Autophagy is an evolutionarily conserved mechanism of cell adaptation to metabolic and environmental stress. It mediates the disposal of protein aggregates and dysfunctional organelles, although non-conventional features have recently emerged to broadly extend the pathophysiological relevance of autophagy. In baseline conditions, basal autophagy critically regulates cardiac homeostasis to preserve structural and functional integrity and protect against cell damage and genomic instability occurring with aging. Moreover, autophagy is stimulated by multiple cardiac injuries and contributes to mechanisms of response and remodeling following ischemia, pressure overload, and metabolic stress. Besides cardiac cells, autophagy orchestrates the maturation of neutrophils and other immune cells, influencing their function. In this review, we will discuss the evidence supporting the role of autophagy in cardiac homeostasis, aging, and cardioimmunological response to cardiac injury. Finally, we highlight possible translational perspectives of modulating autophagy for therapeutic purposes to improve the care of patients with acute and chronic cardiac disease. Adaptation to stress is an arduous challenge for eukaryotic cells. It involves the orchestrated action of multiple pathways to coordinate metabolic activities with nutrient availability, regulate cell cycle and proliferation, and dispose of dysfunctional intracellular elements. These multifaceted programs ultimately direct cell fate toward survival or death, with pathophysiological implications for health and disease . Among tAutophagy is rapidly activated upon stress exposure acting downstream of crucial signaling networks coordinating cell biology with environmental conditions, such as the mTOR, AMPK, GSK-3β, and Hippo pathways . MultiplAs its name (Greek for “self-eating”) implies, autophagy is mainly a catabolic process to dispose off intracellular components, typically dysfunctional/senescent organelles or protein aggregates, by proteolytic degradation into lysosomes. Different mechanisms of lysosomal cargo sequestration distinguish three types of autophagy: (i) chaperone-mediated autophagy (CMA), (ii) microautophagy, and (iii) macroautophagy. In CMA, the protein LAMP2A (lysosome-associate membrane protein 2A) recruits into lysosomes the chaperone HSC70 which selectively recognizes cargoes via KFERQ-like motifs . On the Autophagy involves the coordinated activity of a set of evolutionarily conserved AuTophagy-related Genes (ATGs)  Yamamot. It is iThe knowledge of mechanisms of cargo engulfment in phagophore/autophagosomes has sensibly evolved in the last decade. While autophagy was originally branded as a bulk recycling process, the discovery of CMA and its selectivity in target recognition somehow prompted the investigation of mechanisms of selection . NowadayBesides their original role of mediating intracellular catabolism, ATGs and autophagy machinery in eukaryotes engage in many other nonconventional functions . Some fuAtg5) determined aberrant expression of the cardiac patterning gene Tbx2 with abnormalities of chamber septation and valve development  suppresses cardiomyocyte differentiation via an autophagy-independent mechanism  in neonatal mice resulted in unrestrained autophagy that paradoxically precipitated mitochondrial dysfunction and cardiomyocyte loss (Given the elevated energy demand (6 Kg ATP/day), it is not surprising that adequate mitochondrial function is crucial for cardiac activity and implies an essential role of autophagy as a mediator of mitochondrial quality control . The firelopment . Consistelopment . Surprisechanism . As a foty acids . Notablyyte loss . These fMerCreMer,Atg5fl/fl mice) leads to the accumulation of ubiquitinated elements, affecting sarcomere structure and mitochondrial alignment, favoring the development of contractile dysfunction and left ventricular dilatation  determines defective autophagic flux and affects CMA resulting in a vacuolar myopathy of cardiac and skeletal muscle with progressive cardiomyopathy which predominantly manifests a hypertrophic phenotype  determined age-related cardiomyopathy (+) reduces SIRT1 activity and increases the acetylation of FoxO, ATG5, ATG7, and ATG8, thereby inhibiting their function to restrain autophagy  injury is still not entirely understood. A reason for this is that some conflicting results exist in the literature, as described in the following. During myocardial ischemia in mice, nutrient deprivation leads to the autophagy activation, which is accompanied by activation of AMPK and inhibited by dominant negative AMPK . LikewisFurthermore, the small GTP-binding protein Rheb activates the complex 1 of the mechanistic target of rapamycin (mTORC1) and has been identified as a critical regulator of autophagy during cardiac ischemia, in the setting of metabolic disease . Mice su108-phosphorylated Beclin1. Mechanistically, activation of Mst-1 in energy-deprived cardiomyocytes resulted in Beclin1 phosphorylation, which enhanced the interaction between Beclin1 and Bcl-2 and Bcl-xL.Autophagy during the reperfusion phase is also triggered by oxidative stress, but linked to an upregulation of Beclin 1 and considered detrimental in this condition according to some studies . In rat Impaired autophagic flux during reperfusion may represent a pathological mechanism contributing to cardiomyocyte death. In support of this, reoxygenation of rat neonatal cardiomyocytes after hypoxia increased cell death compared with hypoxia alone, which was accompanied by markedly increased autophagosomes but not autolysosomes, and impaired clearance of polyglutamine aggregates, indicating a disturbed autophagic flux . This deAs opposed to the above-described evidence for impaired autophagy or detrimental effects of autophagy in I/R injury, other studies reported cardioprotective effects of autophagy induction in this condition. Autophagy induction with rapamycin dampened I/R injury in a mechanism involving JAK2-STAT3 signaling in cardiomyocytes . LikewisIn summary, the precise cellular survival or cell death pathways in cardiomyocytes seem highly context-dependent. Autophagy during myocardial I/R injury appears as a double-edged sword, which may initially represent a cellular quality control and prosurvival mechanism, but eventually turns into a detrimental process. This might be linked to disturbed autophagosome degradation. The precise mechanisms and conditions that may turn into a detrimental outcome deserve further investigation, in view of potential therapeutic strategies to improve cardioprotective autophagic flux in the acute phase post-MI. Some preclinical data have indeed shown the beneficial effects of autophagy induction by limiting adverse remodeling in permanent LAD ligation models, e.g., by treatment with trehalose . MoreoveWhile the previous section focused on the role of autophagy in cardiomyocytes during cardiac ischemic stress and reperfusion injury, it is also important to consider the role of innate immune cells in this context. Here, we will focus on mechanisms that are relevant for maintaining cardiac homeostasis in steady-state conditions, as well as in post-myocardial infarction inflammation and subsequent repair processes.+ macrophages. Advanced imaging techniques including light sheet microscopy and confocal microscopy revealed that cardiomyocytes are surrounded by on average five cardiac macrophages and form direct interactions. Cardiomyocytes thereby eject dysfunctional mitochondria and other cargo through an autophagosomal process into particles called exosphers. The uptake of these exosphers by the surrounding macrophages is mediated by Mertk and prevents extracellular waste accumulation and inflammasome activation, which is crucial for cardiac homeostasis. Ischemic cardiac stress by permanent LAD ligation increased mitochondrial ejection via exosphers.To maintain the high cardiac energy demand required for contraction and relaxation, cardiomyocytes contain a large number of mitochondria. The maintenance of a pool of healthy mitochondria is essential for sustaining normal cardiac performance. Therefore, mitochondrial recycling and quality control are tightly controlled via mitophagy. However, given that cardiomyocytes are subjected to intense mechanical stress and metabolic demands, the question arises of how these postmitotic cells with virtually no turnover are able to preserve cellular homeostasis. In a recent study, Atg7 in neutrophil progenitors resulted in an accumulation of immature neutrophils in the bone marrow. More detailed metabolic analyses further revealed that neutrophil differentiation was accompanied by a shift towards mitochondrial respiration with the downregulation of glycolysis, which was blunted in autophagy-deficient neutrophils. Adding exogenous FFAs to Atg7-deficient neutrophil precursors restored their differentiation, suggesting that the oxidation of FFAs produced by autophagy provides the necessary ATP for neutrophil differentiation. A different study demonstrated that autophagy is also required for neutrophil degranulation and NADPH-oxidase-mediated reactive oxygen species production  has been linked to autophagy. FYCO1 is highly expressed in the heart and its role has recently been investigated nditions . FYCO1 dnditions . Althoug failure .Atg5 leads to contractile dysfunction, hypertrophy and cardiomyopathy, consistent with the notion that basal autophagy levels in cardiomyocytes are required for cellular proteostasis , which promotes autophagy in cardiomyocytes by modulating FoxO3a (a member of the FoxO family of transcription factors) . ChangesTaken together, these data provide evidence for the maladaptive role of autophagy in cardiovascular disease, suggesting that there is an optimal zone of cardiomyocyte autophagy that may be beneficial and that treatments resulting in levels of autophagy outside (higher or lower) this therapeutic window are likely to be deleterious .Compelling evidence revealed the crucial role of autophagy in preserving cardiac health by ruling cardiac homeostasis under baseline conditions and participating in the mechanisms of response to pathological injuries. While enhancing autophagy activation has shown beneficial outcomes in aging and longevity in animal models, the identification of a proper therapeutic window in diseased conditions and well-tolerated pro-autophagic drugs is an active research area. Meeting these medical needs will provide novel therapeutics and ultimately improve the outcome of patients with heart disease.


