Neuromodulation of central and peripheral neural circuitry brings together neurobiologists and neural engineers to develop advanced neural interfaces to decode and recapitulate the information encoded in the nervous system. Dysfunctional neuronal networks contribute not only to the pathophysiology of neurological diseases, but also to numerous metabolic disorders. Many regions of the central nervous system (CNS), especially within the hypothalamus, regulate metabolism. Recent evidence has linked obesity and diabetes to hyperactive or dysregulated autonomic nervous system (ANS) activity. Neural regulation of metabolic functions provides access to control pathology through neuromodulation. Metabolism is defined as cellular events that involve catabolic and/or anabolic processes, including control of systemic metabolic functions, as well as cellular signaling pathways, such as cytokine release by immune cells. Therefore, neuromodulation to control metabolic functions can be used to target metabolic diseases, such as diabetes and chronic inflammatory diseases. Better understanding of neurometabolic circuitry will allow for targeted stimulation to modulate metabolic functions. Within the broad category of metabolic functions, cellular signaling, including the production and release of cytokines and other immunological processes, is regulated by both the CNS and ANS. Neural innervations of metabolic (e.g. pancreas) and immunologic (e.g. spleen) organs have been understood for over a century, however, it is only now becoming possible to decode the neuronal information to enable exogenous controls of these systems. Future interventions taking advantage of this progress will enable scientists, engineering and medical doctors to more effectively treat metabolic diseases. Historically treated through pharmaceutical interventions, metabolic functions play a crucial role in the pathophysiology of numerous diseases. Despite the widespread success of pharmacological approaches in treating disease, many problems remain and prevent the alleviation of the symptoms for patients with chronic metabolic illnesses. Sides effects, drug resistance and patient compliance are just a few of these obstacles. Many chronic diseases are, or become, treatment resistant, further limiting the application of pharmaceutical treatments. This has led to a new wave of interest in alternative therapeutic strategies to treat chronic metabolic diseases. A promising approach involves the stimulation of nerves that contribute to the pathology through dysregulation of metabolic functions. Silencing or activating nerves to control organ and tissue functions is referred to as bioelectronic medicine. Rather than pharmaceutical, this approach uses electroceutical interventions to restore function and ameliorate symptoms of disease. Electrical stimulation of the brain and nerves can improve the quality of life in patients suffering from otherwise refractory diseases. However, many challenges remain in the integration of abiotic implants into biological tissues, including foreign body reactions, artificial stimuli and long-term maintenance that requires follow-up invasive surgeries. Strategies using miniaturization, soft materials and biomimicry improve outcomes and prolong device fidelity, however, fundamental limits remain to be overcome. In the case of progressive degenerative diseases, such as Type 1 diabetes (T1D), loss of function due to cell death cannot be replaced through bioelectronic interventions. Engineering rationally-designed multicellular biological circuits, or biocircuits for short, provides a promising solution to overcome the remaining challenges. Autologous, living tissue implants could restore lost tissues and functions, as well as providing life-long, seamlessly biointegrated implants for the treatment of chronic diseases.Neuromodulation of metabolic functions is an exciting approach for restoring health through targeted stimulation of neural circuitry innervating organs and tissues. Metabolism is defined as cellular events that involve catabolic and/or anabolic processes, including control of systemic metabolic functions, as well as cellular signaling pathways, such as cytokine release by immune cells. Compared with neuromodulation of behaviors, electrical stimulation to modulate metabolic functions results in subtler, but no less important, changes in physiology see Fig. a. ElectrMetabolic functions extend beyond processes that control systemic metabolism. All cellular signaling pathways, for instance the production and release of cytokines by resident immune cells, also belong to metabolic functions subject to regulation by neuronal circuits. Cytokines are protein signals produced and secreted primarily by immune cells that trigger changes in immune function, such as inflammation. Inflammation is characterized by swelling, redness, heat and pain and is driven by an increased production and release of pro-inflammatory cytokines typically from resident immune cells (e.g. macrophages). Neurogenic inflammation — neural regulation of immune responses — was first discovered over 100 years ago , 28. AutHistorically treated through pharmacological therapies, metabolic disorders, such as T1D, are now routinely treated through advanced technology-assisted pharmaceutical interventions that employ biosensors  and closbiocircuits for short) of an autologous origin [Pre-clinical studies show promising restoration of glucose responses using β-cell clusters generated from stem cells , 99. Hows origin . We wills origin , 96 to rRegulating metabolism is a vital function for survival and requires the coordinated activities of many physiological systems. The central nervous system (CNS) is integral for the regulation of metabolism by directly sensing metabolic states and releasing neuroendocrine signals. The CNS also communicates with the body via cranial and spinal nerves through both efferent and afferent fibers. Both sympathetic and parasympathetic circuits influence metabolic functions, such as energy expenditure  and circThe brain constantly monitors the metabolic states of the body. Information from peripheral metabolic organs such as the pancreas, skeletal muscles and liver Fig. a is carrDifferent populations of neurons respond to metabolic cues to promote behavioral responses. Two important populations are the pro-opiomelanocortin (POMC) neurons and the agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons . POMC neThe ARC in the hypothalamus contains both neuronal populations and has projections to the periventricular nucleus (PVN). Secondary neurons in the PVN play an important role in controlling the release of neuroendocrine signals to regulate blood glucose levels . This neNeurometabolic circuitry between the hypothalamus and brainstem relay information about the states of the body through multiple pathways , 97. SenNeuroimmune circuitry regulates the metabolic states of immune cells . Both syThe sympathetic nervous system (SNS) regulates energy expenditure, metabolite release and glucose homeostasis through noradrenergic signaling in the peripheral tissues and organs Fig. . β-adrenParasympathetic fibers innervate metabolic regulatory organs, such as the pancreas Fig. . These nSensory neurons innervating barrier surfaces , 106 dynAutonomic regulation of systemic immunity began to be appreciated with the identification and isolation of ACh in the spleen  and demoACh in the spleen reduces splenic inflammation leading to the notion of the “cholinergic anti-inflammatory pathway” , 91, rev®, is a sympathomimetic amine approved for the treatment of obesity [Amphetamines demonstrate that pharmacological control of neurometabolic circuitry can be used to control metabolic functions. Many pharmaceutical interventions targeting neuronal activities alter metabolism based on the mechanism of action of amphetamines. Phentermine, marketed under the generic name ADIPEX-P obesity  and trig obesity . Beyond The discovery and isolation of insulin almost 100 years ago revolutionized the treatment of T1D and allowed patients to maintain a more stable glycemic index. Daily injections of long acting insulin represent the beginning of pharmaceutical treatment for T1D  to advanced technologies for drug delivery and monitoring, including systems of sensors and networked insulin pumps. Bioelectronic medicine continues to progress in the treatment of many other diseases using various neuronal interfaces to control both CNS and PNS functions (Fig. Innervated, stem cell-derived β-cell transplants may provide a robust and life-long symptom management by resupplying both the lost cells and their control neural circuit. Recent advances in the vascularization of biologically engineered transplants  have draβ-cells are electrochemically active cells , 88, 89 Such biocircuit-augumented islet transplants may one day be used as a replacement therapy for T1D. Although still in the early stages of preclinical research, transplanted islets greatly improve the glycemic control in animal models of diabetes. However, they lack the important cholinergic innervation found in situ. Biocircuit-augumented islet transplants containing mature, vascularized and innervated β-cells will better mimic the endogenous glycemic control dynamics inside the pancreas. Such an attempt to restore the endogenous release of insulin could provide a lifelong relief for patients with T1D and may one day become the standard care for T1D.In this review, we have revealed the technological progression from pharmaceutical to bioelectronic medicine as targeted and precise therapeutics for refractory diseases characterized by dysregulation of metabolic functions. Despite the enormous progress in miniaturization and biomaterials, electronic medical implants still suffer the long-term challenges of host rejection, artificial stimulation, and deterioration. Therefore, we have proposed a succeeding solution of biologically engineered smart biocircuit implants. Furthermore, looking through the lens of history, we envision that this technological succession will lead to a future in which rationally designed, multicellular biocircuits will allow for the engineering of autonomously responsive medical implants to replace and restore functions to tissues lost in the pathology of metabolic diseases. Both T1D and chronic inflammatory diseases share similar characteristics in that metabolism, defined as cellular catabolic and/or anabolic processes, is disrupted, leading to systemic complications. Neurometabolic circuitry provides many access points for the neuromodulatory treatment of such diseases. Targeting neurometabolic circuitry using transplantable biocircuits holds a great promise to restore both the lost cells and functions, as well as providing life-long, seamlessly biointegrated prosthetics for the patients.


