately characterize plaque morphology preoperatively to guide patient selection for PVI. Standard imaging modalities, such as duplex ultrasound and computerized tomography angiography (CTA), limit visualization of heavily calcified vessels due to imaging artifacts and variable blood flow.11 Also, x-ray angiography only provides a 2-dimensional (2D) view of the lumen, which limits its ability to accurately characterize plaque composition.12Hard lesions are associated with poor PVI outcomes because they prevent complete guidewire penetration and increase the likelihood of vessel wall dissections, perforations, and early elastic recoil.14Significant advances in magnetic resonance imaging (MRI) using ultrashort echo time (UTE) and T2-weighted (T2W) sequences have improved 3D visualization of plaque composition without the use of contrast and radiation. These high-resolution images can enable histologic-level characterization of plaque morphology to differentiate between hard lesions, such as calcium and dense collagen, and soft plaque components in determining the feasibility of guidewire penetration during PVI planning.This paper reports a case to illustrate the importance of MRI-histology in the preoperative planning of PVIs to treat critical limb ischemia.A 64-year-old female with a history of diabetes, hyperlipidemia, hypertension, coronary artery disease, and atrial fibrillation was referred to our institution for nonhealing wounds of the right foot. The patient had been nonambulatory for the past month due to worsening rest pain in her right foot. Physical examination revealed ulcers in the right leg and toes with absent pedal pulse .14 However, these MRI findings were not available to the surgeon for preoperative planning.CTA of the lower extremities revealed a long segment of noncalcified high-grade stenosis to occlusive disease in the superficial femoral artery (SFA) , with a A decision was reached to perform an arteriogram and attempt recanalization of the lesion. Thus, the patient was brought into a hybrid suite, and a crossover technique was used to access the right common femoral artery from the contralateral groin under ultrasound guidance. Several attempts to subsequently cross the SFA lesion were unsuccessful  and led Five months later, she presented with a 1-week history of right lower-extremity rest pain and numbness and nonhealing foot ulcers due to a bypass occlusion. This was successfully treated with a covered stent. Despite optimal wound care and medical therapy, the wounds persisted and the bypass reoccluded 3 months later, eventually leading to an above-knee amputation. The popliteal artery was harvested for histological analysis and confirmed the presence of dense collagen in the plaque .15In this case, we report on the disparities between imaging modalities in characterizing arterial plaque composition and morphology. Preoperative CTA showed a noncalcified SFA occlusion that guided decision-making to perform a PVI. Failed attempts at crossing the lesion led to further vascular insult and caused critical delays in reperfusion to the limb. Subsequent bypass failure and the need for an above-knee amputation aligns with the current evidence in literature that patients obtaining bypass after failed endovascular attempts have a worse prognosis.16 Preoperative MRI-histology showed an occlusion in the popliteal segment predominantly composed of dense collagen while CTA could not make this distinction. In previous studies, occlusions with dense collagen have proven to be difficult to cross with a guidewire and were associated with higher interventional failure rates.17 In an ex-vivo study utilizing MRI-histology, chronic total occlusions composed of dense collagen with minimal calcium took significantly longer to cross or were considered completely uncrossable. Additionally, the plaques were not discernable from soft lesions on CT or x-ray angiography.13Advanced atheromatous plaques can be classified according to the accumulation of calcium and collagenous tissue with or without extracellular lipids over time.18 Soft plaque components are detectable on both UTE and T2W sequences. Hard plaque components such as calcium and dense collagen are detectable on UTE sequences but appear as void signals on T2W sequences.14 Furthermore, UTE sequences show calcium as hypointense with respect to soft tissue whereas dense collagen is isointense.13 In this case, MRI-histology showed an isointense signal on UTE and a void signal on T2W sequences, which is characteristic of a dense collagen occlusion. Evaluation of the MRI-histology images prior to intervention would have allowed the surgeon to identify additional hard plaque occlusions in the vessel with greater risk of crossing failure and to preemptively discuss treatment alternatives with the patient.The MRI-histology protocol developed by Roy et al. uses MRI signal behavior of plaque to distinguish between soft lesions, which have slower signal decay times, and hard lesions, which have faster signal decay times.There is a critical need to accurately characterize plaque morphology preoperatively in patients with PAD. The combined UTE-T2W MRI-histology protocol offers a novel approach in characterizing soft/hard plaque components and enabling prediction of PVI failures in advance. Additionally, this technique offers the potential of building an anatomical scoring system that quantifies the composition and predicts the cross-ability of CTOs to allow for better-informed treatment decision-making with patients.20 MRI also requires patients to lay in supine positions for prolonged periods of time, which can be particularly difficult for critical ischemia patients because it worsens ischemic pain.21 Furthermore, a learning curve is associated with interpreting plaque morphology using MRI-histology since it is not traditionally used for interventional planning by vascular surgeons. Nonetheless, MRI-histology offers a safe and reliable imaging modality that provides a selective advantage in characterizing plaque morphology and reducing rates of reinterventions and major amputations.Common challenges with adopting MRI in practice include long acquisition times, limited availability, and greater costs as well as claustrophobia in some patients.Atheromatous plaques composed of dense collagen are missed on preoperative imaging, as identified in this case. Consequent decisions to perform PVI often result in failure as dense collagen lesions are difficult to penetrate with guidewire. MRI-histology with UTE and T2W sequences can distinguish between soft plaque and hard plaque composed of calcium and dense collagen. This novel imaging technique offers a comparative edge in detecting PVI failures and selecting patients suited better for PVI versus open surgery in advance.


To compare the clinicopathological features and perioperative outcomes of video-assisted mediastinoscopy esophagectomy (VAME) compared to video-assisted thoracoscopy esophagectomy (VATE) in esophageal cancer.We comprehensively searched online databases  to find available studies exploring the clinicopathological features and perioperative outcomes between VAME and VATE in esophageal cancer. Relative risk (RR) with 95% confidence interval (CI) and standardized mean difference (SMD) with 95% CI were used to evaluate the perioperative outcomes and clinicopathological features.P = 0.001). The pooled results showed that VAME shortened the operation time , and retrieved less total lymph nodes . No differences were observed in other clinicopathological features, postoperative complications or mortality.A total of seven observational studies and one randomized controlled trial involving 733 patients were considered eligible for this meta-analysis, of which 350 patients underwent VAME in contrast to 383 patients underwent VATE. Patients in the VAME group had more pulmonary comorbidities (RR = 2.18, 95% CI 1.37–3.46, This meta-analysis revealed that patients in the VAME group had more pulmonary disease before surgery. The VAME approach significantly shortened the operation time and retrieved less total lymph nodes and did not increase intra- or postoperative complications. Esophageal cancer is the eighth most frequently diagnosed cancer worldwide accounting for millions of deaths each year due to its poor prognosis especially in Asian countries , 2. SurgTraditional minimally invasive esophagectomy releases the esophagus through the thoracic cavity, known as video-assisted thoracoscopy esophagectomy (VATE) . In thisSince the introduction of VAME, surgeons focused on this field have attempted to apply this technology to appropriate patients. Case series and cohort studies have been reported, while the perioperative results were not consistent or even opposed in certain outcomes –25, suchvia OVID), Web of Science and Wiley online library was performed to identify potential studies published before November 23, 2021 that explored the perioperative outcomes as well as clinicopathological features in esophageal cancer patients who received VAME compared to those received VATE. References of the included studies were manually reviewed to identify additional potential available studies. Key words and related variants were used in the search, including esophageal cancer, esophageal neoplasm, video-assisted, mediastinoscopy, thoracoscope, etc. The searching strategy was included as supplementary material. We evaluated all searched results according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)   guidelinStudies satisfying the following criteria were considered eligible for this meta-analysis.Inclusion criteria: randomized controlled trials (RCTs) or observational studies that investigated the clinical effectiveness of VAME compared with VATE; one or more interest outcomes were reported: operation time, retrieved lymph nodes, intraoperative blood loss, postoperative complications, mortality, duration of postoperative hospitalization; only studies reported in English were included.Exclusion criteria: studies without interested parameters including noncomparative studies, reviews, abstracts, case or series reports, new technical studies and letters, robot-assisted surgery was also considered ineligible.via the left cervical approach. The cervical esophagus should be exposed carefully to preserve the recurrent laryngeal nerve. Care must be taken to avoid any damage to the membrane of trachea and main bronchus when dividing the area of the tracheal bifurcation. The abdominal surgery team performed the lower esophageal and gastric dissection via a transabdominal approach either simultaneously or subsequently.The patient was placed in the supine position with bilateral lung ventilation. An incision was made through the left neck, and the cervical surgery team performed upper and middle esophageal mobilization with the video-assisted mediastinoscope Data were extracted independently by two investigators, and conflicts were adjudicated by team discussion. The following outcomes were used to compare the two surgical methods: operation time, lymph nodes retrieved, intraoperative blood loss, postoperative complications, mortality, and duration of postoperative hospitalization. Available clinicopathological features were also compared.via team discussion.The Cochrane handbook risk of bias (RoB2—2019) was used to assess the risk of bias in RCTs. Newcastle-Ottawa Scale (NOS) was employed to assess the quality level of non-randomized studies . The NOSI2 to examine the