The benefit of remote ischemia preconditioning (RIPreC) in pediatric cardiac surgery is unclear. The objective of this systematic review and meta-analysis was to examine the effectiveness of RIPreC in reducing the duration of mechanical ventilation and intensive care unit (ICU) length of stay after pediatric cardiac surgery.We searched PubMed, EMBASE and the Cochrane Library from inception to December 31, 2022. Randomized controlled trials comparing RIPreC versus control in children undergoing cardiac surgery were included. The risk of bias of included studies was assessed using the Risk of Bias 2 (RoB 2) tool. The outcomes of interest were postoperative duration of mechanical ventilation and ICU length of stay. We conducted random-effects meta-analysis to calculate weighted mean difference (WMD) with 95% confidence interval (CI) for the outcomes of interest. We performed sensitivity analysis to examine the influence of intraoperative propofol use.Thirteen trials enrolling 1,352 children were included. Meta-analyses of all trials showed that RIPreC did not reduce postoperative duration of mechanical ventilation  but reduced postoperative ICU length of stay . When only trials using propofol-free anesthesia were included, both mechanical ventilation duration  and ICU length of stay  were reduced by RIPreC. The overall quality of evidence was moderate to low.The effects of RIPreC on clinical outcomes after pediatric cardiac surgery were inconsistent, but both postoperative mechanical ventilation duration and ICU length of stay were reduced in the subgroup of children not exposed to propofol. These results suggested a possible interaction effect of propofol. More studies with adequate sample size and without intraoperative propofol use are needed to define the role of RIPreC in pediatric cardiac surgery.The online version contains supplementary material available at 10.1186/s12871-023-02064-6. Remote ischemic preconditioning (RIPreC) has long been viewed as an attractive approach to mitigate the ischemia–reperfusion injury to heart and other organs induced by cardiopulmonary bypass. Despite some beneficial effects in terms of reductions in biomarkers of organ injury , most raPrevious meta-analyses did not show significant cardioprotective effect of RIPreC in pediatric cardiac surgery , 10. How* OR paediatric OR pediatric OR infant* OR young OR neonate*) AND . The full search strategies for all databases are provided in detail  collected data from each report independently. Main characteristics of trial design, patients, interventions, and outcomes in each eligible RCT were recorded. Important missing or unclear data were obtained or confirmed by contacting the study investigators using emails. The outcomes of interest of this study were postoperative mechanical ventilation duration and ICU length of stay (expressed in hours). They were chosen as measures of effectiveness because prolonged mechanical ventilation and ICU stay are usually consequences of cardiopulmonary dysfunction or slower recovery after cardiac surgery and because they are powerful predictors of both short- and long-term mortality , 14. All2 statistic. Publication bias was visually assessed by inspecting funnel plots and statistically tested using Egger's test. TSA was conducted using a specific software  [Using Review Manager 5 , we conducted random-effects meta-analysis to calculate weighted mean difference (WMD) with 95% confidence interval (CI) for the outcomes of interest. Where data were reported as medians, they were converted to means and standard deviations . HeterogDenmark) . Our assFigure 2 = 92%; Fig. 2 = 0%; Fig. Twelve RCTs reported postoperative mechanical ventilation duration in a total of 1,247 children. Overall, RIPreC did not reduced the duration of mechanical duration (WMD -5.35 h, 95% CI -12.12–1.42; I2 = 91%; Fig. 2 = 38%; Fig. Twelve RCTs enrolling a total of 1,313 children reported postoperative ICU length of stay. Overall, RIPreC reduced ICU length of stay (WMD -11.48 h, 95% CI -20.96 – -2.01; INo evidence of publication bias was detected Fig. . The GRAIn this meta-analysis of 13 RCTs and 1,352 children, the effects of RIPreC on decreasing postoperative mechanical ventilation duration and ICU length of stay were inconsistent in the overall cohort. However, we found significant improvement in these outcomes when only trials using propofol-free anesthesia were analyzed, and the heterogeneity among studies were substantially reduced. Although a firm conclusion could not be reached due to inadequate information size, our findings support the idea that propofol may interfere with the protective effects of RIPreC.The mechanism of RIPreC-induced organ protection is complex and involves both humoral and sensory-neuronal pathways . SeveralThe current study had several limitations. First, most included trials had a small sample size, a short follow-up duration, and were only powered to detect differences in surrogate endpoints such as blood biomarkers. Postoperative mortality and major complications had low incidence and were inconsistently reported. We could not evaluate the effects of RIPreC on these important outcomes. Second, substantial heterogeneity was noted across the included trials with regard to the age of children, the type and severity of heart disease, and the protocol of RIPreC. These factors contributed to the high variance in outcome data distribution. We therefore used random-effects model for this meta-analysis. We also performed a post hoc analysis by using standardized mean difference as the effect measure, and the result was consistent with the primary analysis. Third, we were unable to perform statistical test for the possible interaction effect of propofol because the number of trials were limited and because the proportions of propofol use in some trials were unknown. Thus, the effect of propofol could not be confirmed. Fourth, the protocol of this systematic review and meta-analysis was not registered a priori, and it is best to use a validated search filter For RCTs search.Despite these limitations, our study provides additional evidence that RIPreC may show clinically significant effects in cardiac surgery when propofol anesthesia is not used. The findings of this study provide insights for the design of future researches. Above all, considering the possible confounding effect of propofol and the realizability of required sample size calculated by TSA, it is mandatory for future trials to avoid propofol as part of the anesthesia regimen. In addition, future trials should be adequately powered for clinically important outcomes such as ICU length of stay, rather than merely surrogate outcomes. Since the incidence of postoperative short-term mortality and major complications are low, longer follow-up durations are needed to evaluate the long-term effects of RIPreC on pediatric cardiac surgery.RIPreC does not reduce postoperative mechanical ventilation duration or ICU length of stay after pediatric cardiac surgery. In trials that did not use propofol, significant reductions in mechanical ventilation duration and ICU length of stay were observed, suggesting that propofol may interfere with the protective effects of RIPreC. Future trials with adequate power are needed to evaluate the independent role of RIPreC in pediatric cardiac surgery under propofol-free anesthesia.Additional file 1.


Congenital anomalies in the shape of the coronary arteries are extremely uncommon to encounter in routine clinical practice in interventional cardiology. In this study, we describe two uncommon shape anomalies of the left main coronary artery, that is, U-shaped left main coronary artery and L-shaped left main coronary artery. These anomalies were observed in two consecutive patients who presented with atypical chest pain and exertional shortness of breath. These uncommon shape anomalies of the left main coronary artery hold their clinical significance during intervention as those require robust guide catheter support during the difficult passage of the routine coronary hardwires. Coronary anomalies affect 1% of the general population when invasive coronary angiogram is taken into account . There iCase 1A 56-year-old male, diabetic, hypertensive, and a smoker, presented to the outpatient department (OPD) with effort intolerance, categorized as New York Heart Association (NYHA) Class II, and reported diaphoresis over the last six months, without any history of palpitation, presyncope, or syncope. His heart rate was 80 beats per minute, and his blood pressure was 150/90 mmHg in the right arm supine position. His electrocardiogram (ECG) was within normal limits, and his echocardiography revealed no regional wall motion abnormality with normal ejection fraction. His exercise treadmill test was borderline positive, and he was subjected to an invasive coronary angiogram due to effort-limiting angina. A coronary angiogram revealed an inverted U-shaped left main coronary artery  Classification II for the last six months. He had a heart rate of 80 beats per minute and blood pressure of 144/80 mmHg in the right arm supine position. His ECG and echocardiography were within normal limits. He could not perform an exercise treadmill test due to the presence of osteoarthritis. He was on single antiplatelet therapy, statin, beta-blocker, and nitrate for the last six months. As his angina was not responsive to optimal medical therapy (OMT), he was subjected to a coronary angiogram. An invasive coronary angiogram revealed an L-shaped anomaly of the left coronary artery (Figure The incidence of coronary anomalies in routine echocardiography is estimated to be around 0.17% , while tWe describe the rarest shape anomalies of the LMCA, that is, U-shaped LMCA and L-shaped LMCA, in patients with exertional angina, which have not been described in the literature so far. Although these anomalies are uncommon to be encountered during routine interventional practice, they exert their importance during exertion by increasing the shear stress in coronary blood flow and producing relative coronary ischemia. Shape anomalies of the coronary arteries also carry their importance during the intervention as those acute turns pose a great challenge while passing the routine coronary hardwires.