Transcatheter embolization is a well-established treatment for renalarteriovenous fistula (AVF) in selected cases. Transarterial approach has beenthe conventional route of access of the AVF. In large arteriovenous shunts,however, transarterial approach inherits the risk of distal migration ofembolization material with subsequent pulmonary embolism. We report a case ofgiant high-flow renal arteriovenous fistula treated with coil embolization.Arterial approach was attempted with double catheter technique, howevercomplicated with coil mass dislodgement. We have retrieved the coil mass viatransvenous route with simultaneous pulmonary circulatory protection andsubsequent successful transvenous coil embolization with complete obliterationof the AVF was performed. Our patient was a 54-year-old female with unremarkable past medical history. She wasnoted to have suspected left hydronephrosis and hydroureter on an ultrasound studyduring routine health check .SubsequThe patient had a history of trauma during childhood, in which she fell on steelsticks with puncture wounds over her left back. She did not seek medical help atthat time. In view of the significant size of the shunt and to prevent furthercomplications that may arise, the patient preferred to undergo endovasculartreatment after discussion of risk and benefits.Angiography and endovascular therapy were performed using the Siemens Axiom-Artissystem . On the pre-procedural leftrenal artery digital subtraction angiogram (DSA), a large AVF was confirmed locatedat the left renal upper pole. At least two direct fistula sites were seen onreal-time fluoroscopy leading to the early opacified dilated left renal vein, whichmeasured about 24 mm in calibre. Bulbous dilatation of the vessel just proximal tothe fistulas are seen. .We have navigated into a distal left upper pole arterial branch, just adjacent to thesite of fistula with the use of a 2.8 Fr Direxion HI-FLO microcatheter  and 0.014’’ Transend EX Floppymicro-guidewire . We made two attempts incoiling via this route. With the use of a Ruby detachable coil , failure to anchor the vessel wall with repeated prolapseinto the left vein was encountered. In our second attempt with the use ofdouble-catheter technique, another 2.5 Fr Renegade microcatheter  was navigated to the bulbous dilatation just proximal tothe AVF. An Interlock-18 Fibered IDC Occlusion System  was introduced via the secondmicrocatheter in attempt to entangle the Ruby coil; however, accidental deploymentwas encountered with the coil mass migration into the left renal vein distally.We have decided to snare and retrieve the coil mass through transvenous approach. Viabilateral common femoral vein (CFV) punctures, two 6 Fr guiding sheaths  were inserted through each CFV withboth tips placed at the left renal vein. Two 6 Fr EN Snare Endovascular SnareSystems  12–20 mm were used. The first snarewas placed at the left renal vein to prevent migration of coil mass, while thesecond snare was used for coil mass retrieval . While tAfter retrieval of the coil mass, we proceeded to access the renal AVF viatransvenous approach. The wide calibre of the left renal vein resulted inchallenging retrograde navigation and entrance into the fistula. Combinedtransvenous and transarterial approach and a through-and-through wire technique wereutilized in effort to track the microcatheter from venous side-to arterial side. A300 cm 0.014″ Synchro guidewire  wasthreaded into the left renal vein from arterial side. The Synchro guidewire was thensnared by a 4 Fr 10 mm Goose Neck snare  and then gentlypulled back into the 6 Fr guiding sheath at the venous side. The attempt wasunavailing as high resistance was encountered towards the end of pulling, probablydue to acute angulation, thus this technique was abandoned.The bulbous dilatation just proximal to the fistulas was finally successfully enteredby transvenous approach, by establishing tri-axial access through venous side-usinga 6 Fr guiding sheath at left renal vein, a 5 Fr Cobra one catheter  at left renal vein near the fistula, and a 2.8 Fr Direxion HI-FLOmicrocatheter at the bulbous dilatation. Retrograde navigation to the left upperpole renal arterial branch leading to the fistula was performed. This arterialbranch and the bulbous dilatation were packed by six detachable coils, includingthree Ruby Standard coils , one Ruby Soft coil (8 mm × 60 cm) and two Penumbra Occlusion Device (POD)Packing Coils  . Complete obliteration of thefistula with preservation of most of the renal arterial branches was achieved onimmediate post-treatment angiogram .On follow up time-resolved MR angiogram acquired with a 1.5-T scanner  3 months later, the left renal veinshowed reduction in calibre and no early venous shunting, suggesting successfulobliteration of the renal AVF .1 Majority of renal AVFs are acquired, which can be traumatic or non-traumaticin aetiology. Traumatic causes include blunt or penetrating trauma, biopsy andsurgery. While non-traumatic causes include inflammation, neoplasm or renal arterialdiseases such as dissection or fibromuscular dysplasia.2Renal AVF is a direct communication between artery and vein without interveningvascular nidus. It is an uncommon disease entity with prevalence of about 0.04% inthe general population.Renal AVFs have a range of different presentations. They can be incidental with abruit on physical examination, or can causes flank pain, haematuria, hypertensionand high-output cardiac failure. No established guideline for treatment exists withaccepted indications include large or progressive increase in size of the AVF,symptomatic patients with non-resolving haematuria or haemodynamic compromise fromthe AVF. Treatment options include endovascular approach and surgery.1,3 This classification also serves as a guidance for choice of embolizationmaterial. In Type I non-traumatic AV shunts, a single or few arteries shunt to asingle dilated draining vein. In Type II, multiple arterioles shunt to a singledilated draining vein. While Type III shunts are those with a complex vascularnetwork formed between multiple arterioles and venules.In terms of their angio-architecture, traumatic renal AVFs are often seen as a singledirect fistulous communication between renal artery and an adjacent vein withoccasionally co-existing pseudoaneurysm. For non-traumatic cases, Cho et al hasproposed a classification of peripheral arteriovenous malformation in terms ofangio-architecture which others have adopted its use in renal AV shunts.4 N-Butyl cyanoacrylate (NBCA) use after placement of some coils have also beenused to further achieve complete fistula occlusion.1 Particles such as Gelatin sponge or polyvinyl alcohol (PVA), and liquidembolic agents such as NBCA or Onyx maybe more suitable to be used in Type IIIarteriovenous shunts.5The goal of treatment for renal AVF is a definite closure of direct communicationbetween the arterial and venous components. For traumatic renal AVF or Type Inon-traumatic AV shunts, including our index case, the shunt should be occluded asclosely as possible to the fistulous point to prevent renal infarction. Embolizationwith coils is the mainstay of treatment by encouraging stasis of flow and inducingthrombosis. Detachable coils (such as Ruby coils used in our case) are preferred topushable coils to ensure safe sizing and accurate positioning before final releaseand deployment. Other described methods include the use of Amplatzer device,microvascular plug or stent-assisted coiling.6 Such risk might even be higher while tackling a giant high-flow AVF like inour index case. Flow control with a double catheter technique was described byMaruno et al1 which might have a lower risk of distal migration of embolic material. Twoguiding catheters were introduced to the renal artery via bilateral femoralapproach, one of it being a 5–7 Fr Balloon catheter for occlusion of thefeeding artery. Two microcatheters are then introduced to the fistulous segment viathe guiding catheter and the balloon catheter respectively for application ofembolic materials such as coils and NBCA. With flow control by the balloon cathetercausing decrease in arterial flow within the fistula, risk of distal coil migrationbefore establishing an adequate coil mesh might be reduced theoretically.In terms of the vascular access to the AVF, transarterial approach has long beenused. However, distal coil migration is a well-known complication with reportedincidence up to 8%.6 From the arterial side, a 5 Fr balloon catheter was introduced, with thesimilar aim of flow control as previously described. Both the arterial and venousaccessed microcatheters were placed at the venous sac. From the venousmicrocatheter, embolization of part of the venous sac and draining vein wasperformed first, followed by embolization of the remaining venous sac and feedingartery via the arterial microcatheter. Theoretical benefit of first performing anincomplete embolization via the venous side—is that the pressure within theAVF would not increase, hence might reduce the risk of AVF rupture.Simultaneous transarterial and transvenous coil embolization of large renalarteriovenous fistula was described by Nakayama et al.Transvenous embolization of renal AVF has not been discussed in the English radiologyliterature. In our patient, we have successfully gained transvenous access of theAVF with tri-axial access: a 6 Fr guiding sheath at left renal vein, a 5 Fr Cobraone catheter at left renal vein near the fistula and a 2.8 Fr Direxion HI-FLOmicrocatheter at the bulbous dilatation. Retrograde navigation to the left upperpole renal arterial branch leading to the fistula was obtained via Fathom-16Guidewire  and Silverspeed 0.014Hydrophilic Guidewire . This arterial branch and thebulbous dilatation were packed by six detachable coils .Transvenous access offers a benefit of allowing direct pulmonary circulationprotection from migrated embolic material in giant AVF treatment. In our patient,transvenous approach not only allowed us to retrieve the coil mass which we haveaccidentally deployed, but also to place an additional snare in the proximal portionof left renal vein close to the IVC before the manipulation and retrieval of thecoil mass in the distal renal vein, as a precautionary measure to prevent furtherinadvertent distal migration of the coil mass into the pulmonary arterialcirculation. We subsequently repositioned the protective snare to the IVC when thecoil mass was drawn through the IVC, common and external iliac veins, common femoralvein and the femoral sheath, and eventually removed via the left groin.7,8 In addition, even if the coil mass was trapped by the IVC filter, furthermeasures would then be necessary to remove the filter and the coil mass, such as bymeans of a snare. As pulmonary circulation protection was desired only during theintraprocedural period, the use of a snare would be a safer and more cost-effectiveoption.During the procedure, different pulmonary circulation protection strategies thatcould be offered were considered. Apart from the use of snare as previouslydescribed, a retrievable IVC filter was another option. However, there are otherprocedural complications from IVC filter deployment and retrieval which may occur,including malposition, defective filter deployment and vascular injury.In terms of approach to the left renal vein for coil mass retrieval in our patient,we have considered the options of right transjugular versus transfemoral approach.Benefits of a right transjugular approach include a potentially more favourablecannulation angle of the left renal vein from the IVC and obviation of additionalfemoral punctures. However, as time was of the essence for the coil mass retrieval,we have decided for femoral approach as no additional antiseptic skin preparation atthe neck was needed.In conclusion, we presented a case of a giant high-flow renal AVF successfullytreated with coil embolization. Coil mass dislodgement was encountered duringattempted transarterial double-catheter approach; transvenous approach allowed coilmass retrieval, an additional benefit of simultaneous pulmonary circulatoryprotection, and last but not least, successful reattempt of coil embolization of thefistula.Different types of AVFs in terms of their angio-architecture which guide thechoice of embolization material.Comparing different vascular accesses to the renal AVFs .The pitfall of distal coil migration in the commonly used transarterialapproach of AVF access, especially in patients with giant high flowAVFs.Transvenous approach allow simultaneous pulmonary circulatory protection andembolization of the fistula.


