To present the current evidence and the development of studies in recent years on the management of extragonadal germ cell tumors (EGCT).A systematic literature search was conducted in Medline and the Cochrane Library. Studies within the search period (January 2010 to February 2021) that addressed the classification, diagnosis, prognosis, treatment, and follow-up of extragonadal tumors were included. Risk of bias was assessed and relevant data were extracted in evidence tables.The systematic search identified nine studies. Germ cell tumors (GCT) arise predominantly from within the testis, but about 5% of the tumors are primarily located extragonadal. EGCT are localized primarily mediastinal or retroperitoneal in the midline of the body. EGCT patients are classified according to the IGCCCG classification. Consecutively, all mediastinal non-seminomatous EGCT patients belong to the “poor prognosis” group. In contrast mediastinal seminoma and both retroperitoneal seminoma and non-seminoma patients seem to have a similar prognosis as patients with gonadal GCTs and metastasis at theses respective sites. The standard chemotherapy regimen for patients with a EGCT consists of 3–4 cycles (good vs intermediate prognosis) of bleomycin, etoposid, cisplatin (BEP); however, due to their very poor prognosis patients with non-seminomatous mediastinal GCT should receive a dose-intensified or high-dose chemotherapy approach upfront on an individual basis and should thus be referred to expert centers Ifosfamide may be exchanged for bleomycin in cases of additional pulmonary metastasis due to subsequently planned resections. In general patients with non-seminomatous EGCT, residual tumor resection (RTR) should be performed after chemotherapy.In general, non-seminomatous EGCT have a poorer prognosis compared to testicular GCT, while seminomatous EGGCT seem to have a similar prognosis to patients with metastatic testicular seminoma. The current insights on EGCT are limited, since all data are mainly based on case series and studies with small patient numbers and non-comparative studies. In general, systemic treatment should be performed like in testicular metastatic GCTs but upfront dose intensification of chemotherapy should be considered for mediastinal non-seminoma patients. Thus, EGCT should be referred to interdisciplinary centers with utmost experience in the treatment of germ cell tumors. Germ cell tumors (GCT) arise predominantly from within the testis, but an important subset of about 5% of the tumors are primarily located extragonadal with no testicular primary tumor being detectable .Extragonadal germ cell tumors (EGCTs) are a heterogeneous group of tumors of neoplastic germ cells arising from extragonadal anatomical locations located in the midline of the body. Primary EGCT are considered a special subgroup of GCT with a poorer prognosis due to larger volume and different biology. They result from malignant transformation of germ cells that were either maldistributed during embryonic development or germ cells that naturally occur to control immunological processes or other organ functions at extragonadal locations .EGCTs include seminomatous tumors , and non-seminomatous tumors .Histological, serological and cytogenetic characteristics of EGCTs are similar to those of primary testicular GCT, but differences in clinical behavior suggest that gonadal and extragonadal tumors are biologically different .EGCTs have significantly larger tumor masses at diagnosis. There is a predominance for the occurrence in the anterior mediastinum, especially of non-seminomatous subtypes. A association of EGCTs has been described with Klinefelter syndrome . FurtherThe aim is to present the current evidence on classification, diagnosis, prognosis, therapy and follow-up of EGCT and to highlight recent studies in this special subfield of GCT.This work is based on a former systematic literature search that was conducted for the elaboration of the first German clinical practice guideline . Here, wThe systematic literature search identified nine studies see Fig. . Four ofEGCTs are localized primarily mediastinal or retroperitoneal, but also at any other site along the midline except the testis . The antIn a case series, 320 male patients with confirmed primary mediastinal EGCTs were reported . The hisMediastinal EGCTs are differentiated into seminomas and non-seminomas. Among mediastinal EGCTs, seminomas account for 40% of the non-teratoma EGCT and are thereby more common than in EGCTs in general, where they account for only 20–24% of the tumors. In a large international case series of 635 patients with mediastinal and retroperitoneal EGCTs, 104 patients showed pure seminomas and 524 had non-seminomatous tumors . In contRetroperitoneal EGCTs