With the increasing use of telemedicine in healthcare, studies examining this approach in the context of LCS are urgently needed. We aimed to identify sociodemographic and other factors associated with screening completion among individuals undergoing telemedicine Shared Decision Making (SDM) for LCSThis retrospective study examined patients who completed Shared Decision Making (SDM) via telemedicine between May 4, 2020 – March 18, 2021 in a centralized LCS program. Individuals were categorized into Complete Screening vs. Incomplete Screening subgroups based on the status of subsequent LDCT completion. A multi-level, multivariate model was constructed to identify factors associated with incomplete screening.Among individuals undergoing telemedicine SDM during the study period, 20.6% did not complete a LDCT scan. Bivariate analysis demonstrated that Black/African-American race, Medicaid insurance status, and new patient type were associated with greater odds of incomplete screening. On multi-level, multivariate analysis, individuals who were new patients undergoing baseline LDCT or resided in a census tract with a high level of socioeconomic deprivation had significantly higher odds of incomplete screening. Individuals with a greater level of education experienced lower odds of incomplete screening.Among high-risk individuals undergoing telemedicine SDM for LCS, predictors of incomplete screening included low education, high neighborhood-level deprivation, and new patient type. Future research should focus on testing implementation strategies to improve LDCT completion rates while leveraging telemedicine for high-quality LCS.The online version contains supplementary material available at 10.1186/s12913-023-10185-4. In the years since the National Lung Screening Trial, and subsequent revisions to the United States Preventive Services Task Force (USPSTF) lung cancer screening (LCS) guidelines, LCS uptake has slowly increased, with some states now reporting up to 15% of potentially eligible, high-risk individuals undergoing annual low-dose CT (LDCT) scan . InitialThe COVID-19 pandemic introduced additional challenges for healthcare providers and has led to decreased rates of screen-detected cancer diagnoses and disruptions in care for cancer screening programs –14. In tUpon resuming routine LCS, many healthcare systems pivoted to telemedicine for shared decision-making (SDM) to minimize COVID-19 transmission risk for patients and providers. This pivot was noted by major payers including the Centers for Medicare and Medicaid Services (CMS), and several private insurers, which lead to relaxing telemedicine restrictions in place pre-COVID-19 and increasing reimbursement levels [This change in practice may lead to a cascade of alterations in LCS implementation and has the potential to exacerbate disparities in screening . In the The objective of this retrospective study was to characterize individuals undergoing LCS with SDM via telemedicine as well as to identify potential differences in those who did and did not complete a LDCT scan after SDM. We hypothesized that sociodemographic characteristics of individuals who completed the entire LCS process would be significantly different from those of individuals who underwent SDM, but did not obtain a LDCT scan.All patients in this study were enrolled in the Jefferson Lung Cancer Screening Program; a centralized LCS program at a major urban academic medical center. and were identified through the Program’s LCS Registry version 2021Q2. The Jefferson LCS Program has been screening USPSTF 2013-, CMS-, and/or NCCN-eligible  patients through a centralized nursing-driven model since 2015. Dedicated program staffing is comprised of: 1). A Coordinator who manages referrals, schedules patients and obtains insurance authorization; 2). Two Nurse Navigators who are clinical nurse specialists and assist with SDM, perform tobacco treatment counseling, and review screening results with patients and primary care providers; and 3) A Nurse Practitioner who carries out SDM, organizes diagnostic evaluation for screening patients who require additional testing and procedures, and manages the day-to-day activities of the LCS program. Patients are electronically referred by primary care providers, pulmonologists, or other specialists, but can also self-refer to the LCS Program, and screening eligibility is confirmed by the Coordinator. SDM is carried out by the Nurse Navigator and Nurse Practitioner as described below. All positive screening LDCTs are reviewed by a multi-disciplinary team on a weekly basis, and detailed recommendations on management of screen-detected nodules and workup of incidental findings are communicated to both the patient and the referring primary care provider by the Nurse Navigators and Nurse Practitioner. A standardized intake form is used to collect demographic and clinical data at the time of entry into the LCS Program and is updated prospectively with screening results and subsequent workup. Accuracy of entered data is confirmed by random chart review, and clinical outcomes are updated, both on a quarterly basis. This study protocol – was reviewed and approved by the Thomas Jefferson University Institutional Review Board (IRB) with a waiver of informed consent, given the minimal risk nature of the study . This retrospective analysis was carried out in accordance with all methodological guidelines and regulations of the Thomas Jefferson University IRB, as well as the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.Our LCS Program paused screening of new patients during the period March 18, 2020 – May 4, 2020, due to the first surge of the COVID-19 pandemic. For this study, all individuals who completed SDM and agreed to LCS with LDCT following LCS Program reopening were identified as the Post-Telehealth SDM cohort . An additional cohort of patients who completed SDM and LCS in the year prior to the study period  were identified as the Pre-Telehealth SDM cohort. Individuals residing outside of Philadelphia were excluded from the study to allow for geospatial analyses of Philadelphia neighborhoods. Patients’ sociodemographic information, medical history, and screening-related outcomes were obtained from the LCS Program Registry database.The LCS Program offers SDM that is tailored to patients’ health literacy and general understanding of cancer screening. The Nurse Navigator, supervised by the Nurse Practitioner, reviews basic principles of lung cancer screening with LDCT and discusses potential harms and benefits. Patients are given ample opportunity to raise questions and discuss concerns. Tobacco treatment counseling and pharmacotherapy prescriptions are also provided for individuals who currently smoke. Following the SDM visit, patients elect to proceed or decline screening. For patients who choose to undergo LCS, the LDCT is coordinated by the LCS Program and screening results are reviewed by telephone with patients and by electronic communication primary care providers.Prior to the COVID-19 pandemic, appointments for same-day, in-person SDM and LDCT were scheduled by the LCS Program Coordinator. Following the Program reopening, all SDM was conducted via telemedicine, and LDCT appointments were scheduled immediately afterward by the Coordinator. Decision aids were offered electronically or by mail, and at the end of the SDM appointment individuals were scheduled for an LDCT scan (with most appointments within 7–14 days of SDM). Individuals who missed their LDCT scan received a follow-up telephone call and a reminder letter to reschedule the LDCT appointment.Individuals who underwent SDM via telemedicine were examined for the primary outcome, LDCT completion, and the study cohort was divided into two subgroups for comparison. The Complete Screening Subgroup included individuals who underwent SDM during the study period and subsequently completed LCS with LDCT. The Incomplete Screening Subgroup included individuals who underwent SDM during the same period, but did not follow up with a LDCT scan. Incomplete screening was defined as not undergoing screening LDCT within 1 month of completing SDM through our LCS Program. Factors associated with incomplete screening were identified using logistic regression analyses.Screening adherence was determined using modified National Lung Cancer Roundtable (NLCRT) definitions , 25. ForNeighborhood Deprivation Index (NDI) values for Philadelphia census tracts were obtained from a publicly available dataset via the National Cancer Institute’s GIS Portal for cancer research . The NDIFor all individuals, home address was collected from the LCS Registry and geocoded by census tract utilizing ArcGIS Pro . NDI valWe obtained descriptives, frequencies and cross-tabulations to summarize descriptive data in tables. Bivariate analyses including independent t-tests and chi-square tests were performed to examine characteristics of the Complete Screening and Incomplete Screening subgroups using a p ≤ 0.05 significance threshold. Bivariate logistic regression analysis was conducted for individual characteristics . With a multilevel data structure of neighborhood-level of NDI , multivariate and multilevel analysis was conducted to account for clustering effect. SPSS version 26 was used, with STATA version 17 used for predictive modeling , 33.n = 429, 56.9%) and self-reported their race as White . Over half of the cohort reported current tobacco use , and had a mean smoking intensity of 51.96 ± 23.50 pack-years. A high school diploma or GED equivalent was the most commonly reported level of educational attainment  and a plurality of patients reported being privately insured .A total of 754 unique individuals underwent telemedicine SDM for LCS through the Jefferson Lung Cancer Screening Program during the study period Table . The majp = 0.001). There was no significant difference in distance to screening site between the two subgroups  underwent LDCT (comprising the Complete Screening Subgroup) and 155 patients 20.6%) did not undergo LDCT scan (comprising the Incomplete Screening Subgroup) (Table 0.6% did p < 0.001)  compared with the Complete Screening Subgroup p < 0.00 . Black/African-American race, new patient type, and Medicaid insurance status were significantly associated with greater odds of incomplete screening Table . Upon adp < 0.001) in educational attainment between the two groups, with a lower frequency of individuals with less than a high school (HS) diploma screened in the Post-Telehealth SDM cohort compared with the Pre-Telehealth SDM cohort  and a higher frequency of individuals with a HS diploma . Among the Post-Telehealth SDM patients, there was a lower frequency of individuals with the highest level of educational attainment (greater than a HS diploma), at 38.1% vs. 40.3%, respectively. The Post-Telehealth SDM cohort also had a statistically significantly higher rate of COPD  and lower smoking intensity compared with the Pre-Telehealth SDM cohort . The majority of individuals in the Pre-Telehealth SDM cohort were new patients (73.3%), whereas the majority of patients seen after the transition to telehealth SDM were returning patients (52.3%). A significantly greater proportion of the Post-Telehealth SDM cohort lived in neighborhoods with at least above-average deprivation compared to the Pre-Telehealth SDM cohort .A total of 833 patients underwent SDM in-person for LCS prior to the pivot to telemedicine SDM, in the ten months following the implementation of telemedicine SDM, 754 patients completed SDM. There were no statistically significant differences between the Pre-Telehealth SDM and Post-Telehealth SDM cohorts with regard to age, gender, ethnicity, race, smoking status, BMI, insurance status, or PLCOm2012 lung cancer risk  Among Individuals in the Incomplete Screening and Complete Screening Subgroups. Supplemental Table 2. Baseline Characteristics Of Individuals Receiving Shared Decision Before and After Telehealth Implementation.