heterogeneity among studies. Statistical heterogeneity among studies was defined as an I2 statistic greater than 50%. A fixed-effects model was preferred to a random-effects model when there was no statistically significant heterogeneity. We planned to perform and examine a funnel plot, as well as Begg's test and Egger's test to explore possible publication biases (P < 0.05). Theanalysis was conducted with STATA 14.0 software .The relative ratio (RR) and standardized mean difference (SMD) with 95% CIs were calculated for categorical data and continuous data respectively. We used the Cochran chi-square test and n biases . HoweverRecords were screened from previously mentioned online databases. A manual search and inspection of the reference lists identified no additional relevant studies. After exclusion of duplications, a total of 185 studies remained. Then 166 records were immediately excluded by screening the titles and abstracts. We read the full text of the remaining 19 studies carefully, and 8 studies meeting our criteria were finally considered eligible in this meta-analysis . The ﬂowSix of eight studies were conducted in China and another two were conducted in Japan. Seven studies were retrospective observational studies, of which one was a pair-matched case-control study, and the other one was a RCT. Data from a total of 733 patients were recorded, of which 350 patients underwent VAME in contrast to 383 patients underwent VATE. Patients in the VATE group received thoraco-laparoscopic three-incision esophagectomy, namely, the McKeown esophagectomy, while patients in the VAME group received mediastinoscopy combined laparoscopy or laparotomy esophagectomy. The main data extracted from the included studies are presented in Quality assessment results of the observational studies were depicted in P = 0.966; I2 = 13.2%) or sex  in the VAME group compared to the VATE group. Patients in the VAME group had more pulmonary disease , but not other comorbidities including hypertension , diabetes  and cardiac disease   , Table 2P = 0.432; I2 = 16.1%) in the VAME group compared with the VATE group. The pooled results indicated no difference regarding tumor stage in the VAME group  or tumor location  compared to the VATE group  and less total lymph nodes  in the VAME group, but no difference in intraoperative blood loss  compared to the VATE group . No differences were observed regarding postoperative complications including anastomotic leakage, postoperative pulmonary complications , pneumonia or laryngeal recurrent nerve injury rate , chylothorax , arrhythmia and mortality in the VAME group compared with the VATE group , the results of which were consistent with each single study. Two studies reported preoperative pulmonary function, and forced expiratory volume in one second (FEV1) and FEV1/forced vital capacity were not different between groups partly because of the difference in the study disign (VAME alters the traditional surgical approach, and transthoracic operation is avoided, which is believed to play a significant role in reducing chest injury and maintaining the integrity of the thoracic cavity. Patients with poor cardiopulmonary functions unsuitable for thoracic surgery could now stand for trans-mediastinal surgery, because one-lung ventilation is omitted . From thy disign , 21.Several limitations existed in our meta-analysis. First of all, as a complex operation, outcomes of which were significant association with the surgeon's techniques, clinical heterogeneities among the studies could also affect the validity of our result, and the operation type in the VATE group was also different which inevitably increased the clinical heterogeneity. Moreover, as a new technology, this approach has not been widely applied, and only a limited number of studies with small sample sizes could be obtained for analysis, which reduced the statistical power. Furthermore, there were much difference with regard to study design and outcomes definitions populations, so the internal heterogeneity was a big obstacle to interpret the results. Last but not least, esophageal cancer treatment has changed dramatically over the time period, particularly with respect to the standardized use of induction therapy for locally advance disease, therefore confounding factors are almost certainly present.In this meta-analysis, we compared the short-term outcomes and clinical pathological features in esophageal cancer patients receiving VAME to those receiving VATE. The results revealed that the VAME approach could significantly shorten operation time, but retrieved less lymph nodes. Intro- and postoperative complications were not different between the two groups. Further prospective studies with larger sample sizes are needed to confirm and update our results.


Bove et al. who identify important experimental variables that need to be considered such as size, shape, and density differences of various human/machine force applicators, as well as tissue biomechanical differences based on tissue density and viscoelastic behavior  in designing mechanistic-oriented manual therapy studies . Three articles in this topic address central/peripheral inflammatory cytokines or immunoregulatory effects of either joint mobilization or preventative omega-3 supplementation in various preclinical pain models. Omura et al. demonstrated that ankle joint mobilization reduces nociceptive behavior, pro-inflammatory cytokines IL-1β and TNF in central  tissues, while not altering peripheral (hind paw) tissue cytokine levels in a complete Freund adjuvant induced pain model. Joint mobilization failed to reduce hind paw M1 macrophage infiltration, but did decrease M2 macrophage density after tissue inflammation . Demonstrating central and peripheral neuroimmunomodulatory effects of manually applied peripheral joint mobilization is an important step in identifying potential physiological mechanisms of decreased pain/nociception subsequent to non-pharmacological manual therapy treatment. Preventive omega-3 supplementation produced antihyperalgesic and anti-inflammatory effects in part by reducing pro-inflammatory IL-1β  and TNF  cytokine concentrations . TGF-β1, TNF, and MCP-1 cytokine concentrations were not altered, however IL-10 concentrations were reduced in hind paw muscle but not in skin tissue, as well as the prevention of an injury-induced reduction of anti-inflammatory IL-4 concentrations peripherally . Using an established rat model of forelimb repetitive strain injury  that induces sensorimotor declines, broad neuromuscular inflammation and tissue fibrosis, Barbe et al. found that massage therapy enhanced muscle anti-inflammatory IL-10 concentrations even after the repetitive injury had become fully established. Manual therapy combined with rest elicited modest improvement over rest alone in metrics indictive of neuropathy such as forepaw/forelimb agility, cold sensitivity, slow median nerve conduction velocity and neural fibrosis in repetitive strain injury animals. These results contrast with the robust preventative effects of massage therapy demonstrated previously using this same model . Combined, these preclinical studies provide support for preventative and/or early non-pharmacological interventions in minimizing early effects of pro-inflammatory response at both the peripheral site of tissue injury as well as centrally. Additional research is needed to inform longer term effects and whether the transition from acute to chronic pain can be reduced or prevented using these and/or other non-pharmacological interventions. In the sole clinical study of this Research Topic, Gevers-Montono et al. investigated changes in TNF-α urine concentrations in relation to multimodal chiropractic care . Individuals with chronic low back pain had significantly higher urine TNF-α levels compared to control levels, and chiropractic care resulted in a significant reduction in TNF-α levels accompanied by lower levels of pain and disability. Limitations of this preliminary study include a small sample size, non-standardized number and duration of treatments, and lack of a sham treatment group. Therefore, caution must be exercised in interpretating this early study measuring changes in urine pro-inflammatory cytokines associated with non-pharmacological treatment.This Research Topic is an introduction to much needed mechanistic-oriented research that can eventually inform and/or optimize non-pharmacological clinical interventions for functional improvement and pain management. This collection of articles acknowledges the complexities involved in performing mechanistic-oriented non-pharmacological research in both clinical and preclinical studies. For instance, a persuasive argument concerning application of forces using hands vs. machines is presented by Funabashi et al.) provided a novel perspective of spinal manipulative force distribution within spinal tissues. Force distributions within spinal tissues were determined during simulated spinal manipulation  delivered by a servo-controlled linear actuator to the skin overlying L3/L4 in fresh porcine cadavers. Results indicated that only a small percentage of applied spinal manipulation forces actually reach spinal structures . Of the forces reaching the spinal structures, over 96% are experienced by the intervertebral disc which is comparable to intradiscal pressures reported during daily functional activities such as walking, sitting combined with flexion, and even lower than intradiscal pressures during sit to stand movement or lifting 20 kg. Supraspinous and interspinous ligaments experienced 0.5% of mean forces, while the facet joints and ligamentum flavum experienced 3% of mean forces. Clarifying the proportion of applied spinal manipulative forces reaching deep spinal tissues along with their respective distribution will help advance our understanding of physiological mechanisms underlying this popular form of non-pharmacological treatment for spinal pain, while potentially helping to improve its clinical efficacy and safety.In the only cadaveric study of this Research Topic (Gombaut and Holmes). While most of nociceptive-related research has focused on primary pain receptors and/or afferent cortical activity distribution, the impact of efferent motor processes on sensory processing has received growing interest of late as the motor system is becoming recognized to play important roles in pain management. The primary motor cortex is extensively interconnected with descending pain modulatory regions and sensory processes of the brain. This ALE-meta-analysis article showed that the supplementary motor area has greater activity in persons with atypical afferent activity in persons with no pain vs. persons in pain, as well as above-normal efferent motor activity being associated with decreased activity in brain regions involved in affective processing. Additionally, this article provides support for four hypotheses offering additional insights into the impact of motor processes on central brain regions implicated in nociceptive processing. Looking at the other side of sensory processing offers a potentially important non-pharmacological source of analgesia, physical, and mental health.The final article in this Research Topic was a systematic review and activation likelihood estimation (ALE) meta-analysis on sensorimotor integration and perception (While mechanistic-oriented non-pharmacological research remains in developmental stages as a field of research, public interest and clinical utilization of these interventions continues to increase year over year as evidenced by nearly 30,000 views of this Research Topic in the past 8 months.WR wrote the first draft. KW and DM provided critical comments and editorial suggestions for revisions. All authors agreed on the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