Levodopa-induced dyskinesias (LID) negatively impact on the quality of life of patients with Parkinson’s disease (PD). We assessed the risk factors for LID in a cohort of de-novo PD patients enrolled in the Parkinson’s Progression Markers Initiative (PPMI). This retrospective cohort study included all PD patients enrolled in the PPMI cohort. Main outcome was the incidence rate of dyskinesia, defined as the first time the patient reported a non-zero score in the item “Time spent with dyskinesia” of the MDS-UPDRS part IV. Predictive value for LID development was assessed for clinical and demographical features, dopamine transporter imaging (DaTscan) pattern, cerebrospinal fluid (CSF) biomarkers  and genetic risk score for PD. Overall, data from 423 PD patients were analyzed. The cumulative incidence rate of LID was 27.4% (95% CI = 23.2–32.0%), with a mean onset time of 5.81 years from PD diagnosis. Multivariate Cox regression analysis showed several factors predicting LID development, including female gender , being not completely functional independent as measured by the modified Schwab & England ADL scale , higher MDS-UPDRS part III score , postural instability gait disturbances or intermediate phenotypes , higher DaTscan caudate asymmetry index , higher polygenic genetic risk score , and an anxiety trait . In PD patients, cumulative levodopa exposure, female gender, severity of motor and functional impairment, non-tremor dominant clinical phenotype, genetic risk score, anxiety, and marked caudate asymmetric pattern at DaTscan at baseline represent independent risk factors for developing LID. Italian researchers identify seven independent risk factors for levodopa-induced dyskinesia in Parkinson’s disease (PD) patients. Long-term treatment with levodopa can cause uncontrolled, involuntary movements which adversely affect patients’ quality of life. Lucilla Parnetti and colleagues at the University of Perugia carried out a retrospective study of 423 patients enrolled in the Parkinson’s Progression Markers Initiative to determine factors that are predictive of levodopa-induced dyskinesia at the time of diagnosis. They found that the risk of developing dyskinesia was greater in patients who were female, carried PD-associated mutations, presented higher disease severity at the time of diagnosis or neuropsychiatric symptoms in early PD. Taking these factors into consideration in the very early phase of PD could not only improve management of the disease, but also the design of future biomarker studies and clinical trials. The Parkinson’s Progression Markers Initiative (PPMI) is a large-scale international prospective observational study, started in 2010, designed to identify markers of disease progression in de novo PD patients. Clinical, neuroimaging and CSF/blood biomarkers are collected yearly. We wanted to define factors predictive of LID development already in de novo stage of PD.Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms.Baseline demographic and disease characteristics of the cohort divided by the LID− (patients without LID) versus LID+ (patients developing LID) subgroups are presented in Table p-value = 0.089); visual inspection of martingale residuals against individual covariates supported the linearity hypothesis. The final model included disease duration , Modified Schwab & England ADL score <90 , higher MDS-UPDRS part III , contralateral putamen , the polygenic risk score , and the anxiety trait as measured by STAI subscore .The average time for initiating a dopaminergic therapy was 1 year. Multivariate Cox regression analysis has shown that a combination of several factors was mildly accurate in predicting the initiation of dopaminergic therapy . The Cox proportionality assumption was validated with chi-square test for Schoenfeld residuals  included as covariate. Female gender was associated to a greater risk of developing dyskinesia , and visual inspection of martingale residuals against individual covariates supports the hypothesis of linearity. The final model included female gender . The Cox proportionality assumption was validated with chi-square test for Schoenfeld residuals  and single photon emission computed tomography (SPECT) were used to assess changes in neurotransmitter pathways involved in dyskinesia and, subsequently, to identify imaging biomarkers for LID development. Notably, lower dopamine transporter activity in the putamen evaluated by 18F-FP-CIT-PET in de-novo PD patients has been described as significant predictor of LID.13 Our results indicate that dopamine deficits in the contralateral putamen in de-novo PD patients is an independent predictor of a shorter time to levodopa initiation. Besides, both putamen asymmetry and caudate asymmetry indices evaluated by [123I]FP-CIT-SPECT significantly correlated with the development of dyskinesia, with the caudate asymmetry entering in the multivariate model. These findings reflect previous evidences indicating a positive relationship between the striatal asymmetric index and the magnitude of response to levodopa.20 Thus, PD patients with higher striatal asymmetric index show an increase of both response to levodopa and susceptibility to dyskinesia.First of all, we confirm that female gender represents a crucial non-modifiable predictive factor for LID,21 The reason of a lower risk of dyskinesia among TD patients may lay in different patterns of nigrostriatal denervation, morphologic lesions of the basal ganglia subregions and pathophysiological mechanisms between different phenotypes.5 Furthermore, TD patients usually show lower striatal dopamine depletion compared to RA patients on [123I]FP-CIT-SPECT,22 suggesting a less pronounced predisposition to LID. Nigrostriatal dopamine depletion is one of the main prerequisite for developing dyskinesia and dopaminergic denervation is increased by disease severity. Therefore, it is not surprising that disease severity at baseline represents an important predictive factor for LID. Our findings indicate that UPDRS Part III score in de-novo patients is a significant clinical biomarker to predict dyskinesia. However, it is not fully consistent with data from STRIDE-PD trial which showed UPDRS Part II score as risk factor for dyskinesia, whereas UPDRS Part III did not correlate with dyskinesia development.19 Such contrasting results may be due to the fact that UPDRS motor score does not always reflect precisely the status of presynaptic dopamine denervation evaluated by PET or SPECT.23 The relationship between the severity of disease and the susceptibility to dyskinesia is also supported by the significant inverse correlation we found between ADL Scale score and risk of LID. Thus, patients with higher disease severity testified by greater impairment on daily living activities are more prone to develop dyskinesia. Genetic susceptibility to dyskinesia is of great interest, with conflicting results deriving from several studies focusing on single-nucleotide polymorphisms (SNPs) of different genes. PPMI polygenic risk score was developed to explain the risk of idiopathic PD onset so far and it does not include several genes that are known to increase the risk of developing LID.24 However, to the best of our knowledge, for the first time in this study we highlighted a correlation between cumulative effect of known genetic risk variants of PD and LID development. Such results, if corroborated by extensive genome-wide association studies (GWAS), might represent a focus for future research. Interestingly, we also found that anxiety was associated to an increased risk of dyskinesia. This could be linked to the relationship between dopaminergic dysfunction and neuropsychiatric symptoms in early PD.25The probability of developing dyskinesia in Parkinson’s disease is also influenced by the initial clinical phenotype. Our findings showed that tremor-dominant (TD) phenotype is at lower risk of LID compared to PIGD or Intermediate. Previous studies have already demonstrated that tremor-dominant manifestation at disease onset is associated with a reduced risk of LID compared to rigid-akinetic (RA) phenotype.Although CSF biomarkers did not explain LID onset in the Cox regression, we found that α-syn ranked 6th, according to the variable importance criterion, in the random survival forests model. This suggest that further investigations are warranted for exploring the role of CSF α-syn in predicting LID, with special attention to pay for the observation in larger cohorts or the measurement of oligomeric and phosphorylated forms.26 they were not used for evaluating qualitative and quantitative aspects of dyskinesia in the PPMI. Therefore, our results neither identified predictive factors for different types of dyskinetic complication in PD (chorea versus dystonia) nor found a possible explanation for the severity of dyskinesia.There are limitations in our data, mainly due to the evaluation of dyskinesia. Even if specific scales have been validated to assess dyskinesia in PD,In summary, our findings indicate that data deriving from a large cohort of de-novo PD patients monitored longitudinally are useful in understanding the composite aspects involved in the progression of disease. Our results highlight the role of several factors in determining dyskinesia, thus providing useful information for future design of both biomarker studies and randomized clinical trials.Overall, 423 de novo PD participants were enrolled in the PPMI study between January 2011 and December 2012. Data were obtained from the PPMI database accessed 30 December 2017.The inclusion criteria for entering PPMI were: (i) age >30; (ii) presence of at least two parkinsonian signs such as bradykinesia, rigidity and resting tremor or have an asymmetric resting tremor, or asymmetric bradykinesia; (iii) having received the diagnosis not earlier than two years before enrollment; (iv) documented reduced striatal 123-I Ioflupane dopamine transporter  imaging binding consistent with PD; (v) no ongoing symptomatic therapy. Each PPMI participant received extensive assessment of motor and non-motor features.Each participating PPMI site received approval from an ethical standards committee on human experimentation before study initiation. Written informed consent for research was obtained from all individuals participating in the study.de novo patients, we have investigated several variables available at baseline, including: (i) demographics ; (ii) bradykinesia, rigidity and tremor were assessed according to UK Parkinson’s Disease Society Brain Bank Criteria (iii) motor features -Part II and III, total tremor score, postural instability–gait disturbance (PIGD) score, tremor/PIGD motor phenotype, Schwab-England activities of daily living (ADL) score, bradykinesia, tremor, and (iv) age/education adjusted Montreal Cognitive Assessment (MoCA); (v) non-motor manifestations (MDS-UPDRS-Part I), olfactory dysfunction via University of Pennsylvania Smell Identification Test (UPSIT) score, autonomic dysfunction via Scale for Outcomes in Parkinson’s disease-Autonomic (SCOPA-AUT) total score, REM sleep behaviour disorder (RBD) via RBD screening questionnaire (RBDSQ) score, sleep disturbances via Epworth Sleepiness Score (ESS), anxiety via State‐Trait Anxiety Inventory scores (STAI), depression via Geriatric Depression Scale (GDS-15); (vi) genetic risk score including 28 independent risk variants for PD that have been selected according to the results of a meta-analysis of PD genome-wide association studies,24 also including p.N370S in GBA and p.G2019S in LRRK228; (vii) CSF biomarkers -tau, and phosphorylated tau (P-tau181) and a-synuclein); (viii) dopamine transporter imaging striatal-binding ratios (DATscan) (single-photon emission computed tomography (SPECT) with the DAT tracer 123I-ioflupane at baseline, with striatal-binding ratio calculated for left and right putamen separately using the occipital lobe as reference, obtaining ipsilateral, contralateral, mean measurements and asymmetry indices). The asymmetry index for caudate and putamen was calculated, according to PPMI indications for deriving variables, as the difference between left and right divided by the mean value.With the aim of defining predictive factors od LID development among Levodopa equivalent daily dose (LEDD) was reported for each participant reporting the initiation of dopaminergic therapy. We included total LEDD as the cumulative exposure to all dopaminergic drugs, as well as levodopa LEDD as the cumulative exposure to levodopa until the onset of dyskinesia (observed events) or the study exit (censored events).The primary outcome was the incidence of LID, defined as the first time the patient reported a positive score in the item “Time spent with dyskinesia” of the MDS-UPDRS part IV.29 a machine learning technique to determine important variables for the prediction of individual survival times. Variable selection was carried out using a conservative approach based on minimal depth criterion. Significance level of 5% was assumed for all the analyses.Statistical analyses were performed using R software version 3.4. Continuous variables were described by means and standard deviations, while categorical ones were reported as count and percentages. Predictors of LID onset were assessed using multivariate Cox proportional hazards regression models. In the absence of a conversion event, data were censored at the most recent clinic visit. We have first assessed the role of each risk factor in conjunction with the total LEDD. In order to avoid rejection of potentially important variables due to uncontrolled confounders, a p-value lower than 0.20 was used as screening criterion to consider the risk factor as candidate for the multivariate analysis. Backward elimination based on the Akaike’s information criterion was used to select a final model. Hazard proportionality was assessed through analysis of scaled Schoenfeld residuals whereas martingale residuals were plotted against continuous covariates to detect nonlinearity. As a complementary approach, we have applied random survival forests,