Cortical ischaemic strokes result in cognitive deficits depending on the area of the affected brain. However, we have demonstrated that difficulties with attention and processing speed can occur even with small subcortical infarcts. Symptoms appear independent of lesion location, suggesting they arise from generalized disruption of cognitive networks. Longitudinal studies evaluating directional measures of functional connectivity in this population are lacking. We evaluated six patients with minor stroke exhibiting cognitive impairment 6–8 weeks post-infarct and four age-similar controls. Resting-state magnetoencephalography data were collected. Clinical and imaging evaluations of both groups were repeated 6- and 12 months later. Network Localized Granger Causality was used to determine differences in directional connectivity between groups and across visits, which were correlated with clinical performance. Directional connectivity patterns remained stable across visits for controls. After the stroke, inter-hemispheric connectivity between the frontoparietal cortex and the non-frontoparietal cortex significantly increased between visits 1 and 2, corresponding to uniform improvement in reaction times and cognitive scores. Initially, the majority of functional links originated from non-frontal areas contralateral to the lesion, connecting to ipsilesional brain regions. By visit 2, inter-hemispheric connections, directed from the ipsilesional to the contralesional cortex significantly increased. At visit 3, patients demonstrating continued favourable cognitive recovery showed less reliance on these inter-hemispheric connections. These changes were not observed in those without continued improvement. Our findings provide supporting evidence that the neural basis of early post-stroke cognitive dysfunction occurs at the network level, and continued recovery correlates with the evolution of inter-hemispheric connectivity. Patients with minor stroke can exhibit cognitive difficulties due to disrupted cognitive networks. Marsh, et al. longitudinally evaluated directional functional connectivity in 6 patients and 4 controls. During early recovery, there were increased inter-hemispheric connections directed from the ipsilesional to the contralesional cortex that further evolved only in those with better long-term clinical outcomes.  Unfortunately, despite sparing large cortical regions, patients with smaller, often subcortical, ‘minor strokes’ can nevertheless demonstrate significant difficulties with attention, multi-tasking, processing speed and other executive functions.10Stroke is one of the leading causes of long-term disability world-wide.11–15 However, it is typically characterized by an accumulation of infarcts manifesting as a stepwise decline, or stroke involving a large cortical area traditionally felt to be responsible for various cognitive functions such as language or attention. In contrast, recent studies have demonstrated that even single small infarcts, independent of lesion location, can lead to impairment, resulting in a dysexecutive syndrome that demonstrates variable recovery.17 This constellation of cognitive symptoms occurs reliably within the minor stroke population18 and can be disabling, preventing patients from returning to work and living normal lives.19 Our previous neuroelectrophysiological work using magnetoencephalography (MEG) has shown temporal dispersion of evoked responses during cognitive tasks independent of infarct size or location in this group, suggesting that minor strokes disrupt cognitive function by ‘lesioning the network’.20 To date, formal connectivity studies to explain the underlying aetiology of post-stroke cognitive dysfunction after a minor stroke, specifically those evaluating directional connectivity between key areas of the cortex, are lacking.Vascular cognitive impairment is well described in the literature.19 Interestingly, however, findings of temporal dispersion and alterations in beta-band activity are still seen on MEG at this time point despite functional improvement.20 The mechanism by which many recover remains poorly elucidated. In addition, the longer-term trajectory of these patients is variable. Some individuals continue to improve while others revert to worsened cognitive performance.19 The underlying neurophysiology warrants further investigation.Fortunately, despite early cognitive difficulties, many patients with minor stroke recover well. By six months after infarct, the majority have significantly improved clinically.21 Functional MRI (fMRI) studies evaluating predominantly larger cortical strokes and focused on language and motor impairment have demonstrated subsequent recovery with improved functional connectivity;23 however, few have explored how different directional connectivity relationships may influence outcome. Since cognitive processes generally occur on a rapid scale, for this study we instead use MEG to evaluate connectivity, which allows for the evaluation of neural activity, and hence directional connectivity, on a millisecond scale. The utility of MEG to study post-stroke cognition has been demonstrated in a recent prior study focused on larger, hemispheric lesions.24 To avoid the influence of severe hemiparesis or aphasia on clinical assessment, however, only patients with minor strokes were included in this study. While the definition of minor stroke varies throughout the literature based on stroke severity versus vascular involvement,26 our inclusion criteria focus on small, predominantly subcortical, ischaemic infarcts, allowing for evaluation of generalized disruption of cognitive networks without the confounding effect of direct cortical involvement.This small proof-of-concept study is the logical next step to evaluate the role of functional connectivity in the longitudinal cognitive recovery of patients following minor stroke. To explore the hypothesis that acute cognitive impairment following small infarcts is due to network dysfunction and that specific patterns of network evolution over time are linked to favourable long-term recovery, we formally analyse directional functional connectivity, the influence that one area of the brain exerts on another, using resting-state MEG data from patients with minor stroke collected longitudinally at three visits, each approximately six months apart. Directional functional connectivity can best be described as the relationship between the activity of neurons in group A following the earlier activation of group B and can be measured using Network Localized Granger Causality (NLGC).27 of ten or less , with no large vessel territory involvement (e.g. M1 or M2 occlusion), significant hemiparesis, aphasia or hemispatial neglect. Of note, for those recruited, NIHSS scores were all significantly below the inclusion threshold  at the first follow-up visit. Infarct location and stroke volume were determined using diffusion-weighted MRI , allowing for formal functional connectivity analyses and longitudinal investigation corresponding to clinical change. The remaining participants were unable to be seen due to the COVID pandemic, and, therefore, were not included in this analysis.This study was approved by the Johns Hopkins University institutional review board and all participants provided written informed consent. Resting-state MEG data were collected from six patients returning for follow-up 6–8 weeks after hospitalization (visit 1) for their first ever minor acute ischaemic stroke, and four controls (age-matched within five years) without a history of prior stroke or neurologic disease. Minor stroke was defined as an admission National Institutes of Health Stroke Scale (NIHSS) score MRI see . In addi29 that improved by the second visit. A neuropsychological battery was performed focusing on visual memory [Hopkins verbal learning test (HVLT)-revised: immediate and delayed recall], attention and executive function [Delis-Kaplan Executive Function System (D-KEFS): verbal fluency and trails making tests], and processing speed [symbol digit modalities test (SDMT)]. Additional variables were collected at each visit including the NIHSS score evaluating stroke severity, and the mRS and Barthel Index evaluating functional performance and activities of daily living. Z scores were generated using normative data for each task. A patient was considered to be impaired for that test/domain if they scored >1.5 standard deviations below the mean. Change in score over time was also evaluated, with particular attention paid to the interval between visits 2 and 3  estimates. Resting-state MEG data were collected from the same participants again ∼6 and 12 months later (visits 2 and 3) when they returned for follow-up clinical evaluation. A sampling rate of 1 kHz was used with a 200 Hz low pass filter and a 60 Hz notch filter to remove line noise. The location of the head inside the MEG system was measured using five marker coils and the head shape was digitized using the Polhemus 3SPACE FASTRAK system. The digitized head shape and coil locations were used to obtain the mapping between the sensors onto the sources.A 157-channel axial gradiometer MEG system  was used to record magnetic fields while participants rested in a magnetically shielded room . Recordings were collected while participants lay supine inside the MEG scanner and fixated on a cross projected onto a screen in front of them. As part of our larger protocol, one minute of eyes-open resting-state data were collected and analysed for each patient, The length of the recording was chosen to keep scan times low and is consistent with previous studies.34 After excluding any noisy channels, temporal signal space separation was employed to remove artefacts.35 The data were then filtered between 0.1 and 100 Hz, via a zero-phase finite impulse response filter (using the default setting of MNE-python 0.21.0), after which independent component analysis36 was applied to remove nuisance components due to eye-blinks, facial muscle movements and cardiac artefacts. The initial 5 seconds of the data were discarded, and the subsequent 55 seconds of the data were extracted and downsampled to 50 Hz for all remaining analysis. Finally, the data were filtered within the beta band (from 13 Hz to ∼25 Hz) based on previous results showing significant differences in the beta band between stroke patients and controls.20 We used finite impulse response filters designed to exhibit negligible leakage to make sure that border effects in the frequency domain were minimized and chose a downsampling frequency of 50 Hz to both include the upper end of the beta band (just under 25 Hz) and reduce the runtime of the algorithm.All pre-processing steps were performed using MNE-python 0.21.0.21 In brief, we say that brain region A has a directed GC link to brain region B if statistical predictions of the time-course of the activity of region B are significantly improved by using the previous activity of region A as a regressor, as compared to omitting region A from the set of regressors.37 According to this definition, two regions might possibly show connectivity in either direction, bidirectionally, or not at all.To investigate the changes in cortical connectivity across visits, we utilized the NLGC framework which identifies directed interactions between different cortical regions referred to as GC links.direct inference at the cortical source level of such GC links, from MEG data, without the need for an intermediate step of source localization, thereby significantly reducing the false detection rate incurred by older two-stage methods. In two-stage connectivity analysis methods, the source activities are first estimated