TMobility decline is a major concern for older adults. A key component of maintaining mobility with advancing age is the ability to learn and adapt to the environment. The split-belt treadmill paradigm is an experimental protocol that tests the ability to adapt to a dynamic environment. Here we examined the magnetic resonance imaging (MRI) derived structural neural correlates of individual differences in adaptation to split-belt walking for younger and older adults. We have previously shown that younger adults adopt an asymmetric walking pattern during split-belt walking, particularly in the medial-lateral (ML) direction, but older adults do not. We collected  Understanding how the neural correlates of mobility change with age will help us better understand the degradation of mobility with age. A key component of mobility decline with age is a decrease in adaptability; decreased sensorimotor adaptability has been shown for older adults in both the upper limbs3 and in lower limbs locomotor tasks4. The split-belt treadmill paradigm, in which a treadmill belt under each foot moves at a different speed, forces individuals to adopt a new gait pattern5. This adaptation can be characterized by quantifying how quickly people adapt and through changes in which gait parameters9. Here we focused on identifying brain structural correlates of gait adaptation properties reflected by using the common split-belt treadmill paradigm.Mobility decline is a major concern for older adults. Many components of the human sensorimotor system degrade with age, which can shift the neural controls of mobility from being more automated , to more cognitive 10, and these contributions may change with age11. These findings have mostly been reported in the context of normal over ground walking. For example, Rosano et al reported that smaller sensorimotor and frontoparietal gray matter volumes were associated with shorter step length and longer double support times in older adults12. Additionally, Rosso et al found that higher step length variability related to less gray matter in the anterior cingulate and hippocampus, in older adults13. Hippocampal volume has been a common metric that shows an association with mobility (more volume associated with better performance)15. White matter microstructure , regardless of age, has been shown to associate with better gait performance (increased step length and less variability)16 as well as improved safety margin17, and may also be a factor in inefficient brain function during locomotion (i.e. activity in non-task relevant brain areas)18. Cortical thickness also shows associations with walking performance20, but studies that investigate cortical surface measurements in relation to mobility are limited.Different regions of the brain are thought to contribute to different aspects of mobility20. In concordance with previous reports22, older adults presented with reduced gray and white matter relative to younger adults, particularly within sensorimotor processing areas. The older adults showed a relationship of lower cortical thickness in temporal cortex, shallower sulcal depth in the frontal, sensorimotor, and parietal cortices, larger ventricular volume, and lower axial and greater radial superior longitudinal fasciculus diffusivity (adjusted for free water) with greater dual task cost during walking. In the current paper we examine on the same cohort whether these structural brain metrics are associated with split-belt walking.We recently investigated group differences in cortical surface measurements and their relationship with dual task walking performance23. People with cerebellar dysfunction exhibit a reduced ability to learn and retain adaptations such as step length asymmetry24. Moreover, transcranial magnetic stimulation has been used to show that locomotion adaptation is associated with cerebellar function25. Cerebellar transcranial direct current stimulation (tDCS) has been used in an effort to accelerate locomotor adaptation, but with mixed results. Specifically cerebellar tDCS has been shown to slow readaptation in one study26, result in no differences in readaptation between the sham and stimulation group in another study27, and to produce differing effects in initial adaptation performance based on the polarity of the stimulation27. Additionally, a recent randomized, double-blind tDCS study that suppressed the left posterior parietal cortex increased the number of steps to adapt during the initial adaptation of split-belt treadmill walking, and increased the magnitude of after effects28. The conflicting results of the few studies that have investigated the effects of brain stimulation on split-belt treadmill adaptation may be due to individual variability in stimulation responsiveness29. Moreover, these previous studies have focused on step length and time as indices of adaptation. It is unclear whether the neural correlates of ML adaptive changes would differ.Previous research with patients with brain damage or movement disorders has shed light on the neural correlates of split-belt treadmill adaptation. People with Parkinson’s disease, which largely impacts dopaminergic transmission, do not adapt their step length to the same degree as age matched controls9. Previous research supports the notion that different aspects of locomotion have different neural controls. That is, ML gait parameters likely require higher level neural control32 whereas AP gait parameters may result primarily from passive dynamics. This suggests that a gait parameter such as step length may be more passively controlled compared to a gait parameter such as step width. In our recent publication9, we showed that younger adults adopted an asymmetry in ML gait parameters during the split condition (belts/feet moving at different speeds), whereas older adults maintained symmetry. This finding suggests that the younger adults are behaving differently for a benefit, which in this case may be lower metabolic expenditure. These findings in combination with existing literature leads us to address two questions here: (1) Are there structural brain metrics that are associated with the ability to adopt asymmetry during split-belt walking; and (2) Are there different brain-behavior relationships for younger and older adults? We hypothesized that brain areas commonly associated with locomotion  would be associated with ML asymmetry, but not step length asymmetry due to its hypothesized mostly passive control. Furthermore, given the extensive literature showing more prefrontal cortical engagement in older adults11, we expected older adults to have brain-behavior relationships in different brain areas than younger adults. That is, given that older adults show activity in more of the brain during walking than young adults, their split-belt walking adaptation performance may correlate with brain structural metrics more expansively than seen in young adults.In a recent publication we reported that anterior-posterior (AP) and ML gait parameters show different adaptation effects in response to the split-belt treadmill paradigm, in addition to age differences in ML effects of split-belt walking33. Table We analyzed data from 31 younger adults  and 19 older adults  from the data set described inSubjects provided informed verbal and written consent to participate. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article. The experiment was approved by the University of Florida Institutional Review Board (IRB ID: IRB201801417). All methods were carried out in accordance with relevant guidelines and regulations.All authors provided approval for publication.baseline slow (0.7m/s), baseline fast (1.4m/s), and another baseline slow (0.7m/s) walking trial, each lasting 2 min. These trials acclimated the participants to the slow and fast walking speeds. Then we began the split trial, where the left belt was moving at the fast speed, and the right belt was moving at the slow speed, lasting 10 min. The split trial was followed by an after adaptation trial, where both belts were fixed at the slow speed to identify any aftereffects. Participants also performed a readaptation and a washout trial. The methods for this study were already described in detail in our previous publication9.We administered a treadmill warm-up lasting 5 min at participants’ self-selected speed to allow them to accommodate to walking on the treadmill. For the remainder of the walking trials, the belts moved at a fixed speed for all participants. We then stopped the treadmill before beginning the baseline walking trials, consisting of a TbbParticipants completed MRI scans in a Siemens MAGNETOM Prisma 3T scanner  with a 64-channel head coil. Structural image acquisitions included a 3D Voxelwise analyses were performed on the following brain maps: (1) cerebrum gray matter, (2) cerebellum volume, (3) cortical thickness, (4) sulcal depth, (5) gyrification, (6) fractal dimension, and (7) white matter fractional anisotropy (free-water corrected).T34). Gyrification and fractal dimension are measures of cortical complexity36. CAT12 is an automated T34. We smoothed the cortical thickness map with a 15mm kernel and the sulcal depth, gyrification, and fractal dimension maps with a 20mm kernel (recommended by34).The cerebrum gray matter, cortical thickness, sulcal depth, gyrification, and fractal dimension metrics were derived from the 37 and the Advanced Normalization Tools package . CERES is an automated, cloud-based software that extracts the cerebellum from the raw T41. Next we calculated the Jacobian determinant (modulated image) using CreateJacobianDeterminantImage within ANTs software suite, mimicking the processing steps we performed in CAT12, and multiplied this image to the transformed image to preserve the raw tissue values. Finally, we smoothed the resulting cerebellar volume image with a 2 mm kernel. We examined cerebellar total volumes (white and gray matter) in this analysis due to difficulties associated with separation of cerebellar gray and white matter. The voxel intensity values therefore have a greater range compared to the cerebrum gray matter.We applied a separate processing stream to the cerebellum using the CEREbellum Segmentation (CERES) pipeline42), the FMRIB Software Library , and custom free-water correction performed in MATLAB47. First, we performed a signal drift correction on the raw diffusion-weighted data using ExploreDTI48. Then we used FSL’s topup function to estimate the susceptibility-induced off-resonance field45). We then used the eddycuda function within FSL to correct for eddy current distortions, EPI distortions, and head movements46.Fractional anisotropy was derived from the diffusion-weighted image via a combination of ExploreDTI graphical toolbox  pipeline49 within FSL, to generate a mean fractional anistropy skeleton in common space . The free-water corrected fractional anisotropy images were projected onto the mean fractional anisotropy skeleton using nonlinear registration50. This procedure resulted in a skeletonised free-water corrected fractional anisotropy map, which we used for the current brain-behavior associations analysis.Next, we