Tips From Former Smokerscampaign (Tips) has demonstrated significant impact as a population-based intervention for smoking cessation in the United States. Since 2012, evaluations of Tips have relied on web-panel data to attribute the campaign to smoking cessation outcomes. We re-examined the relationship between market-level doses of the campaign and quit attempts by using Behavioral Risk Factor Surveillance System (BRFSS) data to triangulate prior findings. We found that Tips was associated with increased quit attempts among smokers, which validates prior evaluation research on the impact of Tips. These results suggest that continued investments in Tips may help sustain its impact on cessation-related outcomes.The  Tips From Former Smokers campaign (Tips) television advertisements is associated with increased attempts to quit smoking among cigarette smokers.Research using national online surveys indicates that increases in market-level media buys for the This report validates findings of prior research and addresses potential limitations of research based on web surveys by demonstrating a dose–response relationship between Tips exposure and quit attempts among smokers in the Behavioral Risk Factor Surveillance System, a nationally representative surveillance system.This study affirms that the more exposure to Tips that smokers receive, the more likely they are to make a quit attempt. These findings support year-round implementation of the campaign to maintain smokers’ motivation to quit and increase their likelihood of quitting for good.Tips From Former Smokers campaign (Tips) has been the largest national tobacco education mass media campaign focusing on smoking cessation among adult smokers. Several studies have used multiple methods to demonstrate the campaign’s impact on cessation behavior, including pre–post cohort designs . BRFSS is a national surveillance system that uses landline and mobile phone cross-sectional surveys among US adults. Using these data, we estimated the association between market-level doses of Tips media buys and quit attempts among adult cigarette smokers.Since 2012, the Centers for Disease Control and Prevention’s (CDC’s)  designs , and cro designs . AlthougWe used BRFSS data collected from 2011 to 2015, corresponding to a pre-Tips baseline survey (2011) and serial cross-sectional surveys during the first 4 years of the campaign (2012–2015). BRFSS provides state-specific and national estimates among noninstitutionalized US adults. Surveys were conducted via telephone through random sampling of landline and cellular telephone sampling frames. Data were weighted to represent the US adult population. Tips gross ratings points (GRPs), a continuous measure of campaign dose that varies across US designated market areas (DMAs) and time  (P = .001). Using predicted values from the curvilinear model  were aged 55 or older. Most of the sample (79.1%) was non-Hispanic white; the remaining sample was 8.2% non-Hispanic black, 6.7% Hispanic, and 6.0% non-Hispanic other race. An estimated 60.2% of smokers in the sample indicated making a quit attempt in the past year. For every 5,000 GRP increase in cumulative exposure to Tips ads annually, odds of reporting a past-year quit attempt were significantly increased  . Past-year model , we estiar model .BRFSS data showed that exposure to Tips is associated with higher annual quit attempt rates. This finding is consistent with evidence of the campaign’s impact on cessation behavior, which has focused primarily on its effects on more recent quitting behavior in the past 3 months –4. In geThe primary limitation of this study was that it relied on self-reported recall of potentially distant-past behavior (quit attempts during the past year), which may limit the validity of measurement of our outcome variable. In addition, the timing of Tips GRP delivery during the past year may not have corresponded with the specific timing of quit attempts made for some individuals. However, research shows that Tips GRPs are associated with intentions to quit smoking , and theOur results verify previous Tips campaign evaluation research, which relied on probability-based online surveys. This consistency of findings across multiple data sources and analytic methods further reinforces that the Tips campaign is an effective public health intervention for encouraging smokers to quit. Moreover, this study provides a practical example of using a national surveillance system with campaign exposure data for evaluation applications.In summary, our results provide evidence of the positive impact of Tips on cessation behavior among smokers and validate previous evaluation research. More broadly, these results affirm that the more exposure smokers receive from the campaign, the more likely they are to make a quit attempt. Taken together, these findings support implementation of the campaign at adequate exposure levels consistent with CDC best practice recommendations  to maint


ATG16L1 with susceptibility to inflammatory bowel disease (IBD) have prompted mucosal immunologists to investigate the functional roles of macroautophagy/autophagy in different cell types in the gut. Here we present a recent study that addressed 2 key questions: in which cell type is autophagy deficiency most detrimental during chronic colitis and what is the functional role of autophagy in those cells? We report that autophagy in intestinal epithelial cells (IECs) acts to limit intestinal inflammation by protecting them from TNF-induced apoptosis and we discuss the potential implications for IBD treatment.Genome-wide association studies (GWAS) linking polymorphisms in  ATG16L1 and IRGM, have been linked to IBD by GWAS. Autophagy is a versatile cellular degradation pathway implicated in many stress response mechanisms fundamentally important in nearly every cell type. Therefore, the genetic links identified by GWAS do not give any mechanistic information about the functional consequences, or about the cell types in which the autophagy pathway is important during chronic intestinal inflammation.Inflammatory bowel disease is a complex inflammatory disorder of the gastrointestinal tract thought to arise from a dysregulated immune response towards the microbiota. Although many pathogenic networks underlying disease development have been identified, the exact etiology is unknown, reflecting the complexity and diversity of the disease manifestations. Polymorphisms in several autophagy-related genes, such as Atg16l1 was selectively ablated in distinct cellular compartments. To assess the impact on chronic intestinal inflammation, we used an IBD model triggered by infection with the opportunistic bacterial pathogen Helicobacter hepaticus and simultaneous inhibition of the regulatory arm of the immune response with anti-IL10R blocking antibody. Although previous studies in other systems suggest that autophagy can limit release of pro-inflammatory cytokines by myeloid cells (macrophages and dendritic cells), we found that selective ablation of Atg16l1 in the myeloid compartments has little impact on this bacterially triggered chronic intestinal inflammation. In contrast, mice with selective ablation of autophagy in IECs (Atg16l1VC mice) exhibit severely exacerbated intestinal pathology, characterized by increased accumulation of CD4+ T cells in the lamina propria and elevated levels of pro-inflammatory cytokines.Recently, we addressed this issue by utilizing a Cre-lox genetic approach to generate transgenic mouse lines in which the IBD-associated autophagy gene Atg16l1VC mice is also accompanied by a higher number of apoptotic cells in the epithelium. Increased epithelial cell death could result in impaired barrier function leading to exacerbated pathology; however, it could also be just a consequence of the elevated inflammatory cytokines present in Atg16l1VC mice. This led us to investigate whether autophagy intrinsically regulates cytokine-induced apoptosis in IECs. Using complementary approaches, we found that autophagy directly controls apoptosis in epithelial cells. First, utilizing the recently developed ‘organoid’ system to culture primary IECs ex vivo, we found that Atg16l1-deficient IECs show increased induction of apoptosis following exposure to pro-inflammatory cytokines (TNF + IFNG/IFNγ) compared to wild-type IECs. Second, in vivo injection of TNF induces higher numbers of apoptotic IECs in the small intestine of Atg16l1VC mice compared to wild-type mice. Of note, increased apoptosis in autophagy-deficient IECs is only observed following inflammatory cytokine stimulation or in the context of chronic inflammation; at steady-state, IECs cope well with the lack of autophagy in regard to proliferation and differentiation, and exhibit normal inflammatory responses.The increased pathology in Atg16l1VC mice. Indeed, TNF blockade significantly attenuates disease severity and reduces IEC apoptosis in Atg16l1VC mice. These findings confirm that the exacerbated pathology in Atg16l1VC mice is largely driven by TNF-induced IEC apoptosis (It has been previously recognized that TNF induces IEC apoptosis in the context of IBD and in murine disease models. Our results show that autophagy-deficient IECs are much more sensitive to cytokine-induced apoptosis. Therefore we wondered whether TNF blockade would ameliorate the increased IEC death and intestinal pathology observed in colitic poptosis .Figure TNF is a key cytokine in IBD pathology, and treatment strategies targeting TNF signaling are one of the most effective treatment regimens. Despite the proven importance of the cytokine, it is not completely understood how TNF mediates its pathogenic effects and thus how TNF blockade acts to promote disease resolution. Of note, there is considerable heterogeneity among IBD patients in terms of disease manifestations, inflammatory profile and treatment responsiveness. Indeed, although anti-TNF therapies can be very effective, approximately 40% of IBD patients do not respond to anti-TNF treatment and many more become refractory to treatment. TNF blockers are expensive therapeutics and, to date, it is not possible to predict whether a given patient will respond to anti-TNF therapies. Our results suggest that IBD patients harboring risk alleles that sensitize the epithelial barrier to apoptosis may be more likely to respond to anti-TNF therapies, and if confirmed, this could lead to more efficient deployment of such treatments.