via source localization, followed by identifying GC links from the estimated sources. However, statistical biases incurred during the source localization stage, primarily in the spatial extent of the estimated sources, propagate to the second stage of parameter estimation required for GC identification. This typically amplifies those biases; for instance, spatial spread in a source localization estimate may well be acceptable for that purpose, but when then used for connectivity analysis, it propagates any spatial spread error via both ends of the connectivity measure. Instead, NLGC models the underlying neural source activity via a single second-order sparse vector auto-regressive model that is mapped to the sensors via a forward model. The model parameters are then directly estimated by combining the forward model and auto-regressive estimation into a unified framework, from which the GC links are identified. NLGC automatically assesses the significance of the GC connections using the Benjamimini–Yekutieli (BY) procedure to control the false discovery rate at 0.1%. The resulting connectivity map represents significant directional GC links among 84 cortical sources (ico-1 source space), a subset of which contribute to each specific region of interest (ROI). To achieve an acceptable accuracy in the forward model while ensuring manageable runtime of the algorithm, each of the 84 cortical sources is represented by the first four principal components of corresponding neural sources located in the ico-4 source space. As python implementation of NLGC is publicly available on Github.38The NLGC framework additionally allows the 39 : FPC → FPC, FPC → non-FPC, non-FPC → FPC and non-FPC → non-FPC. The percentage of total significant links was used, rather than the absolute number of significant links, due to its statistical robustness . Analysis distinguishing between ipsilesional and contralesional hemispheric connectivity was not performed at this stage, since controls were also included in this analysis.NLGC analysis was applied to MEG recordings from each individual for each visit. The connectivity maps were then summarized in terms of the percentage of significant GC links to/from bilateral frontoparietal cortices (FPC) including motor and premotor cortex. The FPC ROI consisted of the ‘precentral’, ‘paracentral’ and ‘postcentral’ ROIs of the Desikan–Killiany atlas.39 See  This regSource1(hemi1) → Source2(hemi2) with Source being either FPC or non-FPC, and hemi either the ipsilesional or contralesional hemisphere. Connectivity maps were compared across visits, in order to determine the patterns of change over time associated with neural recovery. Patients whose recovery was categorized as ‘favourable’ were compared to ‘unfavourable’. Given the limited dataset, longitudinal results were reported individually for each patient.To investigate the role of lesion lateralization in network dysfunction and the importance of directional connectivity to longitudinal recovery, our second analysis distinguished between significant GC links identified within and between the contralesional and ipsilesional hemispheres in patients. We represented the connectivity pattern of patients at each visit with a 16-entry array where each entry was the percentage of significant GC links corresponding to 40 were also reported, comparing: (1) differences in the distribution of significant links between patients and controls at each visit, (2) differences across visits for each group and (3) differences between those with a favourable versus unfavourable long-term outcome.Paired sample t-tests with Bonferroni correction20 At visit 1, there was a significant reduction in connections between the bilateral FPC and non-FPC regions compared to controls, regardless of connectivity direction, as well as significant differences in connectivity between non-FPC areas (The connectivity patterns for each group (stroke patients and controls) were consistent across individuals and, in line with previous studies of a mild stroke, independent of lesion location.PC areas . Plots oPC areas . The GC While stroke patients exhibited consistent overall clinical improvement between visits 1 and 2, along with increased connectivity involvement of FPC, subsequent clinical recovery observed at visit 3 was variable . Three pOnly stroke patients were analysed at this level . Individual connectivity maps and group averages are displayed in FPC → FPC was weak in both directions at visit 1. At visit 2, Ipsilesional → Contralesional connections were enhanced for all patients. By visit 3, Ipsilesional → Contralesional was diminished more for favourable patients than unfavourable.Ipsilesional non-FPC → Contralesional FPC was also weak at visit 1 for all patients. While it became stronger and bidirectional at visit 2, for favourable patients this relationship continued to evolve and was unidirectional  by visit 3.Ipsilesional FPC → Contralesional non-FPC was weakly bidirectional at the 1st visit for both groups but at the second visit, the groups diverged . By visit 3, in unfavourable patients Contralesional → Ipsilesional weakened but did not disappear, whereas it remained almost absent for the favourable group.Non-FPC → Non-FPC was strongly Contralesional → Ipsilesional at the first visit, reversed at the second visit, and became strongly bidirectional at the third visit for both groups.Also of note, connections between the contralesional FPC and non-FPC were weakly directional (in favour of non-FPC → FPC) at the 1st visit for both groups, but strongly bidirectional for unfavourable patients over time while remaining weakly directional (non-FPC → FPC) for favourable. Overall, the variable evolution of directional functional connectivity across groups over time resulted in numerous significant differences between groups at visit 3. The continued evolution of the favourable group resulted in fewer inter-hemispheric connections, while the unfavourable group continued to rely heavily on these links.20 Our data show that there is a significant decrease in the percentage of connections going into and away from FPC bilaterally acutely in stroke patients compared to controls. This lack of involvement of these key brain regions, important for planning and executing responses during tasks, may explain delayed reaction times. The increased involvement of FPC bilaterally seen at visit 2, corresponding to clinical improvement, suggests this may be the case. Furthermore, our data suggest the importance of laterality and continued changes in directional inter-hemispheric functional connectivity for the longitudinal recovery of cognitive networks and improvement of symptoms over time. We have shown that improvement in performance at both 6- (visit 2) and 12 months (visit 3) post-stroke is associated with the persistent evolution of intra- and inter-hemispheric connections: with initially increased reliance on connections towards the contralesional hemisphere that becomes less over time for individuals with a favourable long-term recovery profile.This proof-of-concept study using resting-state MEG to evaluate the relationship between neural connectivity and cognitive dysfunction in individuals, both acutely and longitudinally after a minor stroke, supports the hypothesis that impaired functional connectivity is associated with clinical symptoms. Following a stroke, an abnormal pattern is consistent across patients, independent of lesion location, as suggested indirectly by our previous work.42 predominantly with respect to inter-hemispheric coupling.44 Improved function in those participants’ weakness had a direct relationship with strength and the number of inter-hemispheric connections in FPC.45–48 It is important to also note that the strokes within those cohorts were clearly located within motor pathways, which was not the case in our sample, and that motor performance was the primary outcome measure.These specific results are consistent with broader results from previous studies investigating motor recovery. Analysis of resting-state functional connectivity evaluated using M/ electroencephalography (EEG) has shown that control populations exhibit a more balanced network compared to disrupted frontoparietal connectivity observed in stroke patients with motor deficits,50 but a recent review of prior fMRI studies of aphasic patients found reports of disruption of inter-hemispheric connections in auditory and language networks.51 Our current study substantially broadens these results by demonstrating that disruptions of connectivity are associated with cognitive dysfunction even in patients without other significant cortical deficits such as hemiparesis or aphasia. Thus, it illustrates that it is specifically the disruption of the network , rather than dysfunction within specific cortical areas, that is associated with poor cognitive performance.52 Furthermore, the consistent clinical phenotype observed within our cohort, which is independent of lesion location and irrespective of infarct size indicates the importance of network integrity to perform cognitive tasks.Other connectivity studies have focused on stroke patients with language deficits. Some reported abnormal neural dysfunction in perilesional areas acutely after infarct,35 and has already been described in the literature as a potential recovery mechanism based on transcranial magnetic stimulation, Wada testing and cortical neurostimulation.53 Our study is novel in its inclusion of subcortical infarcts and focuses on network dynamics observed using MEG to evaluate cognition. Importantly, the findings parallel those of prior connectivity studies using fMRI, which have demonstrated both inter- and intrahemispheric abnormalities during the early stages of recovery54 that normalize with good recovery.52Our study not only illustrates that broad network dysfunction can occur with a single subcortical infarct but begins to elucidate the compensatory pathways that may be associated with clinical improvement over time. While prior work has evaluated functional connectivity alterations in acute stroke patients undergoing rehabilitative intervention, the role of functional connectivity changes in the natural recovery of cognitive deficits in patients with minor stroke is not fully understood. These mechanisms appear to be independent of lesion size or location and initially involve an increase of signals towards the contralesional hemisphere. Interestingly, it appears that in order for patients to continue to improve, it is necessary for many of these connections to decrease over time, potentially indicating more reliance on the recovering ipsilesional hemisphere at visit 3 in those with optimal recovery profiles. This concept of continued reorganization of function during the subacute period has been proposed previously with respect to language recovery55–58 The high spatial resolution of fMRI has shown a bilateral reduction of connections between the primary motor cortex in patients with chronic stroke compared to healthy individuals.59 After a one-month rehabilitative intervention, connectivity between ipsilesional and contralesional primary motor cortices significantly increased. While many studies have suggested that dynamic changes in the connectivity pattern of the motor cortex61 mainly involve inter-hemispheric connections,63 other studies have found a correlation between motor recovery and functional connectivity strength restoration in frontoparietal, or sensorimotor cortex, mostly in the ipsilesional hemisphere.64–66 In a population similar to ours, using fMRI to evaluate GC, Allegra et al. also found abnormalities in inter-hemispheric connections following a stroke