estimated the free-water fractional volume and free-water corrected fractional anisotropy using custom MATLAB code9. Here, we focus on four spatiotemporal gait parameters that inform us about balance adaption during the split-belt paradigm. These four parameters are described below in the Outcome Variables section. All of the data are represented as a change in response from the average of the baseline slow steps  from the trailing foot to the leading foot heel marker at the leading foot heel-strike.We calculated the percent change from the slow condition  to identify brain-behavior correlations. Due to limited marker supply, we used the middle of the two posterior hip markers as a proxy for the body CoM position51. Here we only consider the symmetry score during the split condition since this is where we previously identified the majority of the group differences9.34. We re-estimated all models with the Threshold-Free Cluster Enhancement  toolbox using the default 5,000 permutations52. For each model, statistical significance was established at p<.05, after family-wise error (FWE) correction. Since we included all the gait metrics in each brain metric model, multiple comparisons across the gait metrics are accounted for, and the family-wise error correction corrects for multiple comparisons across brain voxels. Significant brain clusters were anatomically identified based on the appropriate atlas for that brain metric: the Automatic Anatomical Labeling (AAL3) atlas53 for cerebrum gray matter, SUIT41 for cerebellum volume, DK4054 for surface measures , and JHU-ICBM tract atlas56 for fractional anisotropy.We tested two types of statistical models to address our two questions, for each brain metric map : (1) Are there structural brain metrics that are associated with the ability to adopt asymmetry during the split-belt walking; and (2) Are there different brain-behavior relationships for younger and older adults? All models consisted of linear models with covariates constructed in SPM12 (estimated in CAT12 for surface metrics). Therefore we had a total of 14 separate models (7 brain metric maps x 2 questions) in which we tested for a correlation between each brain metric map and the gait parameters. The distinction between models for questions 1 and 2 was in the organization of the covariates of interest (i.e. the symmetry scores). For question 1, we tested for clusters in the brain maps that shared similar correlations across both age groups, and for question 2, we were interested in the interaction of age group and the gait parameter being tested. The symmetry scores included three gait parameters that inform us about ML balance control including (1) pWe observed statistically significant associations between gray matter volume and CoM asymmetry. Greater CoM asymmetry was significantly associated with greater gray matter volumes in the brain areas shown in red in Fig. entclass1pt{minimapAdditionally, we observed statistically significant associations between cerebellum regional volumes and CoM-CoP. Greater CoM-CoP asymmetry was significantly associated with greater gray matter volumes in the cerebellar areas shown in red in Fig. entclass1pt{minimapWe observed significant associations between sulcal depth and step length. Greater asymmetry in step length was significantly associated with greater sulcal depth in cortical areas shown in red in Fig. ppWe also observed significant associations between gyrification and asymmetry of two gait parameters. Less asymmetry in step length was significantly associated with greater gyrification in cortical areas shown in red in Fig. There were no significant associations between cortical thickness or fractal dimension and any gait parameter asymmetry scores.pWe observed significant associations between white matter tract microstructure  and CoM asymmetry. Greater asymmetry was associated with lower fractional anistropy in the white matter tracts in yellow in Fig. pWe observed an association between cerebellar volume and step-CoM, that differed between groups. Specifically, younger adults showed greater asymmetry in step-CoM associated with cerebellar volume within the cluster identified in Fig. We sought to determine (1) whether any structural brain metrics showed an association with the asymmetry of gait parameters that develops particularly in younger but not older adults during split-belt treadmill adaptation; and (2) whether there were any different brain-behavior relationships between age groups. We identified several brain structural metrics that showed an association with asymmetry, but only one cluster in the cerebellum that had differential associations between age groups. Specifically, the results showed that regardless of age group, greater region specific cerebrum gray matter, cerebellum volume, free-water corrected white matter fractional anisotropy, and cortical gyrification were associated with more asymmetry in ML gait parameters. Region specific sulcal depth and gyrification were associated with step length, and a small cluster in the cerebellum had different brain-behavior relationships with Step-CoM, between groups. Our hypothesis that these associations would be in sensorimotor, cerebellar, and striatal regions was largely supported, although a few associations were also observed for brain regions outside of these areas.9. Specifically, we showed that younger adults adopted more asymmetry in ML gait parameters during split-belt treadmill adaptation, whereas older adults did not adopt this asymmetry. Based on our current understanding of the dynamics involved during human locomotion, and the constraints imposed by the split-belt treadmill paradigm, we believe that the asymmetry adopted by younger adults is metabolically more efficient as they use the passive dynamics of the treadmill belt to their advantage. In addition to these results, multiple reports suggest ML gait parameters require higher level neural control32, therefore we hypothesized that we would find brain-behavior associations for ML gait parameter asymmetry during split-belt treadmill adaptation, but not AP gait parameters (step length).To reiterate the previously reported behavioral results, the AP and ML gait parameters showed different adaptation effects in response to the split-belt treadmill paradigm, in addition to age differences in ML effects of split-belt walking57, but more recent mobile imaging studies suggest it also has a role in walking59. The gyrification results that involved the ML gait parameters indicated more gyrification in the left pars opercularis/insula was associated with more CoM-CoP asymmetry  had differing relationships with step length asymmetry. We further discuss the implications and considerations of these findings in the Considerations section.The gray matter results indicated that more gray matter in the left superior frontal gyrus was associated with more CoM asymmetry Table , and morgth Fig. , where i68 and the cerebellum has descending ipsilateral projections69. That is, the clusters that had significant associations with ML gait parameters, namely the cerebrum gray matter cluster . We were unable to test the specific biomechanical mechanism that enabled this shift due to data collection limitations, but based on our current understanding we believe that this shift requires additional activation of hip or trunk musculature. The current brain-behavior results may suggest that the slow (right) leg hip musculature is the hip that is being “controlled” to enable the ML asymmetry. Others have shown that stance leg hip proprioception affects ML balance72.Interestingly, in most of the statistically significant brain-behavior clusters identified, the peak of the clusters correspond to the input and output of the same side of the body given that the cerebrum has descending contralateral projectionster Fig.  and the ter Fig.  were on ter Fig. . These l74, and is typically activated during visuomotor adaptation78. The younger adults adopted more asymmetry, on average, which is in line with the current results that suggest a positive association in lobule V gray matter for the younger adults. The relatively minimal results supporting this hypothesis may be due to the fact that we only examined brain structure, and not also brain function. Our hypothesis was rooted in the theory that older adults compensate for reductions in peripheral and central degradation by shifting neural resources to, what are typically, non-task relevant brain regions79. However, these theories were based on functional brain measurements, not structural. Future work should investigate the link between brain structure, function, and the relationship with asymmetry of the ML gait parameters during the split condition of split-belt treadmill paradigm.For our second aim we hypothesized that older adults would have stronger brain-behavior relationships for ML gait parameters, and in different regions relative to young adults, but we only identified one cluster that showed different associations with Step-CoM asymmetry Fig. . The dat11 were based on group averages, so it is possible that there are different strategies employed by individuals that were not observed in group averages. Additionally, the behavioral variables are represented as percent change to improve the ability to compare between behavioral variables. Still, a percent change in one variable may not have the same behavioral effects as a percent change in another variable. These reasons might explain why some ML variables show associations with brain metrics, but not others. Third, we did not expect step length to have any associations with the brain metrics, but we did observe two results. However, these results conflicted with one another in that the healthier brain metric was associated with more asymmetry  in one result, and less asymmetry (gyrification) in the other. Gyrification is relatively complex to interpret, for example lower and higher gyrifcation values have been associated with improved cognitive abilities in people with Parkinson’s80.There are several considerations to keep in mind about this work. First, this is a cross-sectional study that sought to identify (1) structural brain metrics that associated with asymmetry of gait parameters; (2) structural brain metrics that differed between age groups. The relatively small sample size may have limited our ability to detect significant age group differences. Second, it is currently not clear why there would be brain-behavior associations for one ML gait parameter, and not another. Our original behavioral results described in Fettrow et alIn conclusion, we identified multiple brain metric clusters that are associated with the development of gait asymmetry during split-belt treadmill adaptation. For all of the significant brain-behavior associations that involved the ML gait parameters, more “healthy” brain metrics  corresponded to more asymmetry. The two significant brain-behavior associations that involved the AP gait parameter showed mixed relationships. This suggests that those who maintain healthy brain structure maintain a more flexible gait pattern pertaining to ML balance throughout their lifespan, and may impact the ability to adapt new locomotion patterns. It may also suggest that step length alterations may not be as influenced by structural brain changes as the ML balance parameters. This work progresses our understanding of how brain structure influences behavior, and in particular balance during walking.