have a clinical behavior very similar to that of testicular GCTs . The genLess frequent sites of EGCT are the pineal gland , os sacrum, prostate, orbita, urinary bladder or liver . EpidemiPathology of EGCTs**Primary EGCTs are considered a special subgroup of GCTs. They result from malignant transformation of germ cells that were either maldistributed during embryonic development or from germ cells that naturally occur at extragonadal sites for the purpose of controlling immunological processes or other organ functions , 31.In principle, the same histological subtypes are present in EGCT as in testicular localized GCTs (seminomas and non-seminomatous EGCT). EGCTs include seminomatous tumors , and non-seminomatous tumors, including embryonal carcinoma, teratoma (mature or immature), yolk sac carcinoma and chorioncarcinoma. EGCTs constituted by two or more histotypes are referred to as mixed germ cell tumors, which classified as non-seminomatous tumors. In mediastinal EGCT, seminomatous tumor components and teratoma components are frequently detectable , 27.There is a clear association between EGCT and Klinefelter’s syndrome, a male genetic disorder characterized by the 47, XXY karyotype, small and soft testis, sterility, eunuchoid habitus, gynecomasty, high levels of FSH and a 20-fold increased risk for breast cancer. Regarding the increased risk of EGCT in Klinefelter´s patients, it is still unclear whether the development of GCTs in patients with Klinefelter’s syndrome is the result of a primary genetic abnormality or of an abnormal hormonal milieu that primes premalignant tumor cells into malignant tumor development .In addition, an increased rate of yolk sac components, elevated AFP levels, and TP53 aberrations are observed in EGCTs compared to testicular GCTs .Primary mediastinal non-seminomatous EGCTs can be the origin of hematologic neoplasms with an incidence of 5–10% . These hEGCTs often present only at advanced stages due to tumor-related symptoms, but they also occur as incidental findings during diagnostic or other therapeutic interventions. The clinical presentation of EGCT varies widely. Avery advanced cases of mediastinal EGCT may present with pulmonary symptoms or venous compression syndromes (including superior vena cava syndrome). When the EGCT is primarily located in the retroperitoneum, abdominal pain, back pain, weight loss, inferior vena cava thrombosis, or hydronephrosis are the main clinical presentations.The most conclusive data regarding clinical symptoms were shown in 2012 in the largest published series of EGCTs with 635 patients by Bokemeyer et al. . PatientIn patients with a primary retroperitoneal EGCT, the main symptoms were abdominal (29%) and back pain (14%), followed by weight loss (9%), fever (8%), vena caval or other thrombosis (9%), palpable abdominal tumor (6%), enlarged cervical lymph nodes (4%), scrotal edema (5%), gynecomastia and dysphagea (3%).The symptoms of EGCT patients are caused by the growing tumor mass. After appropriate imaging with ultrasound and computed tomography/magnetic resonance imaging (CT/MRI), the diagnosis should be confirmed histologically. Depending on the localization, this can be performed by fine-needle aspiration cytology, percutaneous biopsy or specimen resection during mediastinoscopy/laparoscopy . In addiThe role of FDG-PET-CT in the primary diagnosis of EGCT is unclear. However, in evaluating the success of first-line systemic therapy, FDG-PET may have a decisive value. Additionally, Buchler et al. showed that a negative FDG-PET after the completion of EGCT treatment was a powerful predictor of long-term survival with 100% of the patients surviving three years and 89% surviving five years after diagnosis .Retroperitoneal EGCTs are often associated with a "burned-out" tumor of the testis, whereas in mediastinal EGCTs, this is extremely rare . The queIn 2001, Hartmann et al. observed that metachronous testicular GCTs most commonly occurred in seminomatous EGCTs with a cumulative risk of 10% within 10 years . This rihttps://www.eortc.org/IGCCCG-Update) [In the largest international analysis of EGCTs, patients with seminomatous EGCTs with the primary localization in the mediastinum and retroperitoneum had an equivalent prognosis to patients with primary testicular seminoma according to the IGCCCG classification Table  and simi-Update) .Table 3PThe same parameters which identified patients with testicular seminomatous tumors, also predicted the individual prognosis in seminomatous tumors of primary extragonadal origin. Therefore, patients with seminomatous EGCTs should be classified as either "good prognosis" or "intermediate prognosis" according to IGCCCG and treated accordingly.In the case series reported, non-seminomatous EGCTs had