Metal-on-metal hip replacement (MoMHR) revision surgery for adverse reactions to metal debris (ARMD) has been associated with an increased risk of early complications and reoperation and inferior patient-reported outcome scores compared with non-ARMD revisions. As a result, early revision specifically for ARMD with adoption of a lower surgical threshold has been widely recommended with the goal of improving the subsequent prognosis after ARMD revisions. However, no large cohorts have compared the risk of complications and reoperation after MoMHR revision surgery for ARMD (an unanticipated revision indication) with those after non-ARMD revisions .(1) Does the risk of intraoperative complications differ between MoMHRs revised for ARMD compared with non-ARMD indications? (2) Do mortality rates differ after MoMHRs revised for ARMD compared with non-ARMD indications? (3) Do rerevision rates differ after MoMHRs revised for ARMD compared with non-ARMD indications? (4) How do implant survival rates differ after MoMHR revision when performed for specific non-ARMD indications compared with ARMD?This retrospective observational study involved all patients undergoing MoMHR from the National Joint Registry (NJR) for England and Wales subsequently revised for any indication between 2008 and 2014. The NJR achieves high levels of patient consent (93%) and linked procedures . Furthermore, recent validation studies have demonstrated that when revision procedures have been captured within the NJR, the data completion and accuracy were excellent. Revisions for ARMD and non-ARMD indications were matched one to one for multiple potential confounding factors using propensity scores. The propensity score summarizes the many patient and surgical factors that were used in the matching process  using one single score for each revised hip. The patient and surgical factors within the ARMD and non-ARMD groups subsequently became much more balanced once the groups had been matched based on the propensity scores. The matched cohort included 2576 MoMHR revisions with each study group including 1288 revisions . Intraoperative complications, mortality, and rerevision surgery were compared between matched groups using univariable regression analyses. Implant survival rates in the non-ARMD group were calculated for each specific revision indication with each individual non-ARMD indication subsequently compared with the implant survival rate in the ARMD group using Cox regression analyses.There was no difference between the ARMD and non-ARMD MoMHR revisions in terms of intraoperative complications . Mortality rates were lower after ARMD revision compared with non-ARMD revision ; however, there was no difference when revisions performed for infection were excluded from the non-ARMD indication group . Rerevision rates were lower after ARMD revision compared with non-ARMD revision ; this difference persisted even after removing revisions performed for infection . Revisions for infection  and dislocation/subluxation  had the lowest implant survival rates when compared with revisions for ARMD .Contrary to previous observations, MoMHRs revised for ARMD have approximately half the risk of rerevision compared with non-ARMD revisions. We suspect worldwide regulatory authorities have positively influenced rerevision rates after ARMD revision by recommending that surgeons exercise a lower revision threshold and that such revisions are now being performed at an earlier stage. The high risk of rerevision after MoMHR revision for infection and dislocation is concerning. Infected MoMHR revisions were responsible for the increased mortality risk observed after non-ARMD revision, which parallels findings in non-MoMHR revisions for infection.Level III, therapeutic study. Approximately 1.5 million large-diameter metal-on-metal hip replacements (MoMHRs) have been implanted worldwide in the form of stemmed THAs and hip resurfacings. However, MoMHRs have experienced unexpected high short-term revision rates , 27. RevDespite the high revision rates of MoMHRs , 27, at The National Joint Registry (NJR) for England and Wales was established in April 2003 to identify poorly performing implants early [A retrospective observational cohort study was performed using NJR data. The NJR records all hip replacements performed at all hospitals in England and Wales. Patients provide voluntary consent for their personal details to be recorded within the NJR, which is typically obtained before undergoing surgery. These unique patient identifiers subsequently allow linkage of primary hip replacements to any future surgical procedures in which components are removed or exchanged. The NJR achieves high levels of patient consent (93%) and procedure linkage (95%) . FurtherThe study protocol was approved after submission of a formal application to the NJR Research Sub-Committee. Because patients provide informed consent for inclusion of their data in the NJR, further approvals such as from the institutional review board were not required for this study. Anonymized patient data were extracted from the NJR on August 14, 2015. This data set contained details of all primary MoMHRs (MoM THAs and hip resurfacings) recorded in the NJR in patients who subsequently underwent revision surgery for any indication between August 1, 2008, and August 14, 2014 (n = 5867). The former date represents when the NJR introduced the term adverse soft tissue reaction to particulate debris on the data capture forms as a revision indication for surgeons to select. We have elected to classify this revision indication as ARMD throughout, given that this is currently the most commonly used and accepted term in the literature . Before Hip revisions were excluded if it was not possible to confirm that the primary hip replacement had a MoM bearing surface (n = 2) and when incomplete data were available for revision procedures involving two or more stages (n = 73) Fig. . We alsoThis study was specifically designed to assess the effect of MoMHR revision indication on the subsequent risk of intraoperative complications, mortality, and rerevision. Despite using a large registry cohort, the number of events for each endpoint was suspected to be relatively small. Adjusting for all patient and surgical covariates was likely to lead to overfitting of any statistical models with other covariates having the potential to incorrectly influence the findings between revision indication and the subsequent risk of intraoperative complications, mortality, and rerevision. Furthermore, baseline characteristics differed substantially between the ARMD and non-ARMD groups Table .Given the potential for confounding by revision indication to affect comparison of the study endpoints, revision procedures for ARMD and non-ARMD indications were matched for multiple potential confounding factors using propensity score techniques , 9. The All surgeons in England and Wales complete a data capture form after performing any primary or revision hip arthroplasty. These forms are subsequently submitted to the NJR and entered into their database. For all arthroplasty procedures, the NJR collects data on patient demographics and the surgical procedure, which were all used in the matching process The three study endpoints of interest were intraoperative complications during MoMHR revision , all-cause mortality, and all-cause rerevision surgery after revision. Implant survival rates in the non-ARMD group were also determined for each specific revision indication with each individual non-ARMD indication subsequently compared with the implant survival rate after ARMD revision.2). The NJR does collect information on the arthroplasty components implanted. However, data on femoral head size and bearing surface at the MoMHR revision procedure were not consistently available (either truly missing or ambiguous and therefore considered missing). This most notably occurred when incomplete revision procedures were performed . Multiple imputation methods were used to provide estimates for the missing data values in the three covariates with incomplete data with a total of 50 imputed data sets generated. Imputation models included all other covariates with complete data available as well as the study endpoints  given they all carried information about the missing covariate values. As a sensitivity analysis, the study endpoints were also assessed using a complete case data set, which excluded BMI only given the large proportion of missing BMI data (35%) .There was missing data for three covariates . BMI contained a significant proportion of missing values as well as a number of implausible values  were examined both before and after matching to assess for any covariate imbalance between ARMD and non-ARMD revisions with SMDs of ≥ 10% considered suggestive of covariate imbalance .Cumulative patient and implant survival rates after MoMHR revision were determined using the Kaplan-Meier method. The endpoint for implant survival was rerevision surgery . Patients not undergoing rerevision or death were censored on the study end date August 14, 2015). The study endpoints after revision surgery were compared between ARMD and non-ARMD groups using logistic (intraoperative complications) and Cox  regression models. To account for clustering within the matched cohort, a robust variance estimator was used in the Cox regression models with a conditional logistic regression model used for assessing intraoperative complications , 2015. T, 30. As We used R  to perform the propensity score matching and Stata  for all other analyses. Probability values < 0.05 and 95% confidence intervals (CIs) were used.Supplemental Digital Content 2).There was no difference between the ARMD 2.4%) and non-ARMD (2.5%) MoMHR revisions in terms of the risk of intraoperative complications . The overall all-cause mortality risk was 1.6% (n = 41) with a mean time from revision to death of 2 years . A regression model adjusting for two covariates with residual imbalance after matching (time from primary to revision and year of revision) produced similar results as the unadjusted models .All-cause rerevision rates were lower after ARMD revision compared with non-ARMD revisions Table . The 5-yCompared with ARMD revision, implant survival rates were lower when MoMHR revisions were performed for infection, fracture, loosening and/or lysis, dislocation/subluxation, and unexplained pain Table . RevisioEarly studies observed MoMHR revisions performed for ARMD had a high risk of rerevision, poor patient-reported outcomes, and inferior results compared with non-ARMD revisions , 19, 23.Supplemental Digital Content 3). Third, the non-ARMD group comprised a heterogeneous collection of revision indications, which could feasibly range from simple problems  to complex ones (such as infection with severe osteolysis). All non-ARMD indications were grouped together for this study because (1) these represent all modes of conventional hip arthroplasty revision, whereas ARMD represents an almost unique mode of revision in MoMHRs [This study has a number of limitations. First, using observational data means, we cannot infer causality. Second, our inclusion criteria may have introduced selection bias. Excluding incompletely recorded staged revisions may have affected reporting of the study endpoints in non-ARMD revisions because most staged revisions are performed for infection. We also excluded non-ARMD revisions with “other” indications, which may have represented undiagnosed or incorrectly recorded ARMD, especially during the early years , 13, 21.n MoMHRs , 20; andn MoMHRs . NeverthSupplemental Digital Content 1). Fifth, despite matching, there is potential for residual confounding. However, the observed effect sizes were large; therefore, it is unlikely any unmeasured factors would be large enough to change the direction of the effect sizes. Matching may also have reduced the generalizability of our findings given that almost half of the unmatched cohort was excluded from the matched analysis. Many pre-2012 revisions were excluded after matching, which may represent patients with the most difficult and aggressive ARMD who experienced the