The onset of cardiomyopathy is a common feature in sepsis, with relevant effects on its pathophysiology and clinical care. Septic cardiomyopathy is characterized by reduced left ventricular (LV) contractility eventually associated with LV dilatation with or without right ventricle failure. Unfortunately, such a wide range of ultrasonographic findings does not reflect a deep comprehension of sepsis-induced cardiomyopathy, but rather a lack of consensus about its definition. Several echocardiographic parameters intrinsically depend on loading conditions (both preload and afterload) so that it may be challenging to discriminate which is primitive and which is induced by hemodynamic perturbances. Here, we explore the state of the art in sepsis-related cardiomyopathy. We focus on the shortcomings in its definition and point out how cardiac performance dynamically changes in response to different hemodynamic clusters. A special attention is also given to update the knowledge about molecular mechanisms leading to myocardial dysfunction and that recall those of myocardial hibernation. Ultimately, the aim of this review is to highlight the unsolved issue in the field of sepsis-induced cardiomyopathy as their implementation would lead to improve risk stratification and clinical care. Since 2016, sepsis has been defined as life-threatening organ dysfunction caused by a dysregulated host response to infection . MeanwhiSeptic cardiomyopathy was first described in 1921—before the advent of antibiotics—by E. Romberg, in his Lehrbuch der Krankheiten des Herzens und der Blutgefäße (Textbook of Diseases of the Heart and Blood Vessels) as septische akute Myokarditis (septic acute myocarditis). It may be broadly defined as an acute cardiac dysfunction unrelated to ischemia that manifests in different ways: arrhythmias, left and/or right ventricular impairment during systole or diastole, with or without reduction in cardiac output ,6,7 Tab.Progress in cardiac imaging now makes available several parameters of cardiac performance—historically limited to ejection fraction assessment—but they have paradoxically increased the uncertainty on how to precisely define septic cardiomyopathy. Further issues challenging a global consensus on septic cardiomyopathy include: (i) the potential role of cardiovascular background as premorbid cardiac status; (ii) the need of assessing cardiac function in a setting of highly variable conditions, as determined by inotrope use, autonomic dysregulation of heart rate/arrhythmias, fluid challenge, rise in lactate and reduction in mixed venous oxygen saturation  5,6,7].,6,7.5,6,Studies on septic cardiomyopathy report a broad range of prevalence ranging from 10% to 70%. Lacking a broad consensus on definition, the epidemiology of septic cardiomyopathy remains elusive. Such a variability reflects the definition used in study designs and the burden of confounding factors: male sex, age, high lactate levels at admission and pre-existing cardiac performance . Long-teEndothelial, metabolic, and immune response abnormalities are generally involved in the pathogenesis of ventricular dysfunction and arrhythmias during sepsis, whereas the potential role of myocardial ischemia seems limited. Impaired blood flow autoregulation in coronary microcirculation and altered metabolism of lactate, free fatty acid, and glucose likely play a leading role. Septic myocytes may indeed switch their primary energy substrate from free fatty acids to glucose with detrimental effects on contractility, similarly to that observed during post-ischemic myocardial hibernation . However++) homeostasis by blunting the amplitude of intracellular currents and concentrations. Dysfunction of intracellular calcium transporters and decreased calcium sensitivity in cardiac myofilaments (due to phosphorylation of inhibitory troponin I) are cornerstones of the impaired excitation-contraction coupling. Ultimately, endotoxemia impairs sarcolemma diastolic Ca++ extrusion with consequent overload [The hyperinflammatory—not counterbalanced—response is historically reported as a paradigm of sepsis. Early clinical trials then focused on blunting inflammatory response by common anti-inflammatory drugs such as glucocorticoids, non-steroidal anti-inflammatory drugs or target therapy, with very limited results . The extoverload ,41,42,43overload ,45. The Signals regulated by the TLRs expressed on myocyte surface  lead to transcription of several pro-inflammatory cardiac depressive factors and cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α and complement anaphylatoxin C5a ,47. LV eNitric oxide (NO) is synthesized by nitric oxide synthase (NOS) in different cells of the CV system including cardiac myocytes, and it exerts important roles in maintaining tissue homeostasis by reducing oxidative stress. Indeed, via the cGMP pathway, NO regulates vascular tone, has an antioxidant effect, inhibits leukocyte and platelet adhesion to the endothelium, and increases myocardial contractility . InflammIncreased activation of the sympathetic system is a major compensatory reaction to septic-related vasoplegia. During sepsis, β-adrenergic receptors (βARs) are downregulated, and the responsiveness to catecholamines is reduced in the whole cardiovascular system ,60. WhenActivation of endothelial cells in consequence of an infective stimulus leads to the synthesis of inflammatory cytokines, increased expression of cell adhesion molecules, loss of the barrier function by glycocalyx shedding, edema, apoptosis, hypercoagulative state and vasoplegia . SeveralSepsis is characterized by altered myocardial lipoprotein metabolism and mobilization of triglycerides and free fatty acids to overwhelm the systemic suppression of energy production . PhysiolA combination of clinical, biochemical and hemodynamic parameters is increasingly described as the best approach to identify and stratify septic cardiomyopathy.Echocardiography is considered the first line approach for the global assessment of patients with septic shock. The use of ultrasound in this field has progressed over years but the application of echocardiography for diagnosis/monitoring of septic cardiomyopathy remains challenging. The dependence on loading conditions is a not overcoming intrinsic limitation for several echocardiographic parameters, which rather reflect the degree of fluid resuscitation/vascular leak  and vasoplegia/response to vasoactive drugs  . This isA rise in end-diastolic volume is common in septic shock patients—especially in those receiving large volemic replacement—and likely associated with poor outcome. The rationale for considering diastolic dysfunction in sepsis-induced cardiomyopathy relies on the upstream effect on pulmonary circulation, right heart, and finally tissue edema. However, the mining of diastolic dysfunction in sepsis cardiomyopathy remains to be elucidated. The concept of sepsis-induced cardiomyopathy is originally based on the abnormal LV function, but the risk ratio of patients with concomitant diastolic dysfunction is not yet established. In particular, the TDI-derived velocity of the mitral annulus during early diastole (e’)—considered relatively preload independent—and the ratio with the peak of trans-mitral inflow velocity (E) are substantially associated with mortality . HoweverRight ventricle (RV) dysfunction is increasingly being reported in patients with sepsis. It can be defined as a fractional area change (FAC) less than 35% or tricuspid annulus systolic plane excursion (TAPSE)—the most reproducible measure—less than 16 mm. Systolic RV pressure may also be easily calculated from tricuspid regurgitation flow. RV dysfunction is common in severe sepsis/septic shock. Its prevalence ranges from 40% to 60% at admission but significantly increase when the enrollment lasts up to 72 h. RV dysfunction correlated with longer stay in ICU, and independently associated with higher risk of both early and long-term mortality ,97,98. NThe afterload-related cardiac performance (ACP) is a relative old concept firstly introduced in 2011 and defined as :ACP (%) predicted may be calculated as a function of systemic vascular resistance (SVR):In turn, Cardiac Output (CO)In preliminary studies, ACP estimation correlates with both APACHE II and SOFA scores, even improving mortality prediction in both early and late stages of sepsis. ACP is now considered as valid prognostic marker in sepsis and septic shock, ACP values lower than 80% are associated with a higher risk of mortality in septic patients ,102. WheThe lack of a consensus definition and the uncertainties on pathophysiology of septic cardiomyopathy makes it difficult to identify and validate biomarkers of disease. Being associated with cardiac injury, troponins and natriuretic peptides rise during sepsis and correlate with the degree of myocardial dysfunction . The mecBrain natriuretic peptides (BNP and NT-proBNP) are secreted by myocardial cells in response to stretch. This would candidate BNPs as surrogate biomarkers of LV dysfunction. A significant association with both systolic and diastolic LV dysfunction was actually—but not unequivocally—demonstrated for BNPs. Preliminary data also link the rise in BNPs with RV dysfunction . HoweverThe emerging field of non-coding RNAs (ncRNAs) recently opened new scenarios for modulation of inflammation in sepsis, including sepsis-related cardiomyopathy 101. Among the wide array of ncRNA, a massive amount of experimental data concerns microRNAs (miRNAs) with good potential for clinical translation . Among tThe cytokine storm makes it difficult to identify biomarkers of sepsis cardiomyopathy across cytokines/interleukins. A single observational study has reported an association with IL-8 . SomethiThe most important goal in the field of septic cardiomyopathy might be its recognition. The lack of a consensus definition led to divergence about its clinical relevance, whereas the advance in echocardiographic technology/algorithm is worryingly—and paradoxically—tangling up the search for a general agreement. Of paramount importance for standardizing the definition of septic cardiomyopathy would be to discriminate whether this is primitive and how it can induce hemodynamic perturbances. In addition, the dynamicity of changes in myocardial function should be considered. There is also growing awareness that mild declines in cardiac performance are rather to be considered as an adaptive response. In line with these missing points, studies outlining treatment goals for sepsis cardiomyopathy are lacking. The “early goal-directed therapy” still remains the current approach, since 2001, although this was not confirmed in later clinical trials  ,113,114.