a worse prognosis than seminomatous EGCTs with a 5-year survival rate of 62% for retroperitoneal and 45% for mediastinal non-seminomatous EGCTs . The anaPatients with retroperitoneal non-seminomatous EGCTs are classified according to the serum tumor marker constellation of the IGCCCG classification and are treated analogously to metastatic testicular non-seminomatous GCTs. Several other studies corroborated these results –42.Patients with seminomatous EGCTs should be treated according to the IGCCCG classification prognostic group, with three cycles of bleomycin, etoposide, cisplatin (BEP) for good prognosis and four cycles of BEP for intermediate prognosis patients. An alternative chemotherapy regimen in case of contraindications to bleomycin in good prognosis patients is four cycles of etoposide, cisplatin or substituting bleomycin by ifosfoamide if a subsequent pulmonary operation is planned , 4EGCT patients with pure seminomatous germ cell tumors have a better prognosis than non-seminomas, especially because seminoma cells are highly susceptible to cisplatin-based chemotherapy and ionizing radiation. A residual tumor resection is not routinely required. In three retrospective studies of patients with mediastinal seminomatous EGCTs (case numbers ranging from 7 to 17), 5-year overall survival (OS) rates of 71% and 100% were reported , 16, 18.In a case series of 52 patients with a retroperitoneal pure seminoma and 51 patients with a mediastinal pure seminoma, the 5-year progression-free survival (PFS) and the 5-year OS rates were 87% and 90%, respectively . 75% of Similar to the therapy of testicular CS II GCTs, retroperitoneal seminomatous EGCTs can be treated with radiotherapy if tumor extension is limited. Unfavourable prognostic factors for pure seminomas are the presence of liver metastases or metastases in two or more different organs; however, this leads to a classification of intermediate prognosis in these cases, as seminomas, both metastatic from testicular origin or extragonadal are never categorized as IGCCCG “poor prognosis” .The standard chemotherapy regimen for patients with a mediastinal non-seminomatous EGCT consists of four cycles of cisplatin-based combination chemotherapy either BEP or PEI. Only few studies with limited numbers of cases have been reported on primary mediastinal non-seminomatous EGCTs , 18, 42.In non-seminomatous EGCT, residual tumor resection (RTR) should be performed analogously to metastatic testicular GCT after the completion of chemotherapy. In primary mediastinal non-seminomatous EGCT resection of all visible residuals (even < 1 cm) should be aimed for, and post-chemotherapy elevated serum tumor markers should not discourage surgery. In this context, some studies performed multivariate analyses, all of which emphasized surgical therapy after initial systemic therapy as an important prognostic factor , 13.No prospective studies have investigated the role of high-dose chemotherapy in the first-line treatment of extragonadal germ cell tumors so far. In a meta-analysis of 524 patients with non-seminomatous germ cell tumors in 2002 by Bokemeyer et al., 59 patients (13%) were treated with high-dose chemotherapy . In the In contrast to all other non-seminomatous EGCTs, mature teratomas are resistant to chemotherapy. If there is clear histologic evidence of a mature teratoma and no elevation of serum tumor markers for GCTs, surgical resection of the EGCT is the best therapeutic option.In summary, all patients with mediastinal non-seminomatous EGCTs are classified in the poor prognosis group. Furthermore, the chemosensitivity of primary mediastinal non-seminomatous EGCTs appears to be lower compared to testicular and/or retroperitoneal EGCT, as vital carcinoma portions are frequently found in resected post-chemotherapeutic ETGC mediastinal residuals , 45. AccNon-seminomatous mediastinal EGCT have a poor prognosis with a 5-year OS of 40–45%, with inferior response rates to chemotherapy, especially in recurrence. The prognosis of retroperitoneal EGCT is better and similar to that of metastatic testicular GCT. The literature search for the follow-up of EGCT did not yield any relevant results. It is important to note that patients presenting with poor prognosis EGCT should be followed-up individually by specialized centers. The follow-up intervals of clinical examinations, ultrasound of the testicles, determination of tumor markers and radiological examinations (MRT/CT scans) should be similar to those of patients with metastatic GCT but must be adapted to the individual needs of the patient. EGCT patients have an increased risk for death from cardiovascular disease and those with mediastinal non-seminomas for the development of hematopoetic malignancies compared to testicular