that when improved, correlated with clinical improvement.58 This supports the theory that the resolution of impaired directional functional connectivity is important for recovery. Similarly, disruption of inter-hemispheric connectivity irrespective of lesion location or size has also been reported previously after stroke in patients with motor impairment using fMRI,62 as well as hemispatial neglect. Critically, however, using MEG allows us to evaluate cognitive processes that occur on a millisecond scale, and, furthermore, in our study infarcts did not involve any eloquent cortex or areas traditionally associated with cognitive impairment. We demonstrate that a single subcortical lesion, independent of location, is enough to disrupt generalized connectivity in a predictable way. Whether these changes are modifiable with rehabilitation paradigms, non-invasive stimulation, or pharmacotherapy, remains to be seen. Further exploring the compensatory network alterations that must occur in order to allow individuals to continue to recover is an important first step towards developing and testing effective treatment strategies.Other studies have focused on extracting network-level changes over time, specifically in the motor cortex of acute stroke patients, utilizing various neuroimaging techniques including fMRI, MEG, and EEG.67–69 By using the NLGC framework, these shortcomings are addressed by directly inferring the cortical GC links from the MEG data, without resorting to intermediate localization estimates. NLGC also addresses a common shortcoming of existing directional connectivity analyses which typically require long data durations to be able to uncover the underlying connections reliably at a low false detection rate. Our results here show that the identified GC networks are consistent at both the individual and group levels, thus demonstrating that 55 seconds of high temporal resolution resting-state data MEG data suffices to reliably detect GC networks in the beta frequency band, consistent with previous validation analyses.21Previous work in physiological functional connectivity analyses can be categorized based on methodology into two groups: source- and sensor-level connectivity analysis. While the former needs an intermediate source localization step to estimate the source activities followed by connectivity inference, the latter takes advantage of the putative relationship between locations of the sensors and cortical areas to interpret the connectivity patterns. However, both approaches are known to suffer from false detections and spatial mis-localizations, especially in resting-state studies.70 Such beta-band activity, which is known to be critical for processing speed and the motor planning needed to generate responses,72 is easily captured with M/EEG.74 Unusual beta-band activity has been detected in patients with motor deficits, including those suffering from stroke;75 however, Kulasingham and colleagues20 recently also observed that patients with only minor stroke and abnormal processing speed but no significant hemiparesis demonstrated similar changes. The reduced bilateral Rolandic beta activity during the recovery period irrespective of lesion location (and most notably with strokes outside of the motor pathway), suggests that even such small and distant lesions may result in global network impairment, which is consistent with our findings. It is important to note that those abnormalities in beta power persisted regardless of clinical improvement, illustrating that power within the beta band alone is not driving behaviour, or responsible for the continued evolution of directional functional connectivity observed in this study. Interestingly, measures of connectivity in the beta band have also been implicated in contributions to fMRI measures of connectivity,76 but here they can be seen directly.For this population of individuals with minor stroke and cognitive impairment, we chose to evaluate functional connectivity using MEG. fMRI, with its relatively low temporal resolution (i.e. seconds not milliseconds), cannot capture critical neural processes such as beta-band activity in the motor cortex.Critically, our results demonstrate consistent connectivity patterns in the control group across visits, as expected. In contrast, the detected GC networks for the patients’ first visit exhibit significantly reduced FPC involvement in cortical connectivity. By the second visit, the GC connections involving FPC markedly resemble those of the control group, with enhanced connections bidirectionally, but particularly towards the contralesional hemisphere. This may indicate the flow of information away from the damaged hemisphere as a potential mechanism for compensation within the network. By visit three, there are fewer of these connections and less reliance on communication with the contralesional hemisphere, perhaps as the damaged hemisphere begins to heal and increases its role in network dynamics once again for those who continue to improve, demonstrating the need for the continued evolution of the network to optimize recovery. Importantly, there appeared to be divergent patterns of directional functional connectivity between those with favourable versus unfavourable long-term recovery profiles, even early on, though most pronounced at visit 3. These network-level functional changes are strong candidates for the compensatory mechanisms of cognitive recovery, and their presence on MEG suggests it may be a useful biomarker of recovery or even a potential predictor of longer-term function and is useful clinically. It also suggests that augmentation of the network through pharmacologic mechanisms or neurostimulation, enhancing or inhibiting input from specific areas at various stages of recovery, may help to hasten or augment improvement.This study does have limitations. It is a small sample size, consisting of six patients and four controls from a single center. Strokes are heterogeneous in their location. However, the pattern of clinical deficits, as well as the pattern of neural activity measured by MEG, is consistent across patients, independent of stroke location, and distinct from the control group. The NLGC methodology demonstrates consistent robust results even in such a small sample, that is consistent with prior studies evaluating similar brain regions, as well as prior indirect evidence in patients with minor stroke symptoms. In addition, patients were divided into ‘favourable’ and ‘unfavourable’ long-term recovery based on their overall multi-domain performance but had some variability. While we were able to directly illustrate the overall consistency between groups by adding longitudinal plots of the directional connectivity, a larger study would be needed to evaluate the connectivity of specific cognitive networks that may affect individual task performance. Finally, while network-level functional changes may represent compensatory mechanisms and serve as a potential target for future augmenting therapies, we lack the ability to conclusively determine their significance and whether they represent the cause or effect of recovery patterns.predicting long-term outcome. A larger study, evaluating additional frequency bands and specific cognitive networks is needed, along with secondary analyses evaluating the implications of stroke laterality on recovery patterns.Despite these limitations, our findings support many key concepts: (1) early post-stroke cognitive dysfunction appears to be associated with impaired functional connectivity that is independent of lesion location in individuals with minor stroke; (2) an increase in inter-hemispheric connections, with initial reliance on an increase in the connections between hemispheres, is associated with clinical improvement months after recovery; (3) MEG may be a useful biomarker to explore connectivity changes associated with the recovery and surrogate outcome metric for future treatment trials, though further studies with a larger sample size are needed to determine if the number of inter-hemispheric links is directly correlated to the degree of clinical improvement and whether it may also have a role in


Eye movements are often directed toward stimuli with specific features. Decades of neurophysiological research has determined that this behavior is subserved by a feature-reweighting of the neural activation encoding potential eye movements. Despite the considerable body of research examining feature-based target selection, no comprehensive theoretical account of the feature-reweighting mechanism has yet been proposed. Given that such a theory is fundamental to our understanding of the nature of oculomotor processing, we propose an oculomotor feature-reweighting mechanism here. We first summarize the considerable anatomical and functional evidence suggesting that oculomotor substrates that encode potential eye movements rely on the visual cortices for feature information. Next, we highlight the results from our recent behavioral experiments demonstrating that feature information manifests in the oculomotor system in order of featural complexity, regardless of whether the feature information is task-relevant. Based on the available evidence, we propose an oculomotor feature-reweighting mechanism whereby (1) visual information is projected into the oculomotor system only after a visual representation manifests in the highest stage of the cortical visual processing hierarchy necessary to represent the relevant features and (2) these dynamically recruited cortical module(s) then perform feature discrimination via shifting neural feature representations, while also maintaining parity between the feature representations in cortical and oculomotor substrates by dynamically reweighting oculomotor vectors. Finally, we discuss how our behavioral experiments may extend to other areas in vision science and its possible clinical applications. Although you attempt to ignore all other colors, you occasionally find yourself distracted by the same pair of bright red socks, which repeatedly draw your gaze back to them. Anecdotes like this illustrate how visual features guide our voluntary and reflexive eye movements in our daily lives, a phenomenon also routinely observed in primate vision experiments. For example, when humans or monkeys perform goal-directed search for a previewed target, their eye movement selections  and sacc2.Feature-guided eye movements require several processing steps: the spatial position of potential eye movement targets must be encoded, each potential target must be feature-weighted according to behavioral goals, a winner in the set of potential targets must be selected, and the spatial code of the winner must be converted into movement instructions and sent to the extraocular muscles. All these processing steps are observed in the oculomotor substrates of the primate nervous system.The primate oculomotor system encodes the loci of visual stimuli and potential eye movements as direction-amplitude vectors on orderly retinotopic motor maps, whereby sufficient activation of a specific vector elicits an eye movement with the corresponding direction and amplitude . This iscf.Two alternative explanations could account for feature-reweighting of competing incipient oculomotor programs routinely observed in oculomotor research: oculomotor substrates process visual features independently of and in parallel to the perceptual system, or alternatively, potential eye movements encoded in oculomotor substrates could be dynamically feature-weighted by the perceptual system. Although the latter account is widely held—that feature inputs from the perceptual system are pivotal for feature-guided eye movements cf.