GCK mutations, and the sulfonylurea-hyperresponsiveness conferred by activating KCNJ11 or ABCC8 mutations, or loss-of-function HNF1A or HNF4A mutations, often decisively guide clinical management. In monogenic insulin-resistant diabetes, subcutaneous leptin therapy is beneficial in some severe lipodystrophy. Increasing evidence also supports use of ‘obesity therapies’ in lipodystrophic people even without obesity. In beta cell diabetes the main challenge is now implementation of the precision diabetes vision at scale. In monogenic insulin-resistant diabetes genotype-specific benefits are proven in far fewer patients to date, although further genotype-targeted therapies are being evaluated. The conceptual paradigm established by the insulin-resistant subgroup with ‘adipose failure’ may have a wider influence on precision therapy for common type 2 diabetes, however. For all forms of monogenic diabetes, population-wide genome sequencing is currently forcing reappraisal of the importance assigned to pathogenic mutations when gene sequencing is uncoupled from prior suspicion of monogenic diabetes.Integration of genomic and other data has begun to stratify type 2 diabetes in prognostically meaningful ways, but this has yet to impact on mainstream diabetes practice. The subgroup of diabetes caused by single gene defects thus provides the best example to date of the vision of ‘precision diabetes’. Monogenic diabetes may be divided into primary pancreatic beta cell failure, and primary insulin resistance. In both groups, clear examples of genotype-selective responses to therapy have been advanced. The benign trajectory of diabetes due to pathogenic The online version of this article (10.1007/s00125-022-05720-7) contains a slideset of the figures for download, which is available to authorised users. Diabetes mellitus affects around 9.3% of the world population . In the INSR)—was in 1988 )PPARG, is the master regulator of adipose tissue biogenesis, and its pharmacological activation by pioglitazone or other thiazolidinediones (TZDs) seems an obvious strategy in lipodystrophy. Many reports attest to metabolic benefits of TZDs in partial lipodystrophies , bu, buPPARGes , the second commonest monogenic lipodystrophy, which is caused by mutations in the e itself , 82. A p ligands .PPARG has been subject to ‘saturation’ mutagenesis coupled to massively parallel assay of mutation consequences. This has produced experimental evidence for the functional consequences of the large majority of possible PPARG missense mutations [PPARG loss-of-function mutation. This sets the stage for more formal testing at scale of precision TZD therapy in FPLD3, and provides a paradigm with potential applicability to many other forms of monogenic diabetes.Uniquely among genes causing monogenic insulin resistance, utations , and hasLMNA gene [Several complex syndromes feature insulin-resistant diabetes with frank lipodystrophy, or resemble lipodystrophy metabolically with lesser degrees of abnormal adipose distribution. It is reasonable to assume that the principles of management of lipodystrophy apply to these disorders. No more precision therapies are yet proven to be efficacious for metabolic endpoints, although the US Food and Drug Administration (FDA) recently licensed lonafarnib, a farnesyltransferase inhibitor that reduces accumulation of damaging fragments of lamin proteins, in Hutchinson–Gilford syndrome, a rare premature ageing disorder caused by defects in the MNA gene . As lipoMNA gene . These mFew health economic analyses of either screening for or treatment of monogenic insulin-resistant diabetes have been undertaken. The high cost of recombinant human leptin therapy  meant that economic modelling was important prior to approval of leptin therapy in lipodystrophy by the UK National Institute for Health and Care Excellence . This moMany people with potentially treatable monogenic beta cell and insulin-resistant diabetes are currently misclassified as having type 2 diabetes. An immediate priority is thus to facilitate identification of patients for genetic testing. A widely used MODY probability calculator that incorporates disease biomarkers and simple clinical data , 89 has Any attempt to screen genetically for monogenic diabetes and to intervene based on results will need to take into account the clinical penetrance of gene variants. Fully penetrant, Mendelian, monogenic disease is to some extent a self-fulfilling construct arising from ascertainment of affected patients and families based on their phenotype (in this case diabetes). It has been of great value for early phases of study of genetic disease, but in some cases has become untenable as the spectrum of genetic variation has been revealed by NGS in large populations , 92. In The importance of monogenic disease extends beyond clinically recognisable subtypes nested within diabetes populations, as NGS suggests overlap between monogenic and ‘common’ type 2 diabetes . More thMTNR1B, PPARG, SLC30A8, HNF1A, PDX1, PAM) that confer risk of type 2 diabetes that is intermediate between common SNPs and mutations causing monogenic diabetes [AKT2 and TBC1D4, both involved in insulin signalling and implicated in monogenic insulin resistance, have been described [TBC1D4 mutation carriers, some evidence for precision exercise intervention has recently been advanced [Taking one step further, the possibility that a significant portion of type 2 diabetes heritability may be attributable to rare, functional gene variants has long been mooted. This was encouraged by the limited early success of GWAS focused on commoner gene variants. Sequencing of large populations has indeed identified some rare variants


Given the growing number of prediction algorithms developed to predict COVID-19 mortality, we evaluated the transportability of a mortality prediction algorithm using a multi-national network of healthcare systems. We predicted COVID-19 mortality using baseline commonly measured laboratory values and standard demographic and clinical covariates across healthcare systems, countries, and continents. Specifically, we trained a Cox regression model with nine measured laboratory test values, standard demographics at admission, and comorbidity burden pre-admission. These models were compared at site, country, and continent level. Of the 39,969 hospitalized patients with COVID-19 , 5717 (14.3%) died. In the Cox model, age, albumin, AST, creatine, CRP, and white blood cell count are most predictive of mortality. The baseline covariates are more predictive of mortality during the early days of COVID-19 hospitalization. Models trained at healthcare systems with larger cohort size largely retain good transportability performance when porting to different sites. The combination of routine laboratory test values at admission along with basic demographic features can predict mortality in patients hospitalized with COVID-19. Importantly, this potentially deployable model differs from prior work by demonstrating not only consistent performance but also reliable transportability across healthcare systems in the US and Europe, highlighting the generalizability of this model and the overall approach. The early identification of patients at high risk for death can improve triage and resource allocation, particularly when numbers of COVID-19 cases overwhelm health systems4.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of cases of coronavirus disease 2019 (COVID-19) in nearly every country. While most patients with COVID-19 have a mild form of viral pneumonia, an appreciable subgroup develops rapid onset of severe disease. Several large national studies have demonstrated that a variable and potentially significant proportion (ranging from 5% to 70%)2. However, most models have not been tested across hospital systems and countries to determine generalizability. Few studies have included patients from multi-national cohorts. The international nature of this disease begs the question of whether models derived using data from one site or one country can be used in another. Is transportability possible if the experience of one site or country could help another make better decisions?Numerous studies have reported models using clinical data, including laboratory values, to predict patients at high risk of death for COVID-195 as an international research collaborative of nearly 300 hospitals from four countries in order to collect standardized patient-level electronic health record (EHR) data to examine the epidemiology, pathophysiology, management, and healthcare system dynamics of COVID-19. Using the 4CE data, we examined the relationship between pre-selected laboratory values6 and mortality across institutions and countries. We compared prediction models using single laboratory values at admission to a prediction model containing multiple laboratory values. Across all models, we evaluated geographical differences  among the outcome prediction models to better understand if models trained on data from one country and institution can be used elsewhere.We formed the 4CE Consortium7 across different countries during the initial pandemic period  of individual laboratory test in predicting mortality after hospital admission for COVID-19 varies substantially cross countries, the accuracy of the mortality risk prediction model is remarkably consistent between US and Europe. Further, the estimated log hazard ratios from the best-performing Cox model are largely consistent across different healthcare systems with respect to their directions and magnitudes. Third, the mortality prediction model using commonly measured laboratory tests and baseline demographic and comorbidity burden trained at healthcare systems performs well both locally and externally when transported to other sites. Interestingly, the transportability does not appear to depend on the continent or country. Taken together, the key innovation of our study that differs from prior studies is the transportability and the potential generalizability of the COVID-19 mortality prediction model that seems independent of the specific healthcare system.each participating healthcare system with local collaborators and centrally to address potential imprecision due to healthcare system-specific variations in data extraction and incompleteness of datasets . These critical quality control steps, which are often underappreciated in multi-center EHR data research, further differentiate the 4CE research efforts from other COVID-19 research efforts. Second, we observed a significant level of heterogeneity in the predictiveness of individual laboratory tests and the locally trained mortality risk models across the participating healthcare systems. The heterogeneity could result from differences in patient population, clinical practice and EHR system. To address this concern, we performed random-effects meta-analyses to account for the heterogeneity across sites. Importantly, the best-performing model showed evidence of good transportability despite of the heterogeneity.The study also has several limitations that we took measures to mitigate. First, EHR data have variable degree of intrinsic noise, missing data, and available documentation due to differences in clinical practice that contribute to differences among healthcare systems. Indeed, we found healthcare system-level  differences were greater than country-level differences. By leveraging our federated system of common EHR data elements and capturing healthcare system-level heterogeneity, the 4CE consortium is uniquely positioned to identify international differences in patient characteristics and outcomes as well as to test model transportability. To mitigate the quality issue of EHR data, we performed extensive and iterative quality controls at As the pandemic persists and new SARS-CoV-2 variants emerge, two clinically relevant questions remain unanswered: (1) does the mortality prediction model continue to perform well across healthcare systems and countries? (2) can the prediction model predict long-term mortality after COVID-19 hospitalization? To address these questions, we are planning future analyses using patient-level data at each participating healthcare system to assess the temporal trends of the model performance throughout the pandemic waves and at individual patient-level over longer period. We will revise and adapt to temporal changes in clinical scenarios. In this study, we observed that AUCs are generally consistent across genders. Since age is a significant risk factor for mortality, conditioning on the age group, the model performance for distinguishing high-risk vs. low-risk patients within the age group is expected to be lower than the overall accuracy. Further developing age-specific risk prediction models warrants further research. Beyond mortality prediction, the 4CE consortium has established a platform of harmonized data capture through its federated system with iterative and methodical expansion of data