GCTs. These aspects need to be considered during follow-up. However, as many patients with EGCT can be long-term cured, they should be included into specific testicular cancer survivorship programs .EGCTs are a very rare tumor entity with specific biological and clinical features. In the case of seminomatous histology, the prognosis is best represented by the IGCCCG classification, regardless of the location of the EGCTs, either in the mediastinum or retroperitoneum. However, the majority of EGCT patients have non-seminomatous components. Patients with retroperitoneal non-seminomatous EGCT should also be treated according to the IGCCCG risk classification. However, patients with mediastinal non-seminomatous EGCT are always classified as “very” poor prognosis. Upfront high-dose chemotherapy appears to be the best therapeutic option for these patients, since the chance of survival using an effective salvage chemotherapy in case of relapse is extremely low. Performing residual tumor resection (RTR) should be the standard procedure for non-seminomatous EGCT patients after initial chemotherapy, especially in patients suffering from mediastinal EGCTs, whenever technically feasible. Because of their poor prognosis and several potential clinical problems associated with the disease and treatment, these patients should be treated and followed-up in specialized centers.Due to the rarity of EGCT cases, a detailed analysis in prospective randomized trials is hardly possible, so that the assessment of the best diagnostic and therapeutic options has to be based on retrospective studies.The problem with the current systematic review is the lack of validated data from the last 10 years. Few statistically relevant studies in recent years could be identified, so important studies from earlier decades were also included in the review process.


Pericardial thrombosis that complicates pericardial bleeding is a life-threatening emergency in interventional cardiology, and surgery remains the only definitive treatment option. We report the first case of successful intrapericardial thrombus aspiration using a dedicated thrombus aspiration catheter in the early stage of pericardial thrombosis.A 76-year-old woman with non-valve atrial fibrillation underwent percutaneous left atrial appendage (LAA) closure for secondary prevention of stroke. A 24-mm Watchman device was deployed under fluoroscopic guidance. Post-deployment angiography revealed LAA perforation, which led to the rapid onset of cardiac tamponade. Emergency pericardiocentesis was performed and the deep-seated device was redeployed at a more proximal position to seal the distal perforation. Pericardial bleeding was controlled after the drainage of 400 ml of blood. However, the patient re-developed cardiac tamponade following a period of stability. The patient was diagnosed with early-stage pericardial thrombosis based on echocardiographic findings of a hypoechoic effusion in the pericardial space. Thrombus aspiration using a pigtail catheter and long sheath failed; however, we performed successful intrapericardial thrombus aspiration using a dedicated thrombus aspiration catheter. We drained 120 ml of sludge-like blood, and the patient underwent successful conservative management without surgical intervention.This case report highlights the potential usefulness of a percutaneous intrapericardial thrombus aspiration technique using a dedicated thrombus aspiration catheter in selected patients with early-stage pericardial thrombosis, as a less invasive alternative to cardiac surgery. Cardiac tamponade is a potentially fatal complication in patients who undergo percutaneous cardiac interventions –3. ProceReportedly, the incidence of pericardial effusion that necessitates intervention was 4.8 and 1.9% in randomized left atrial appendage closure (LAAC) trials of PROTECT AF and PREVAIL, respectively , 7. More2DS2-VASc score of 7, and a HAS-BLED score of 3 underwent percutaneous LAAC for secondary prevention of stroke.A 76-year-old woman with a history of non-valve atrial fibrillation (AF), hypertension, diabetes, prior ischemic stroke, a CHAThe LAAC procedure was performed under local anesthesia, deep sedation, and fluoroscopic guidance. A decapolar catheter was inserted through the right femoral vein into the coronary sinus to guide transseptal puncture. Unfractionated heparin (100 U/kg) was administered immediately following transseptal puncture to achieve an activated clotting time of 330 s. The left atrial pressure was 33/15 mmHg. Left atrial appendage (LAA) angiography  at the rWe performed emergency pericardiocentesis via a subxiphoid approach under fluoroscopic guidance. A pigtail catheter was inserted into the pericardial cavity to drain blood, and the aspirated