highest risk of complications and reoperation [Supplemental Digital Content 3).A fourth limitation was that despite using multiple imputation, missing data for some variables (namely BMI) may have affected the findings. However, sensitivity analysis based on the complete data set (excluding BMI) produced similar findings and effect sizes , infections (débridement and washout), and periprosthetic fractures . Eighth, registries potentially underreport revisions , althougThere were no differences in the risk of intraoperative complications between matched ARMD and non-ARMD revisions with femoral fractures representing the most common complications as reported during conventional THA revisions . We are Although patients undergoing ARMD revisions had half the risk of death compared with all non-ARMD revisions, there was no longer a difference in the mortality risk between the groups when revisions performed for infection were excluded. This suggests that infected MoMHR revisions were responsible for the increased risk of mortality initially observed after non-ARMD revision. In non-MoMHR revisions, the risk of mortality is higher when procedures are performed for periprosthetic infection compared with aseptic indications , 30. ThiThe observation that ARMD revisions have half the risk of rerevision compared with non-ARMD revisions is contradictory to previous observations with this finding persisting even when the revisions for infection were removed from the non-ARMD group. Numerous small studies have reported an increased risk of early complications and reoperation after their initial experience with ARMD revision surgery , 19, 23 Although many non-ARMD indications  had inferior implant survival compared with ARMD revisions, MoMHRs revised for infection and dislocation/subluxation had the poorest implant survival. Managing periprosthetic joint infection is challenging with a high risk of complications and reoperation reported after conventional THA revisions for infection , 22. ThiIt is worth acknowledging that 19% of rerevisions performed in the whole matched cohort were performed for ARMD, which appears high. Recurrence of ARMD has been frequently reported after MoMHR revision surgery performed for both ARMD and non-ARMD indications , 17. TheContrary to previous observations, this large nationwide study observed that patients undergoing MoMHR revision surgery for ARMD have approximately half the risk of rerevision compared with matched non-ARMD revisions. We suspect worldwide regulatory authorities have positively influenced rerevision rates after ARMD revision by promoting regular patient surveillance and recommending that surgeons exercise a lower revision threshold. We conclude that performing early revision surgery for ARMD has not been associated with additional morbidity compared with non-ARMD revisions and consider the threshold for performing ARMD revision surgery need not be lowered further. The high risk of rerevision after MoMHR revisions performed for infection and dislocation is concerning and requires further investigation. Infected MoMHR revisions were responsible for the increased mortality risk observed after non-ARMD revision, which parallels findings in infected non-MoMHR revisions.


Coronary artery disease (CAD), which remains a leading cause of mortality worldwide , is causJCAD (previously KIAA1462), a novel gene at the 10p11.23 CAD locus [JCAD expression and relate JCAD expression modules to endothelial cell phenotype and YAP, supporting our findings that JCAD regulates endothelial cell function via YAP.In a recent study  we invesRHOA, which encodes the Rho GTPase RhoA, a negative regulator of the Hippo pathway, has also been linked to CAD in a recent GWAS [JCAD knockdown [ent GWAS . RhoA prnockdown . In the Atherosclerotic plaques develop at sites of low or oscillatory shear stress, while laminar shear stress is atheroprotective. Notably, recent work has identified RhoA and YAP as key mediators of these effects ,6. AtherThe RhoA-JCAD-Hippo-YAP pathway is a promising new drug target for the treatment of CAD. RhoA is a modulator of the non-lipid lowering atheroprotective effects of statins and statin treatment of endothelial cells inhibits YAP activity ,6. In adRHOA and JCAD associated with increased risk of CAD and recent mechanistic studies have shown that these two genes regulate the Hippo signalling pathway and YAP activity to control endothelial cell function in atherosclerosis. Targeting this pathway via new or existing inhibitors such as Fasudil might provide a new treatment opportunity for CAD.In summary, GWAS have identified genetic variants in


Regulation of cellular ATP level is critical for diverse biological processes and may be defective in diseases such as cancer and mitochondrial disorders. While mitochondria play critical roles in ATP level regulation, we still lack a systematic and quantitative picture of how individual mitochondrial-related genes contribute to cellular ATP level and how dysregulated ATP levels may affect downstream cellular processes. Advances in genetically encoded ATP biosensors have provided new opportunities for addressing these issues. ATP biosensors allow researchers to quantify the changes of ATP levels in real time at the single-cell level and characterize corresponding effects at the cellular, tissue, and organismal level. Along this direction, several recent single-cell studies using ATP biosensors, including the work by Mendelsohn and colleagues, have started to uncover the principles for how genetic and nongenetic parameters may modulate ATP levels to affect cellular functions and human health. This Primer explores how a systematic understanding of cellular ATP regulation and function at the single-cell level is now becoming possible with the help of CRISPRi-based screening and genetically-encoded ATP biosensors. Fig 1). In addition, the biosynthetic function of mitochondria has far-reaching implications in stress responses and diseases [Fig 1). Understanding how mitochondrial dysfunctions contribute to human diseases is thus challenging and requires a systems-level knowledge of mitochondrial biology.Mitochondria originated from an ancient alpha-proteobacterium engulfed by a eukaryote ancestor and have coevolved with the host for a long period of time . Mitochodiseases –6. Alongdiseases , 3, 7  screen with an improved ATP biosensor [Fig 2A). Importantly, control experiments with a mutated ATP-sensor were included in all contexts, allowing the removal of non-ATP–dependent effects.Despite the improvements in ATP biosensors, most single-cell work utilizing these sensors has been limited by throughput because of the difficulty of studying single cells in high throughput. In a recent publication of iosensor . In thisFig 2A). Specifically, some mitochondrial gene deficiencies decrease cellular ATP level only in respiratory conditions but not in conditions when glycolysis is engaged, indicating that glycolysis may compensate for the decreases in ATP when OXPHOS is perturbed. This result highlights the plasticity of metabolic systems as well as the challenges for linking genotypes to disease phenotypes. This may further explain the lack of direct evidence connecting dysregulated ATP levels to mitochondrial diseases. Therefore, the results by Mendelson and colleagues call for more attention to context-dependent ATP level regulation when studying energy failure.Based on the screen, the authors uncovered many genes that play major roles in cellular ATP level maintenance. Most of these genes are protein subunits of mitochondrial ribosomes and proteins involved in mitochondrial genome transcription and translation. Interestingly, genes related to mitochondrial protein synthesis show a more severe effect on ATP level than genes coding individual respiratory-chain components. This result suggests that combined mitochondrial defects  result in more severe energy failure than the dysfunctions of single respiratory-chain–complex subunits (which could be compensated by unknown mechanisms). In addition, the authors identified new genes unrelated to mitochondria function but reduce ATP production from mitochondria. These genes may modify cellular ATP level by influencing ATP consumption, suggesting the complex feedback mechanisms underlying ATP regulation. Furthermore, their data reveal metabolic-context–dependent ATP level regulation .To further explore how additional environmental factors regulate cellular ATP levels, the authors characterized the effect of supplementing the culture media with coenzyme Q10 (CoQ10), a widely available dietary supplement for treating mitochondrial disorders without clear mechanisms . InteresFig 2A). More specifically, for mitochondrial-related genes whose deficiencies reduce ATP levels, their deficiencies only impact growth when OXPHOS is active. Based on these observations, the authors proposed an energy-based therapeutic approach to eliminate cancer cells by exploiting context-specific growth inhibition of cancer cells that have certain gene mutations (that affect cell growth in a context-dependent manner).To dissect how dysregulated cellular ATP levels affect downstream phenotypes such as growth rates, the authors analyzed growth rates of cells under different genetic and environmental perturbations. They found that ATP dysregulation affects cell growth rates in a metabolic-context–dependent manner (The study by Mendelsohn and colleagues demonstrates how quantifying cellular ATP concentration at the single-cell level in a high-throughput manner help to establish links between genotypes and cellular phenotypes or diseases. For the identified genes that are linked to particular phenotypes, it will be of great interest to investigate whether and how temporal and spatial ATP level dynamics play roles in these phenotypes. This would require the development of live-cell assays for monitoring ATP signals and the downstream processes simultaneously in the same cells.The screening methodology developed by Mendelsohn and colleagues could be extended to additional gene libraries and address how other genetic pathways may contribute to cellular ATP level regulation. It can also be used for the screening of metabolic substrates and/or drug combinations as candidate therapies for energy failure. To arrive at a systems-level understanding of mitochondrial biology and metabolism in general, similar single-cell–based screening approaches can be adapted to other metabolic products (e.g., NADH , lactateMore generally, single-cell approaches open up new opportunities for understanding the causes and consequences of cell-to-cell variability in metabolites. In both bacterial and mammalian cells, it has been reported that ATP levels can display a large cell-to-cell variability even in a clonal population , 28. Whi