elements to enable the clinical investigation of a wide range of domains pertaining to COVID-19 such as coagulopathy and thrombotic events, acute renal failure, pediatric manifestation, neurological complications as well as the post-acute sequelae syndrome . We will apply the approach from this study to assess other prediction model transportability within our international network of participating healthcare systems.We make several noteworthy observations of clinical relevance. First, the laboratory tests predictive of mortality in patients hospitalized for COVID-19 represent the combination of acute inflammatory response  and underlying physiological function as well as the acute response of critical organ systems . These routinely collected laboratory indicators of systemic response to the SARS-CoV-2 viral infection in conjunction with easily ascertainable baseline demographic and comorbidity burden formulate a clinically deployable prediction tool of mortality risk following hospital admission for COVID-19. Second, the relatively modest accuracy of individual laboratory values in predicting mortality is likely due to its large variation within each participating healthcare system. This combination of commonly measured clinical laboratory tests dramatically improved the prediction performance over individual laboratory tests, and performed better than a larger panel of clinical laboratory tests. A key clinical insight is that clinical laboratory tests beyond the commonly measured routine tests may not inform mortality, which is the most important clinical outcome. Third, the performance of the final model was relatively stable over the hospital course and did not improve beyond the initial hospital days. This finding suggests that additional factors contribute to mortality as the hospital course for COVID-19 patients prolongs. Of particular clinical relevance, it supports the utility of commonly measured routine clinical laboratory test values  at admission to identify patients at high risk for mortality who would warrant early and aggressive intervention as well as close monitoring, particularly in the setting of limited healthcare resources.We included all patients hospitalized at participating 4CE sites with an admission date from 7 days before to 14 days after the date of their first reverse transcription polymerase chain reaction (PCR)-confirmed SARS-CoV-2 positive test result. The first admission date within this 21-day time window was considered the index admission date. Throughout this work, “days since admission” refers to this index date.Data were available from 39,969 patients from 284 hospitals (affiliated with 16 sites) across four countries: France, Germany, Spain, and the United States. See Supplementary Table Patients and the public were not involved in the design, conduct, or reporting, or dissemination plans of the research.We consider death as the main COVID-19 outcome. Death was identified via standard coding and discharge data aggregation from each site. Each partner institution used local criteria to identify in-hospital mortality.Sixteen sites representing 284 Hospitals assembled patient-level data for detailed analyses, including twelve US sites, and four international sites. Individual healthcare systems then ran separate analyses using the patient-level data within their local firewall and only reported the final analytic results to the central institution for meta-analysis. A schematic of our workflow is presented in Fig. Most sites used the open source i2b2 (Informatics for Integrating Biology and the Bedside) software platform to obtain the data. More than 200 organizations worldwide use i2b2 for purposes that include identifying participants for clinical trials, drug safety monitoring, and clinical and epidemiological research. Those 4CE sites with i2b2 used database scripts to directly query their i2b2 repository, calculate the counts and statistics, and export the data files. The 4CE sites without i2b2 used the Observational Medical Outcomes Partnership (OMOP) Common Data Model or their own clinical data warehouse solutions  and querying tools to create the required files.6, We provided each site with a single standard Logical Objects, Identifiers, Names and Codes (LOINC) identifier for each test, but sites often needed to map tests to additional LOINC or custom codes within their EHR. We addressed barriers that arose during initial efforts to extract these laboratory values by stratifying region-specific laboratory test types to reduce extraction errors and enable standardization.We focused on nine laboratory tests that are commonly measured (missing rate <30% at most sites) and associated with mortality in patients with COVID-19 based on prior reportsWe conducted site-specific quality control. Each site ran an R script for the following additional quality control checks: consistency of the total counts of total cases across all datasets within each site, consistency between the 3-digit diagnosis codes and the ICD dictionary, and consistency of the range of laboratory data from each site with the normal range observed from all sites. Sites checked and fixed the data if their laboratory values were consistently lower or higher than the other sites or otherwise implausible.We estimated the country-level daily incidence of new patients hospitalized with COVID-19 during the study period from March 1, 2020 to September 30, 2020. Specifically, for each country, we summed the daily incidence of new patients hospitalized with COVID-19 at each site within that country per 100,000 people of the country and multiplied this by an adjustment factor, defined as the ratio between the country’s overall inpatient discharge rate and the overall inpatient discharge rate of all 4CE sites in that country irrespective of COVID-19 status. We then reported the adjusted 7-day average incidence of new COVID-19 hospitalizations per 100,000 of the country population.We divided our analysis into two parts: (1) prediction of mortality using individual laboratory values and a comprehensive algorithm derived from multiple laboratory values, comorbid conditions, and demographics available at each site and (2) comparison of these models across sites, countries, and continents.9. We used the 10-fold cross-validation to estimate the AUC when evaluating the model performance within each local site. The mortality risk prediction model was not trained at Spain because the data were not available at the time when we collected the model training results. To assess the transportability of the mortality risk prediction models across different sites, we validated the algorithm trained at local individual healthcare centers using independent dataset from remaining external sites including the healthcare center from Spain. We used random effects meta-analysis on the prediction performance measures across sites to summarize country level, continent level, and overall average performances.We evaluated the ability of a biomarker and demographics-based algorithm to predict mortality using admission data. We removed patients who died at admission. We developed mortality risk prediction models using a set of nine common laboratory tests with missing rates <30% at most sites, adjusting for demographic variables and the Charlson comorbidity index. We derived the risk models by fitting penalized Cox proportional hazards model. We evaluated the accuracy of the risk models for predicting mortality by t-days since admission based on the time-specific AUCIRB Approval was obtained at Assistance Publique—Hôpitaux de Paris, Beth Israel Deaconess Medical Center, Bordeaux University Hospital, Hospital Universitario 12 de Octubre, Massachusetts General Brigham, Northwestern University, Medical Center, University of Freiburg, University of Pittsburgh, VA North Atlantic, VA Southwest, VA Midwest, VA Continental, and VA Pacific. An exempt determination was made by the IRB at University of California Los Angeles, University of Michigan, and University of Pennsylvania.Further information on research design is available in the Supplemental MaterialReporting Summary


Vaccination has made a substantial contribution to global health improvement throughout history. The coronavirus disease 2019 (COVID-19) vaccinations have provided us with a ray of hope for combatting the ongoing pandemic and saving lives. However, following COVID-19 vaccination, a wide spectrum of cutaneous adverse effects have been observed. We report a case of dyshidrosiform bullous pemphigoid, a rare clinical variant of bullous pemphigoid, following COVID-19 vaccination in an elderly female patient. The biopsy revealed subepidermal splitting with positive direct and indirect immunofluorescence studies. Since the World Health Organization (WHO) declared it a global pandemic in March 2020, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions of people worldwide. The massive impact of COVID-19 has led to the world's largest immunisation campaign. All approved COVID-19 vaccinations in the UK meet strict standards of safety, quality, and effectiveness .The patient was a 90-year-old woman who was admitted to the hospital on 30 March 2021 with a widespread itchy eczematous rash involving the trunk and extremities, and left leg swelling. The patient was on long-term warfarin, bisoprolol, amlodipine, bendroflumethiazide, and ursodeoxycholic acid for atrial fibrillation, hypertension, and primary biliary cirrhosis, respectively. Her blood pressure medications had been initiated more than 10 years ago, and her drug list had not changed recently. The patient’s family history was unremarkable, and she had never had a skin problem before.The eruption had begun one week after her first COVID-19 vaccination (Pfizer-BioNTech) on 29 December 2020. Her general practitioner had tried hydrocortisone 1% cream, moisturiser, oral antihistamine, and permethrin 5% for suspected scabies. However, her skin condition persisted. After her second dose on 18 March 2021, the rash worsened considerably with severe itching.On examination, there were widespread eczematous rash and excoriation marks involving the trunk and extremities. The face, palm, soles, and mucous membranes were spared. Left leg swelling was observed and the patient was investigated for possible deep vein thrombosis (DVT). Histology of the skin lesion showed features of the chronic eczematous process with mild perivascular chronic inflammation, and occasional neutrophils and eosinophils. The initial clinical impression was of a post-vaccination eczematous rash; the patient was discharged on oral prednisolone after ruling out DVT, and this vaccine reaction was reported through the UK Yellow Card Scheme. On 16 May, the patient was re-admitted with severe itchy and painful large intact blisters involving the palms and soles  respectively. Circulating anti-BMZ IgG autoantibodies were detected by the indirect immunofluorescence technique Figure .Bullous pemphigoid is an uncommon immunobullous disorder that typically presents in the elderly with generalised pruritic tense blisters on urticated or normal skin backgrounds. It is caused by acquired autoimmune IgG against two hemidesmosomal antigens (BpAg 180 and 230) in patients with underlying genetic predisposition . DyshidrPrevious reports have suggested that bullous pemphigoid can be triggered by vaccination. Cases of bullous pemphigoid have been reported after the administration of tetanus , rabies Pérez-López et al. have described a case of bullous pemphigoid induced by COMIRNATY® (Pfizer-BioNTech COVID-19 vaccine) three days after the vaccination . COVID-1In our patient, the diagnosis of bullous pemphigoid was not made on the first admission due to the lack of an immunofluorescence test. Dyshidrosiform bullous pemphigoid can be reliably diagnosed based on the clinical presentation combined with histopathological and immunofluorescence results.The temporal relationship between the onset of rash and the first dose, and the worsening of rash after the second dose support the hypothesis of a possible causative relationship between the administered vaccine and the appearance of bullous pemphigoid in our patient. Similar to drugs that are well-known triggers for bullous pemphigoid, vaccinations might modify the immune response or alter the antigenic properties of the BMZ, thereby inducing this immunobullous disorder .This report draws attention to the cutaneous adverse effects of COVID-19 vaccines and the importance to detect and report these complications as the global immunisation efforts continue. Bullous pemphigoid has been reported in the medical literature following COVID-19 vaccinations. We reported a case of dyshidrosiform bullous pemphigoid, an uncommon clinical variant that primarily affects the palms and soles following the administration of the COVID-19 Pfizer-BioNTech vaccine. This immunobullous condition could be caused by the vaccine affecting body immune responses or the antigenic features of the BMZ.