pericardial blood was immediately returned to the femoral vein via a sheath. Protamine (30 mg) was simultaneously administered to reverse heparin activity. The patient’s systolic blood pressure returned to 95 mmHg after aspiration of 150 ml of blood. The device was retracted and redeployed at a more proximal position to effectively seal the LAA and distal perforation . After cFollowing 10 min observation, the patient’s heart rate showed intermittent slowing with a decrease in blood pressure to 90/62 mmHg. A temporary pacing lead was placed into the right ventricular to maintain a ventricular rate of > 60 beats per minute. Fluoroscopy revealed a near-normal-sized cardiac silhouette , and minThe patient’s blood pressure was temporarily stable at approximately 90/60 mmHg; therefore, intrapericardial thrombus aspiration was attempted before surgery. However, thrombus aspiration failed using a pigtail catheter, which was replaced by an 8.5 F long sheath . Unfortunately, thrombus aspiration through the sheath was also unsuccessful. Thereafter, we used a dedicated thrombus aspiration catheter. A 6F guiding catheter  was inserted through the long sheath into the pericardial cavity via an angioplasty guidewire , and a thrombus aspiration catheter  was advanced into the pericardial cavity via the guidewire. Following manipulation of the guiding catheter and guidewire, we could maneuver the thrombus aspiration catheter to successfully aspirate the thrombus from multiple sites across the pericardium , 7. SludThe pigtail catheter was removed on the second postoperative day after echocardiography confirmed the absence of pericardial fluid reaccumulation. We observed shrinkage of the round thrombus, which appeared as a strip that measured 1.8 cm × 0.7 cm in size near the right ventricular apex . AnticoaPericardial thrombosis is a life-threatening emergency, and therapeutic pericardiocentesis is challenging. We report the first case of successful intrapericardial thrombus aspiration using a dedicated thrombus aspiration catheter in the early stage of pericardiac thrombosis complicating LAAC, providing a percutaneous treatment of early pericardial thrombosis.Percutaneous LAAC serves as an alternative to oral anticoagulation for stroke prevention in patients with non-valve AF by mechanical occlusion of the LAA. The LAA is a thin-walled structure ; therefoEmergency pericardiocentesis is performed to relieve cardiac tamponade in patients with hemodynamic instability. Pericardiocentesis is an effective conservative treatment approach in most patients with pericardial tamponade that complicates LAAC . In our However, the patient returned with cardiac tamponade again after a period of stability and was diagnosed with pericardial thrombosis, following echocardiographic evaluation. Surgical treatment is the only definitive therapeutic option available for pericardial thrombosis  and to dIntra-procedural surveillance of transesophageal echocardiography (TEE) was not performed, which serves as a significant limitation of this study. TEE enables timely detection of pericardial effusion and thrombosis, and can outline the process from pericardial effusion to thrombus formation. Our case is quite unique because pericardial thrombosis was detected during the early stage in this patient. Emergency surgery is inevitable in patients with complete pericardial thrombosis or hemodynamic instability. We do not recommend the routine use of intrapericardial thrombus aspiration utilizing a thrombus aspiration catheter for the management of pericardial thrombosis; however, in selected cases, it may serve as a potential percutaneous method that obviates the need for open chest surgery and the ensuing morbidity. Whether the closure device should be deployed to seal the site of leakage for tears located within the LAA remains questionable. Our single-center experience supports this operation; however, few studies have discussed this topic, and future investigations are warranted to validate our findings.Pericardial thrombosis is a life-threatening emergency, and pericardiocentesis for management of this complication is often challenging; therefore, surgical treatment remains the only definitive therapeutic strategy. In this report, we highlight the effectiveness of a percutaneous technique of intrapericardial thrombus aspiration using a dedicated thrombus aspiration catheter in selected patients with early pericardial thrombosis.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The patients/participants provided their written informed consent to participate in this study.B-FM and C-QW wrote the manuscript. Q-SW and Y-GL revised the manuscript and were in charge of the design of this study. All authors approved the manuscript for publication.