—a more dIn this article, we have several goals: (1) to dispel the notion that oculomotor substrates are sufficient for feature-guided eye movements, and to argue instead that feature-reweighting of oculomotor vectors is driven by dynamic input from the perceptual system; (2) summarize recent experiments revealing the feature-dependent time scale of visual encoding in the oculomotor system; (3) based on these experiments, propose a broad theoretical account of the interplay between perceptual and oculomotor systems that facilitates top-down feature-guided eye movements and bottom-up feature encoding in oculomotor substrates more broadly; and (4) lastly, to discuss how the same experimental paradigms used to measure the latency of feature information in the oculomotor system can be used to answer other questions in vision science and possibly even offer a practical diagnostic tool in clinical neuropsychology.3.For neural systems to be even theoretically capable of guiding behavior to specific visual features, they must include feature filters that intrinsically encode specific visual features. In this section, we summarize experimental evidence spanning decades that demonstrates that oculomotor substrates depend upon cortical inputs for feature information. In this view, oculomotor substrates contribute to target selection by integrating visual feature information onto spatial movement coordinates. If so, oculomotor and perceptual substrates ought to be functionally dissociable. Therefore, in this section we also summarize the evidence from ablation, inactivation, and microstimulation studies supporting this functional dissociation.3.1.cortical visual hierarchy. The cortical visual hierarchy is primarily organized such that vision is successively projected to increasingly anterior cortical sites along the posterior-to-anterior axis. Intriguingly, the cortical visual hierarchy also exhibits functional hierarchical organization, as the receptive field size, visual onset latency, and representational complexity of visual neurons within modules successively increases at each level of the anatomical hierarchy. Although there is debate about whether the functional-anatomical hierarchical correspondence has meaningful implications for the nature of visual processing more broadly . These feature representations are then projected upstream to the next processing stage where they are pooled or transformed into increasingly complex feature representations . As neurtarget selection. Target selection refers to the oculomotor behavior whereby a target must be discriminated from distractors and selected for an eye movement. Often, this discrimination is based on visual features  layers of SC: orientation  for which the lesioned cortex was specialized. Fascinating examples include achromatopsia and akinetopsia, the inability to perceive color or motion (respectively), reviewed elsewhere e.g., . These oper se; however, to make visually-guided saccades into their lesioned visual field, they reply upon idiosyncratic compensatory strategies that exploit vision from their intact visual field  non-invasively infer the oculomotor encoding time course of a visual stimulus and (2) compare this time course between different visual features that constitute the visual stimulus see .In our paradigm , 2023, hSeveral recurring patterns of behavior were observed using this paradigm see : (1) at The most clear and parsimonious interpretation of these behavioral results is that, in oculomotor substrates like SC, the visual onset burst encoding the distractor was spatially averaged with the developing target-directed saccade program see . First, 4.1.The most intriguing results from our SDOA paradigm arose when we compared the saccadic perturbation  time course between different distractor visual features. In the original implementation , we compA 20–30 ms lag between color and luminance encoding is consistent with the visual onset latency differences observed in the magnocellular and parvocellular layers of the lateral geniculate nucleus (LGN), between layers 4B/4Cα and 4Cβ in V1, or between the thick and pale thin layers of V2 . The ana4.2.channels of the cortical visual hierarchy. But it remained difficult to determine whether feature information is projected into the oculomotor system from the relevant stage of processing in the cortical visual hierarchy. We therefore recently repeated the original paradigm replacing the distractor features with static and motion-animated gratings  where simple geometric subunits represented in downstream modules are concatenated into coherent objects , 2006. A5.base representation , then the same cortical module(s) are recruited to encode all visual stimuli. Thus, the cortical bottleneck applies equally to all stimuli in this context. We therefore do not expect a visual onset burst latency difference between stimuli, as is seen. After the feature-dependent cortical modules are recruited for the task and begin representing the visual stimuli, the cortical feature discrimination process begins. Once commenced, these relevant cortical module(s) dynamically reweight the oculomotor vectors to maintain parity between oculomotor and cortical feature representations. Thus, we observe target features activate and distractor features deactivate over time in oculomotor substrates during target selection.Neurophysiological investigations of saccadic target selection typically utilize discriminations between different features of the same visual attribute . In these experiments, oculomotor visual onset bursts for targets and distractors have identical latencies. Shortly thereafter however, the activation level of the target gradually increases, while the activation level of distractors gradually decreases . These odiscrimination in oculomotor substrates, but more broadly feature representation in oculomotor substrates. In two of our experiments   similarlAnother important consideration is that examining the onset of feature sensitivities as opposed to visual onset latencies likely provides a better indication of when feature information arrives in oculomotor substrates. As discussed, oculomotor stimulus encoding evident in neural spikes is usually feature invariant for the initial ~100 ms after stimulus onset . Our own6.3.We argued strongly that feature information manifests in oculomotor substrates only after antecedent featural processing in cortical substrates. However, a number of studies suggest that this relationship is far more reciprocal than has been outlined here. In a seminal experiment, These observations clearly and elegantly demonstrate that feature representations in visual cortices are modulated by reciprocal feedback from upstream oculomotor substrates. What is less clear from these experiments is whether the modulation of downstream sensory representations is feature-based or purely spatial. Afterall, microstimulating FEF also produces behavioral effects akin to exogenously cueing spatial attention , 2004, sOther experiments have provided evidence of feature processing in oculomotor substrates manifesting earlier than in select visual cortices. showed that feature discrimination occurs in FEF 30–50 ms before it occurs in V4 during cued visual search for complex objects. Similarly, First, it is entirely possible that the choice of visual modules on these tasks were higher in the visual hierarchy than was sufficient to discriminate the stimuli. That is, perhaps if an earlier module was recorded from, feature discrimination would occur earlier in the visual module than in the oculomotor module. For example, substituting V2 for V4 in the case of LGN with V1 in the case of Clearly, reciprocal interactions between oculomotor substrates and sensory cortices are well-supported experimentally. However, reciprocal sensorimotor interactions are not mutually exclusive with the theory posited here. Future investigations could examine potential latency differences between stimulus attribute types  and may discover that although feature discrimination in oculomotor substrates does precede feature discrimination in visual cortices , discrimination for more complex features occurs later than simpler features within those oculomotor substrates.7.The SDOA paradigm can be used to answer a broad range of questions in vision and cognitive science and has many clinical applications. Inferring stages of processing has been a central theme of vision and cognitive science throughout the entire contemporary period e.g., . Our parThere is a clinical tradition of using eye movements for early diagnosis of neurological disease and abnormality (for review, see 8.Visual features often guide primate eye movements  and can The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.DK drafted the manuscript and prepared the figures. DK and MF revised the manuscript. MF approved final draft of the manuscript. All authors contributed to the article and approved the submitted version.


Notch signaling is necessary for the development of many organ systems, including the nervous system, biliary system, and visual and auditory sensory systems. This signaling pathway is composed of DSL ligands and Notch receptors. Upon the interaction of those components between neighboring cells, the intracellular domain of the Notch receptor is cleaved from the cell membrane to act as a transcription factor. To date, many mechanistic insights, including lateral inhibition and lateral induction, have been proposed from observation of patterning morphogenesis and expression profiles of Notch signaling-associated molecules. The lack of a direct measurement method for Notch signaling, however, has impeded the examination of those mechanistic insights. In this mini-review, recent advances in the direct measurement of Notch signaling are introduced with a focus on the application of genetic modification of Notch receptors with the components of the Cre/loxP system and Gal4/UAS system. The combination of such conventional genetic techniques is opening a new era in Notch signaling biology by direct visualization of Notch “signaling” in addition to Notch signaling-associated molecules. The Notch signaling pathway is a well-conserved signaling pathway  that is Drosophila neurogenesis, where Notch signaling dictates undifferentiated ectodermal cells to differentiate into neural cells that are located in a scattered fashion in epidermal cells  formation , retina Drosophila neurogenesis. A recent computer simulation study suggested that ductal plate formation  was achieved under some special DSL ligand or Notch receptor production rates (production rates of either DSL ligand or Notch receptors were low in hepatoblasts) otherwise achieving fine-grained patterning  and interspersed glial cells. During their development, ganglion cells are first generated from multipotent retinal progenitor cells and other types of cells, and those layers are subsequently generated  would affect the visualization of ongoing Notch1 signaling. For example, on one hand, the intestinal crypt cells were labeled with ongoing Notch1 signaling in the Gal4/UAS system . On the in vivo  has been developed  (they named this synthetic Notch receptor as “synNotch”) . They exin vivo . Integraeveloped , just fuFinally, some transgenic mouse resources, including UAS-Cre-T2A-miRFP670 mice (RIKEN BRC Number: RBRC11716) and R26GRR mice (RIKEN BRC Number: RBRC04874), are available from the National BioResource Project of Japan through the Institute of Physical and Chemical Research (RIKEN). Although past studies have provided many mechanistic insights, Notch signaling biology in patterning morphogenesis is still ongoing.