While various types of SMPCs are currently available from several sources, human pluripotent stem cells (PSCs) offer an efficient and cost-effective method to derive SMPCs. As human PSC-derived cells often display varying heterogeneity in cell types, cell enrichment using cell surface markers remains a critical step in current procedures to establish a pure population of SMPCs. Here we summarize the cell surface markers currently being used to detect human SMPCs, describing their potential application for characterizing, identifying and isolating human PSC-derived SMPCs. To date, several positive and negative markers have been used to enrich human SMPCs from differentiated PSCs by cell sorting. A careful analysis of current findings can broaden our understanding and reveal potential uses for these surface markers with SMPCs.Skeletal muscle progenitor cells (SMPCs), also called myogenic progenitors, have been studied extensively in recent years because of their promising therapeutic potential to preserve and recover skeletal muscle mass and function in patients with cachexia, sarcopenia, and neuromuscular diseases. SMPCs can be utilized to investigate the mechanisms of natural and pathological myogenesis via  The most pronounced symptom of neuromuscular disorders is loss of skeletal muscle mass and strength, which causes functional decline and loss of independence in patients  the origins of SMPCs; (2) signaling mechanisms that drive lineage progression; (3) optimal isolation techniques; (4) selective enrichment of populations with clinical relevance, either for in vitro modeling and/or ex vivo therapy; and (5) potential genetic manipulations and/or pharmaceutical interventions to correct deteriorating muscle phenotypes. Similarities or differences in SMPC surface marker expression might be indicative of their stemness, myogenic differentiation propensity, and lineage potential to assume non-myogenic fates.This review catalogs the current findings on cell surface markers to identify human SMPCs. Here we focus on surface markers that have been reported in human PSC-derived SMPCs and compare their expression in other systems. Specific cell markers and/or cell surface proteins can be used for isolation, identification, and characterization of viable SMPCs. A better understanding of how SMPC markers are regulated There are various types of progenitor cells that have the ability to differentiate into skeletal myocytes. These cells include muscle satellite cells, muscle-derived stem cells (MDSCs), side population (SP) cells, mesoangioblasts and pericytes  can be isolated from adult muscle biopsies by a combination of enzyme digestion and serial plating to collagen-coated culture plates, as these cells are less adhesive compared to other cell types in skeletal muscle  cells are named after their ability to efflux the DNA-binding dye Hoechst 33342 and form a side population on Fluorescence Activated Cell Sorting (FACS) analysis  of immunodeficient NOD scid gamma (NSG) mice. In contrast, CD56−/CD29+ cells showed insufficient or non-existent myofiber regeneration + cells were isolated from human adult skeletal muscle, these cells expressed a series of myogenic cell markers such as Pax7, Pax3, Myf5, MyoD, Myogenin, and Myocyte Enhancer Factor 2C. Further, the isolated cells can differentiate into myotubes in vitro and when transplanted into NSG mice . The triple positive cells demonstrated robust regenerative capacity in vivo, as human-specific satellite cells and myofibers were confirmed in the muscle of NSG mice at 10 months post-transplantation  was upregulated in human PSCs following Pax7 induction   is a glycoprotein typically expressed on endothelial cells and leukocytes , has been utilized for isolation and identification of human myogenic cells in an extensive list of publications. CD56 expression is observed on SMPCs derived from PSCs  has been detected in growth plates, articular cartilage, and hypertrophic chondrocytes  as well as endothelial markers (CD31 and von Willebrand factor)  and implanted into the muscle of Lewis male rats, the grafted cells were positive with sarcomeric tropomyosin, a protein that regulates muscle contraction, at 2 weeks post-transplantation  is a well-acknowledged marker of endothelial cells. This molecule plays a crucial role in angiogenesis and tumor growth  is well-studied for its important role in development, cell migration, immunology, angiogenesis, cancer progression, and myogenesis  and CD146+ MP cells showed low engraftment rate  cells were selected from human fetal muscle cells by scatter gating following FACS analysis, the CD146-based selection could enrich a population of myogenic cells. However, freshly isolated cells remained heterogenous: only ~50% of CD146CD184, or commonly recognized as C-X-C chemokine receptor type 4 (CXCR-4), is a molecule with potent chemotactic activity for lymphocytes. It is crucial for homing hematopoietic stem cells to their adult marrow − cells were purified from differentiated PSCs and then sorted into c-Met+/CD184+, c-Met+/CD184−, c-Met−/CD184+, and c-Met−/CD184− fractions. Immunocytochemical analysis immediately after sorting revealed that both c-Met+/CD184+ and c-Met+/CD184− fractions contained highly pure SMPCs. In contrast, c-Met−/CD184+ fraction contained both SMPCs and SOX1+ neural cells, and c-Met−/CD184− fraction did not have any SMPCs. Although CD184 alone could not enrich SMPCs, CD184 expression may be indicative of myogenic lineage progression. Interestingly, both c-Met+/CD184+ and c-Met+/CD184− fractions expressed early myogenic genes Six4 and Pax3  at day 23 of post-myogenic differentiation of PSCs  were able to generate myofibers with high efficiency in vitro and in vivo  that had been genetically corrected by CRISPR/Cas9 technology. These CD271+ SMPCs exhibited superior myotube-forming potential; even higher than the cells in the CD56+, CD146+, or CD184+ fractions , has recently been recognized as a positive marker to identify SMPCs and MSCs , all ErbB3+ cells from the four PSC lines were positive with CD271. These ErbB3+/CD271+ SMPC lines exhibited higher capacity for muscle differentiation than double-negative fractions  and then myogenic differentiation was induced. Among the three fractions, there was no difference in the number of Pax7+ cells and Myf5+ cells  or transmembrane and associated with Src kinases (TRASK), is present on epithelial cells  could distinguish three cell types: myogenic cells without adipogenic capabilities, non-myogenic cells with adipogenic capabilities, and myogenic cells with adipogenic capabilities, respectively  has been used to separate myogenic and adipogenic cells. CD15+ cells. When CD10+/CD24− cells were enriched from a variety of PSC lines , the isolated cells showed a high level of myotube formation following terminal differentiation , is a member of the immunoglobulin superfamily. CD31 is primarily used to detect endothelial cells , and a minority of pericytes and mesoangioblasts with adipogenic potential (CD34−/CD56− cells)   were isolated from human adult muscle as myoendothelial cells, endothelial cells, and myogenic cells, respectively. When their ability of cell survival and muscle regeneration was compared by intramuscular implantation into SCID mice, CD56+/CD34+/CD144+ myoendothelial cells demonstrated the most significant results , human natural killer 1 (HNK-1), or LEU-7. CD57 is a neuroectodermal marker expressed on natural killer cells and T-lymphocytes  has been known to show expression in MSCs, activated endothelial cells, and macrophages , it may be redundant to enrich using this surface marker, as the purity may not improve by much. The same applies to negative SMPC surface markers that are already minimally expressed in unsorted populations. A surface marker barely expressed in the unsorted population may play an important biological role but would not be useful as a target for live cell isolation. Similarly, if a surface marker is also highly expressed on non-SMPC cell types, it would no longer serve to distinguish SMPC identity from the background cell populations.in vivo capacity of muscle regeneration should be taken into consideration alongside the ability of the cells to differentiate into muscle in vitro. Forming new muscle fibers, repopulating the satellite cell niche, and vascularization of the affected area are all crucial to establish the structural integrity and functionality of the regenerated muscle tissue. It is possible that unsorted SMPC populations may perform better after transplantation, as these more heterogenous unsorted populations could contain cells that play a supporting role for muscle repair and regeneration. “Enriched” SMPC populations may show an increased rate of myotube formation in vitro where conditions are strictly controlled. However, these cells may engraft more poorly than unsorted populations due to the absence of non-SMPC support cells. Therefore, the purpose of SMPC enrichment should be considered when selecting surface markers, as the resulting cell population most ideal for in vitro modeling may not also be the most ideal for transplantation studies.We also need to carefully compare the rate of improvement in muscle differentiation efficiency between the unsorted and sorted populations. When quantifying the success rate of SMPC enrichment, the Our literature search further verifies that a surface marker profile cannot be assumed to be similar for all SMPC lines. A surface marker could enrich SMPCs from one cell line very well only to be rendered useless in another cell line. For example, CD271 and ErbB3 efficiently enriched SMPCs derived via both transgene-free and transgene-based methods from several PSC lines (Hicks et al., When differentiating skeletal myocytes from human PSCs, there has been inconsistency between studies with regards to evaluating differentiation efficiency and myocyte maturity (reviewed in Jiwlawat et al., in situ locations within the same donor can have distinct molecular signatures (Harel et al., de novo SMPCs” derived from PSCs. Additionally, contradictory reports on marker expression on SMPCs imply that different culture conditions may lead to the heterogeneity of SMPCs. Different culture media and durations would influence the expression of specific markers in timepoint- and sample-dependent manners. Ultimately, it would be more helpful if a sole marker was available to specifically enrich only SMPCs. For other stem cell types such as HSCs and MSCs, cell surface markers are already well-characterized and defined for identification. In contrast, our knowledge in the field of myogenic progenitors is still developing. To advance, additional studies are needed to discover specific markers that can be used alone to detect a pure population of SMPCs.To date, a majority of SMPC surface markers were profiled based on the knowledge from satellite cells, resident SMPCs located between the basal lamina and sarcolemma of adult muscle fibers. Even though these possible markers can be used to sort SMPCs into subpopulations, it remains uncertain whether these subpopulations are homogeneous in their function and lineage commitment. Moreover, given the fact that satellite cells from different in vivo regenerative capacity using intramuscular transplantation, the results may also vary depending on the animal models used, how muscle injury was induced, the number of cells transplanted, the duration between transplantation and analysis, and the position in muscle used for section preparation and analysis. Furthermore, calculation of myotube formation efficiency may differ based on the usage of immunohistochemical staining, the counting of positive cells in a field of view, the number of nuclei per myotube, and the percentage of nuclei within myotubes. Since the ability to generate fully matured myotubes is pivotal for transplanted SMPCs to have clinical significance, a comprehensive analysis of the anatomical features, physiological functionality and fiber type expressed should be performed to gauge the state of myotube maturity.Lastly, another concern is that throughout the reports there is inconsistency on how to evaluate the myogenic potential in sorted cell pools. Some studies examined commitment to the myogenic lineage based on a pooled expression of common muscle cell markers, whereas several other studies only identified the expression of one marker. When comparing Recent studies have offered valuable knowledge regarding cell surface markers to identify SMPCs. While promising positive and negative markers have been identified using different SMPC types, it remains challenging to use them for sorting human PSC-derived SMPCs in efficient ways. Furthermore, there is still a need to standardize methods of quantifying SMPC properties in order to facilitate comparisons between surface marker expressions. This would allow for precise utilization of SMPC surface markers to enhance the enrichment and differentiation of SMPCs. Having control over the composition of SMPC populations could lead to new state of the art uses for disease modeling, drug testing, and therapeutic development.S-RT designed the outline of manuscript, performed manuscript search, and primarily prepared the manuscript. SR and EL provided critical suggestions about the contents and edited the manuscript. MS proposed conception and design of the manuscript and wrote the manuscript. All authors approved the final version of the manuscript.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.