Infarctions of the corpus callosum are rare due to a rich blood supply. Corpus callosum derives its blood supply from four vessels from the anterior and posterior circulation and for this reason, they have a rare, atypical presentation. There is scarce literature regarding this pathology. Corpus callosum infarcts usually present with non-specific signs and symptoms. Here, we describe a case of corpus callosum infarction in a 5-year-old boy who was a known case of acute lymphoblastic leukaemia. He presented with disseminated varicella infection and developed tonic-clonic seizures. MRI brain was performed and a diagnosis of corpus callosum infarct was made. The patient was treated conservatively. Corpus callosum makes the largest association fibre of white matter . HoweverCorpus callosum functions as a sensory and motor pathway as well as a communication between the left and right cerebral hemispheres . InfarctWe present the case of a 5-year-old male child who was a known case of pre-B-cell acute lymphoblastic leukaemia (ALL) and was under treatment in our hospital. The patient was undergoing chemotherapy for the known primary diagnosis. The treatment protocol was UKALL interim Guidelines Regimen B . He had a history of angioinvasive aspergillus with invasion into the hard palate in 2020, for which he had received antifungal therapy and debridement of fungal sinuses disease. The patient had direct contact with chickenpox through siblings and developed chicken pox in January 2022. Polymerase chain reaction (PCR) for herpes simplex virus (HSV)-1, HSV2, and varicella-zoster virus  was performed, which turned out to be positive for varicella-zoster virus. The results of the real-time PCR (blood specimen) is given in Table The patient remained in the ICU due to chicken pox pneumonia. During his ICU stay, he developed tonic-clonic seizures, for which MRI was performed. MRI showed multifocal infarcts involving the genu and body of corpus callosum and internal capsules bilaterally. The MRI brain axial diffusion-weighted imaging (DWI)/apparent diffusion coefficient (ADC) images Figures , 2 depicThe MRI brain axial fluid-attenuated inversion recovery (FLAIR) sequences are shown in Figures MRI brain axial FLAIR sequence is shown in Figure Figure The patient was treated in an ICU setting with acyclovir (280 mg three times a day) for four weeks. He gradually recovered until asymptomatic and was discharged from ICU.The corpus callosum has a rich vascular supply by branching arteries from both the anterior and posterior circulation, comprising anterior and posterior peri callosal arteries . Further, the corpus callosum is also supplied by branches from the anterior communicating arteries  . TherefoRich and extensive collateralization of the anterior and posterior circulation supplying the corpus callosum results in protective redundancy and resistance of the posterior peri callosal arteries to occlusion by the emboli due to its right angle formation with its parent vessels, resulting in the rarity of corpus callosum infarcts. However, background encephalitis resulting in multifocal vasculopathy as in this presented case can result in the patient developing this rare entity. Further, background malignancy resulting in an immunocompromised state of the patient poses an additional threat. Other than encephalitis, various causes of corpus callosum infarction include atherosclerosis, embolization, vasospasm, hypoxia, and hyper coagulopathies.The presenting symptoms of acute corpus callosum infarction are non-specific. These may include headaches, limb weakness, movement disorders, and memory impairment . IschemiThe most common cause of viral encephalitis in immunocompetent and immunocompromised patients include infection from HSV-1, varicella-zoster virus, and Epstein-Barr virus . VasculoTreatment options for varicella-zoster virus-induced vasculopathy are mostly empirical due to the lack of randomized controlled trials. Empirical therapy generally includes the drug acyclovir, given either in combination with steroids or without steroids. However late diagnosis or misdiagnosis because of non-specific and atypical presentation of the disease results in only around 60% cure rate of patients diagnosed with varicella-zoster virus vasculitis. The duration of treatment is, however, variable and depends on the patient’s clinical condition .Varicella-zoster virus vasculitis is an important and treatable cause of vasculopathy on the background of encephalitis. Especially in immunocompromised patients, varicella-zoster encephalitis results in multifocal vasculopathy that needs to be diagnosed and treated properly and timely. Correlation between clinical presentation and imaging findings is required for timely diagnosis. Since the rarity of corpus callosum infarcts poses a diagnostic dilemma, timely radiological imaging and diagnosis would be helpful in high-risk patients. Particularly, in patients with varicella encephalitis, hemorrhagic corpus callosum infarcts can be managed better with prompt diagnosis.