Early palliative care (PC) with standard oncology care has demonstrated improved patient outcomes, but multiple care delivery models are utilized. This study prospectively evaluated the feasibility of an embedded PC clinic model and collected patient-reported outcomes (PROs) and caregiver needs.In this observational study of embedded outpatient PC for patients with advanced thoracic malignancies treated at The Ohio State University Thoracic Oncology clinic, patients received same-day coordinated oncology and palliative care visits at one clinic location. PC encounters included comprehensive symptom assessment and management, advanced care planning, and goals of care discussion. Multiple study assessments were utilized. We describe the feasibility of evaluating PROs and caregiver needs in an embedded PC model.Forty patients and 28 caregivers were enrolled. PROs were collected at baseline and follow-up visits. Over a 12-month follow-up, 36 patients discontinued study participation due to hospice enrollment, death, study withdrawal, or COVID restrictions. At baseline, 32 patients (80%) rated distress as moderate-severe with clinically significant depression (44%) and anxiety (36%). Survey completion rates significantly decreased over time: 3 months , 6 months , 9 months , and 12 months .We found that an embedded PC clinic was feasible, although there were challenges encountered in longitudinal collection of PROs due to high study attrition. Ongoing assessment and expansion of this embedded PC model will continue to identify strengths and challenges to improve patient and caregiver outcomes. Thoracic malignancies are among the most common and deadly cancers, both in the USA and internationally . BecauseMulti-disciplinary oncologic care, including palliative care referral, is an American Society of Clinical Oncology clinical practice recommendation for lung cancer . DespiteTo improve palliative care access, The Ohio State University (OSU) Thoracic Oncology Clinic established an embedded Onco-Pall clinic in September 2018. To evaluate this practice model, we conducted a prospective evaluation of feasibility as well as patient- and caregiver-reported outcomes. We report here on this experience.Conducted between December 2018 and August 2020, this was a single-center, prospective pilot study of adult patients with either a new or established diagnosis of an advanced thoracic malignancy. All patients referred to Palliative Medicine from the Thoracic Oncology Clinic were offered study participation; those who enrolled in the study were evaluated by Palliative Medicine at the Onco-Pall embedded clinic. Patients that declined study enrollment but were interested in receiving palliative care were given the option to be seen at OSU’s free-standing palliative care outpatient clinic or through our Onco-Pall embedded model in the Thoracic Oncology clinic. The Onco-Pall embedded clinic included a single-physician clinic available 2 days per week in The Ohio State University Thoracic Medical Oncology clinic. The clinic workflow is described in detail below  with advanced or metastatic cancer of the chest  receiving treatment at The Ohio State University Thoracic Oncology clinic. Both new and established oncology patients were included. New patients were defined as those who either were treatment naïve or had started treatment for metastatic disease within the last 30 days. Established patients were all patients with advanced cancer receiving anti-cancer therapy for > 30 days prior to study enrollment. There was no limit on prior therapies. Patients who were already established with outpatient palliative medicine or enrolled in hospice were excluded. Inpatient palliative care consultation prior to study enrollment was permitted.Patients were asked to identify a caregiver to participate in the trial although this was not required for patient participation. Caregivers included any support person involved in the patient’s care .This study was reviewed and approved by The Ohio State University Institutional Review Board prior to patient enrollment. Patients and caregivers provided informed consent prior to study participation.The primary intervention was referral for palliative care assessment in the Onco-Pall embedded palliative care clinic. Patients were evaluated by the palliative care physician in the Thoracic Oncology Clinic and were given information regarding the study. Patients expressing interest met with the study clinic research coordinator to undergo the informed consent process. The palliative care physician evaluation was tailored to individual patient needs, but included symptom management , advanced care planning , caregiver support, and referral for adjunctive supportive services as needed . To assess symptoms, patients and caregivers completed study assessments as described below (see study assessments).The addition of a palliative care physician in the Thoracic Oncology Clinic also involved standardization of controlled substance prescribing practices per best-practice guidelines . A contrThe Thoracic Oncology Clinic includes up to 12 exam rooms  with an adjacent infusion suite with 19 infusion chairs. Each medical oncology attending physician is supported by one or two nurses, depending on patient volume, and shares a patient care associate (PCA) with another attending physician. The Thoracic Oncology Clinic also has a dedicated medical oncology phone triage nurse and clinical pharmacist (PharmD). The on-site palliative medicine physician received support from one dedicated nurse and a shared PCA. Palliative medicine also has a shared off-site clinical pharmacist and designated phone triage nurse for palliative providers. A nurse case manager and social worker for the Thoracic Oncology team were also available to assist the palliative medicine physician with patients in the Onco-Pall embedded clinic. Medical oncology providers (physicians or advanced practice providers (APPs)) placed palliative medicine referrals per standard practice depending on patient needs. Referrals indicated preference for the Onco-Pall clinic. Patients were then scheduled for same-day visits with medical oncology and palliative medicine. The palliative medicine physician maintained an independent patient schedule with 30-min return visits and 60-minute new patient visits.On the day of the visit, patients were evaluated either during a joint visit or sequential visits, depending on patient needs. Separate nursing assessments were performed by oncology and palliative nurses at check-in. Joint visits were generally conducted for complex symptom management or goals of care discussions. Sequential visits by the palliative medicine team could be conducted either in oncology clinic exam rooms or in an adjacent chemotherapy infusion suite depending on patient schedule. Patient care questions were coordinated by direct physician-to-physician communication in the team workroom as palliative medicine shares the same workspace with medical oncology.Concerning clinical capacity, the palliative medicine physician maintained an independent clinic schedule. The number of shared versus sequential provider visits was not tracked.The primary outcome was feasibility of the embedded, palliative care model including perceived demand , clinician capacity (scheduling access for embedded visits), resource assessment , and collection of patient- and caregiver-reported outcomes. Referral rate was defined as the total number of palliative medicine referrals placed during the study period. The time to referral and changes in referral patterns are reported separately . SecondaPatients completed surveys to evaluate symptoms including depression, anxiety, and functional status. The National Comprehensive Cancer Network (NCCN) Distress Thermometer and Problem List and Functional Activity Scale (FAS) –14 surveDescriptive statistics were used to summarize demographic information with totals and percentages used for categorical data and means and standard deviations used for continuous data. Percentage data were analyzed and reported for each section of the questionnaires and summarized in figures sorted by issues of least concern to most concern. Although patients may have completed the survey at multiple time points, only the baseline responses are displayed as too few patients completed subsequent surveys to allow for longitudinal analyses. All analyses and graphs were generated in R version 4.1.A total of 40 patients were enrolled between December 2018 and September 2019. Patient demographics are detailed in Table n=24, 80%) rated their distress level as moderate-high (score ≥ 4) on the NCCN Distress Thermometer (Table >8) , particularly in the first 6 months after enrollment. In the first 3 months, only 60% of patients completed the 3-month follow-up . At 6 months, 7 out of 17 eligible patients completed surveys (41%). Hospice referrals and patient deaths were again the most common reasons for non-completion. At 9 and 12 months, 44% and 50% of eligible patients, respectively, were able to complete the surveys. The acceptability questions at 3 months were completed by 16 patients, with results indicating that patients preferred the current care model. Patients also gave feedback regarding surveys and requested “less questions.” One patient felt visits were too long.The study CONSORT diagram Fig.  details n=28) are summarized in Fig. Caregiver outcomes  & Symptom Monitoring with Triggered Referral Pathways for Thoracic Cancers,” in which patients will be able to select and answer questionnaires that are applicable to individual concerns. Additionally, MyPROfile-TC will implement cutoff scores and response flags to alert differing, individualized first points of contact based on patient responses. Communications will then follow a specific provider flow, depending on the measure, for the appropriate routes of care management. This will be a valuable tool tailored for patients with a thoracic cancer and their caregivers, with the goal of proactive, timelier responses to patient and caregiver concerns, improving quality of life with the eventual goal of decreasing the need for acute or emergent healthcare such as emergency department visits and hospitalizations. Optimizing an embedded Onco-Pall thoracic clinic using this patient-centered approach and tailoring to patients’ needs and preferences is an area of future research.One limitation of this data was the significant drop-out rate over the 12-month study period. Our baseline patient-reported outcome results indicate that attrition was related to high symptom burden, hospice referral, and death, which suggests that using a shorter time frame in collecting patient-reported outcomes from patients may be needed for most patients. For future assessments, focusing on newly diagnosed patients or those earlier in their disease course, ideally within the first 2 months of diagnosis, may provide more insight on patient-related outcomes due to increased follow-up time. Another limitation of this trial was the limited caregiver data including absence of demographics and mental health evaluations. While other studies have performed depression/anxiety assessments in caregivers, we did not include this in our pilot; it is an area of future investigation. Ultimately, our results suggest caregivers may benefit from additional support services such as psychology/counseling, caregiver support groups, or access to services such as transportation. Targeted interventions designed to improve caregiver needs and outcomes could provide great benefit to those caring for someone diagnosed with an advanced thoracic malignancy. Despite these limitations, this feasibility study provided rationale and outcomes data, which allowed us to obtain a full-time palliative care APP within the Thoracic Oncology clinic.In conclusion, we determined the embedded palliative care workflow was well-accepted and feasible in our Thoracic Oncology Clinic for providers, nursing, and patients. Referrals increased with associated improvement in patient access, but patient symptom assessment longitudinally was challenging. We plan to continue to evaluate models to improve palliative care access and improve patient and caregiver outcomes through the launch of MyPROfile-TC, specifically designed for patients and caregivers with advanced thoracic malignancies.