The main goal of such procedures is not to improve the resection extent but to safely acquire viable tissue representative of the lesion for further comprehensive histological, immunohistochemical, and molecular analyses. Herein, we review advanced optical techniques for improvement of safety and efficacy of stereotactic needle biopsy procedures. These technologies are aimed at three main areas of improvement: (1) avoidance of vessel injury, (2) guidance for biopsy acquisition of the viable diagnostic tissue, and (3) methods for rapid intraoperative assessment of stereotactic biopsy specimens. The recent technological developments in stereotactic biopsy probe design include the incorporation of fluorescence imaging, spectroscopy, and label-free imaging techniques. The future advancements of stereotactic biopsy procedures in neuro-oncology include the incorporation of optical probes for real-time vessel detection along and around the biopsy needle trajectory and  Brain needle biopsies are indicated for deep-seated or multiple brain lesions and for patients with poor prognosis in whom the risks of resection outweigh the potential outcome benefits. A recent systematic review and evidence-based clinical practice guideline investigating the role of stereotactic brain biopsy for low-grade gliomas provided level III evidence in support of brain biopsies and recommended that surgeons consider using advanced imaging techniques to improve diagnostic accuracy . In suspThe current standard-of-care method for stereotactic brain needle biopsy involves a 1.6- to 2-mm-diameter needle cannula insertion through a cranial burr-hole aligned to a predetermined trajectory. The two cannulas have overlapping side windows. When the desired position is reached, these windows are aligned, and brain tissue is lodged into cannula using suction and cut by sliding the inner cannula.Despite the minimally invasive nature of the needle brain biopsy, the limitations and risks are still present and include the following:◦ Not-specified non-diagnostic biopsy rate−5.2% , 9% 4),,4), 10.7◦ Biopsy performed without intraoperative frozen section-−11%;◦ Biopsy performed with frozen section on demand−1% ;Non-diagnostic biopsy yield. The frequency of non-diagnostic biopsies ranges in various studiesTechnical failure rate is 2.4–3.7% ,,7), 4.35Complications rate:Mortality rate was 0.6% , 1.34%  in varioVessel injury is one of the most feared complications during minimally invasive stereotactic procedures. The rounded tip design of the biopsy needle intends to push aside any vessel encountered along the biopsy needle trajectory. However, such a design does not completely eliminate the potential for vessel injury during the forward movement of the needle. Moreover, the risk of vessel injury is believed to be higher during the side-cutting movement during biopsy acquisition. Therefore, apart from techniques for navigation on the anatomical level, like MR spectroscopy , 11, perThis paper aims to provide a concise review of novel fluorescence-based and other optical techniques for improvement of safety and efficacy of minimally invasive stereotactic needle biopsy procedures in neuro-oncology. The main goal of such procedures is not to improve the resection extent but to safely acquire viable tissue representative of the lesion for further comprehensive histological, immunohistochemical, and molecular analyses. Here, we do omit discussion of MR, computed tomography, and ultrasound Doppler , 15-basein vivo (using the miniaturized probes) or ex vivo after the biopsy has been acquired (using either miniaturized or benchtop systems).We performed a literature search in the PubMed database using the terms “biopsy,” “stereotactic,” “fluorescence,” “Raman,” “spectroscopy,” “brain,” “optical,” and “optical probe” in various combinations. Our search included papers published up to November 2018. We did not set a lower bound for this search. The titles were scanned and relevant articles were selected for full-text review, resulting in relevant articles for analysis as presented in the n = 1), this needle endoscope was used instead of the standard brain biopsy needle mandarin to visualize fluorescence during probe advancement. The actual biopsy acquisition was performed with a small forward biting biopsy forceps. Although bright PpIX fluorescence from the viable tumor core was visible, no fluorescence in the surrounding needle positions was evident. For vessel visualization, a 200 mg/kg dose of ICG was used in the mouse model. With this, near-infrared ICG fluorescence appeared inside the blood vessels at an excitation of 785 nm  and indocyanine green (ICG)  22). Pp. Pp22). Ruhm et al. investigated forward-viewing microfiber probe for ICG detection using a computer simulation of ICG fluorescence excited and detected through the same fiber-optic system in homogeneous human brain tissue . AlthougAnother recently reported tool is a 2.2-mm-diameter forward-viewing needle probe that combines fluorescence spectral detection and laser Doppler flowmetry . The proRamakonar et al. reported the performance of a side-viewing probe that fit a standard side-cutting brain biopsy needle for optical coherence tomography (OCT) imaging and differentiation of solid tissue and vessels  27). Th. Th27). ex vivo porcine brains demonstrated that a side-viewing double fiber probe for remission spectrometry inserted in a side-cutting biopsy needle can determine the proximity of the vessel to the needle -induced PpIX fluorescence is diagnostic for malignant tumors and can be used to assess stereotactic biopsy samples before submitting them to pathology, while the absence of fluorescence can filter out necrotic areas and inflammatory reactive tissue without malignant cells. This method was confirmed in multiple studies –40. DeteSimilarly to 5-ALA, fluorescein sodium can be used to assess stereotactic biopsy specimens under the special fluorescence mode of the surgical microscope. High-grade glioma tissue shows strong yellow fluorescence when excited at about 488 nm . Being aICG may also be used as a highlighter of the tumor tissue –54. Althex vivo and scanned with a confocal microscope  , 64. A pVarious microscopy imaging methods that are not dependent on the drug-induced contrast and instead rely on intrinsic optical properties of the tissues recently received clinical attention. Such methods could be used for rapid intraoperative assessment of the acquired stereotactic brain biopsies to increase diagnostic yield and improve pathology workflow.ex vivo histological assessment of brain tumor biopsies. SRH provided high-resolution digital images that look similar to the standard hematoxylin and eosin staining ; however, the development of reflectance and multiphoton microscopy techniques and militarization of microscopes would allow label-free tumor tissue identification through a biopsy needle in the future. There is a marked diversity in qualitative and quantitative optical methods for brain tumor tissue identification, and each of them requires a significant learning curve and dedication. So far, the most progress has been achieved with 5-ALA-induced PpIX, which is highly specific for malignant tissues and can be detected spectroscopically with a single optical fiber inserted in the biopsy needle.in vivo diagnostics.Another limitation is that most of the discussed methods require timely interpretation and adjustments of multiple parameters during the procedure to ensure optimal performance, which is not always practical and may lead to information overload. For example, results of quantitative spectroscopy are usually displayed on the screen in a graph form. This information could be converted into an auditory format, which would be easy to understand and non-disruptive during the surgery . FinallyWhen considering the design of an ideal probe, it should incorporate vessel detection as well as tumor detection modules, most likely in forward and side views simultaneously for the safest possible probe insertion and biopsy acquisition. Machine learning, coupled with optical visualization technologies, would be a basis for computer-aided, real-time tissue image analysis for the selection of the best probe trajectory or location for biopsy acquisition. Besides these technologies that are used for vessel avoidance and tumor detection, future development of probes could also include augmented or virtual reality for clinicians to perform more accurate probe trajectory planning.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.