We discuss the case of a 42-year-old woman who presented with severe left cubital tunnel neuropathic pain and subsequently developed a vesicular rash spanning the C8-T1 dermatomal distribution. These symptoms resolved after initiation of acyclovir, highlighting VZV brachial plexopathy as a potentially treatable etiology of acute onset severe neuropathic pain. Herpes zoster, or shingles, is a common condition caused by reactivation of the varicella-zoster virus (VZV), a double-stranded DNA alphaherpesvirus . ShingleWe present the case of a 42-year-old who presented with five days of severe left cubital tunnel pain and ulnar sided hand paresthesias, ipsilateral acute shoulder pain, and a vesicular rash in the C8-T1 distribution which resolved with antiviral treatment– consistent with a clinical diagnosis of lower trunk herpes zoster. An unusual aspect of this case was that it presented with pain without objective neurological deficits.A 42-year-old otherwise healthy woman presented to hand surgery clinic with five days of acute onset severe pain over her left cubital tunnel, three days of ipsilateral shoulder pain, and one day of a vesicular rash along her ulnar palm and dorsal ulnar forearm. She was without recent injury, immunization, or illness. Her history was notable for self-limited varicella zoster infection in childhood. Prior to this episode she endorsed intermittent episodes of nighttime waking with paresthesia of her ring and small finger but did not carry a diagnosis of cubital tunnel syndrome.Her physical exam was notable for the presence of a clustered vesicular rash over her hypothenar eminence and dorsal ulnar forearm which she said only appeared that day. She had trace edema, and severe tenderness to palpation over the ulnar nerve at the left cubital tunnel without overlying rash. She had no objective loss of strength of the upper extremity and was without intrinsic weakness or clawing. Notably, her cubital tunnel compression (elbow flexion test) and Tinel’s tests were positive, though she displayed normal two-point discrimination across all fingers.Initial differential diagnosis included Varicella zoster reactivation of the brachial plexus lower trunk versus Parsonage Turner syndrome (PTS). She was treated with one week of Acyclovir. Given lack of objective motor or sensory deficits the decision to proceed with EMG, MRI or urgent cubital tunnel decompression was deferred. Objective findings were notable for persistent cubital tunnel swelling and a positive cubital tunnel compression test. Within two weeks of initiating acyclovir, she experienced significant improvement in her symptoms. As seen in This case report details an unusual presentation of herpes zoster involving the lower trunk of the brachial plexus, characterized by acute ipsilateral shoulder pain followed by neuropathic pain in and then eruption of a vesicular rash along the C8-T1 dermatomes.Cases of lower trunk brachial plexopathy associated with zoster reactivation have rarely been described in the literature. Those reported have generally been associated with moderate to severe sensory or motor impairment ,7. SegmeA case report published by Cukic is most similar to our patient, describing a woman with acute pain of the right scapula, elbow and the ulnar aspect of the forearm who later developed a hemorrhagic vesicular rash in the distribution of the ulnar nerve . Their pInitially, due to the ipsilateral shoulder discomfort, a diagnosis of Parsonage Tuner Syndrome (PTS) was considered. PTS, also referred to as brachial plexus neuritis or neuralgic amyotrophy, typically presents as severe pain across the shoulder preceding weakness of the muscles of the shoulder, arm, wrist, or hand . The mecNucleoside analogues such as acyclovir, valacyclovir, or famciclovir have replaced vidarabine and interferon alpha as the standard treatment for Herpes Zoster, most effective when initiated within 72 h of rash onset ,14. AcycIn conclusion, we describe a patient with acute pain of the shoulder who subsequently developed a vesicular rash along the C8-T1 dermatomes. While previous studies have described brachial plexus involvement by herpes zoster, generally these cases are associated with weakness or sensory impairment. Interestingly, our patient had pain as the primary manifestation, likely in part due to nerve edema and secondary compression of the ulnar nerve within the cubital tunnel. It is important to acknowledge that while VZV is a clinical diagnosis, our case report has several limitations including lack of EMG, nerve conduction studies, MRI imaging or VZV serology. These diagnostic studies were deferred as they were not clinically indicated or necessary for appropriate treatment for this patient but were a part of her plan if she didn’t promptly improve. Nevertheless, we believe our case report adds value to the literature given the paucity of information regarding brachial plexus VZV neuropathy. Our patient’s symptoms completely resolved within weeks after initiation of acyclovir. Fortunately, this patient happened too present to our clinic on the day the rash first appeared, allowing prompt initiation of treatment. This case highlights a potentially treatable etiology that should be on the differential of acute onset severe neuropathic pain.


Breast cancer is the predominant cancer affecting females in Australia. With the rising obesity rates, the number of obese breast cancer patients is also rising. Full complex breast reconstruction is known to carry significant risk of complications in obese patients, hence we sought to utilize Goldilocks mastectomy as an alternative middle-ground option between standard mastectomy and complex breast reconstruction.A 63-year-old obese female presented with left nipple inversion. Ultrasonography revealed a 9.7 mm dilated retroareolar duct within the left breast, indicating lobular carcinoma. Subsequent biopsy analysis revealed estrogen/progesterone receptor (ER/PR)-positive cancer with equivocal human epidermal growth factor receptor 2 (HER2) status and a Ki67 index of 10%. Concurrently, a discrete area of conspicuous breast tissue prominence displayed characteristics of invasive ductal carcinoma with similar receptor status but a reduced Ki67 index of less than 5%. Traditional breast reconstruction options were unfavorable due to obesity, prompting consideration of a tailored Goldilocks mastectomy. The procedure was uncomplicated, and follow-up assessments revealed commendable wound healing, alongside the restoration of symmetrical breast contours.Conclusion: This study highlights the significance of Goldilocks mastectomy as an invaluable technique in the comprehensive management of breast cancer, particularly for obese patients characterized by a body mass index (BMI) exceeding 35 and substantial medical comorbidities. Breast cancer is the most common cancer among females in Australia and is the second most common cancer diagnosed in Australia . ConcurrA 63-year-old obese female presented for investigation of left nipple inversion. Ultrasonography revealed a 9.7 mm dilated retroareolar duct within the left breast, replete with internal debris. Subsequent biopsy analysis revealed the presence of lobular carcinoma, characterized by estrogen receptor (ER) and progesterone receptor (PR) positivity, equivocal human epidermal growth factor receptor 2 (HER2) status, and a Ki67 index of 10%. Concurrently, a discrete area of conspicuous breast tissue prominence, situated at the 10 o'clock position, approximately 5 cm from the nipple, displayed strong posterior acoustic shadowing on ultrasound. Histological examination of the biopsied tissue confirmed the presence of invasive ductal carcinoma, similarly demonstrating ER/PR positivity, and equivocal HER2 status, albeit with a reduced Ki67 index of less than 5%.The patient underwent further consultation with a breast surgeon and plastic surgeon to discuss mastectomy options. It is noteworthy that she did not want a standard mastectomy. Unfortunately, her obesity rendered traditional breast reconstructive options, including therapeutic mammoplasty, implant-based reconstruction, and free flap procedures, untenable due to elevated susceptibility to adverse outcomes, including tissue necrosis and infection.To address this complex predicament, a tailored approach involving a Goldilocks mastectomy was offered to her. Figure Subsequent follow-up assessments at three weeks, two months, and six months post-operatively, as pictured in Figures Goldilocks mastectomy is a form of skin-sparing mastectomy with a Wise pattern incision, followed by the formation of a breast mound using residual inferior mastectomy flap tissue. This technique was first described in 2012 by Richardson and Ma. The name is inspired by the fairytale character Goldilocks, in that this technique offers a more esthetic outcome compared to conventional mastectomy but at the same time avoids the complexity of formal breast reconstruction . DespiteThe surgical steps can be outlined as follows. Wise pattern markings are made pre-operatively with the patient standing. The apex of the reduction pattern is positioned along the breast meridian projecting forward from the level of the inframammary fold. Vertical limbs are then drawn at an 80-degree angle. The medial and lateral horizontal lines are then drawn Figure . These lThe key benefit of Goldilocks mastectomy is that it is a single-step procedure, avoiding the need for a second procedure and hence reducing the potential complications of a second surgery as well as implant or flap-related complications . PatientAs with any skin-sparing mastectomies, the Goldilocks technique removes all breast tissue preserving as much skin as possible along with the inframammary fold. The difference between Goldilocks mastectomy and other skin-sparing mastectomies is that immediate breast reconstruction is achieved using local residual mastectomy flaps rather than implant or distant flaps. Therefore, the Goldilocks technique is better suited for women with larger breasts or breast ptosis, who will have sufficient local soft tissue to re-create the breast mound . SmallerFurther advancements have allowed the preservation of the nipple-areolar complex using a dermal pedicle or a Skin-sparing, Wise patterns, Internal Mammary perforator (SWIM) flap -15. GoldGoldilocks mastectomy is not only a surgical technique but a tailored solution between standard mastectomy and conventional breast reconstruction. It addresses the needs and considerations of patients with obesity and significant medical comorbidities. This study serves as yet another descriptive example of the effectiveness and value of Goldilocks mastectomy, and we hope to see an increase in the application of this technique in enhancing outcomes and patient satisfaction in the realm of breast cancer treatment.