Rapid eye movement (REM) sleep behaviour disorder (RBD) is considered the expression of the initial neurodegenerative process underlying synucleinopathies and constitutes the most important marker of their prodromal phase. This article reviews recent research from longitudinal research studies in isolated RBD (iRBD) aiming to describe the most promising progression biomarkers of iRBD and to delineate the current knowledge on the level of prediction of future outcome in iRBD patients at diagnosis.Longitudinal studies revealed the potential value of a variety of biomarkers, including clinical markers of motor, autonomic, cognitive, and olfactory symptoms, neurophysiological markers such as REM sleep without atonia and electroencephalography, genetic and epigenetic markers, cerebrospinal fluid and serum markers, and neuroimaging markers to track the progression and predict phenoconversion. To-date the most promising neuroimaging biomarker in iRBD to aid the prediction of phenoconversion is striatal presynaptic striatal dopaminergic dysfunction.There is a variety of potential biomarkers for monitoring disease progression and predicting iRBD conversion into synucleinopathies. A combined multimodal biomarker model could offer a more sensitive and specific tool. Further longitudinal studies are warranted to iRBD as a high-risk population for early neuroprotective interventions and disease-modifying therapies. Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia clinically characterized by active dream enactment, including screaming, flinging, or falling off from bed, that may cause injuries to patients and their bed partners . AccordiIsolated RBD (iRBD) is now considered the expression of the initial neurodegenerative process underlying synucleinopathies, including Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA)  and consiRBD is considered a marker of neurodegeneration with strong predictive value and scarce sensitivity. The likelihood ratio of PSG-proven iRBD for development of a synucleinopathy has been estimated at 130, more than three times higher than that of detecting striatal dopamine loss on molecular imaging . By contIn the future, iRBD could be considered a condition which is useful to be targeted with new disease-modifying therapies, currently in development aiming to interrupt the pathological processes towards the development of synucleinopathies at an earlier stage. The study of iRBD pathology can allow the understanding of biological alterations preceding the clinical manifestation of a synucleinopathy, thus anticipating personalized treatments at a stage where cellular damage could be reversible . To do sThis article reviews the most relevant results from recent longitudinal research studies in iRBD, with the intent of describing the most promising progression biomarkers of iRBD and to delineate the current knowledge on the level of prediction in iRBD patients at diagnosis and their future outcome Table .Table 1LProdromal PD is a clinical entity characterized by the presence of motor and non-motor symptoms, such as alterations in motor dexterity, autonomic dysfunction, mood, olfaction, and cognition, that reflect the progressing neuronal damage in the brain . Many of123I]FP-CIT SPECT, a marker of presynaptic dopamine transporter (DAT) availability FP-CIT SPECT FP-CIT uptake, and a predictor of cognitive decline in patients with low CSF levels of both α-synuclein and low amyloid-β42 FP-CIT SPECT and transcranial sonography have been shown to detect subclinical changes in iRBD patients, similar to pathology seen in early PD [123I]FP-CIT SPECT, combined with hyperechogenicity of the substantia nigra, using transcranial sonography, had a predictive value of 100%, with 55% specificity, after 2.5 years to predict the conversion of iRBD patients to a neurodegenerative synucleinopathy [123I]FP-CIT SPECT scans show progressive loss of striatal DAT in iRBD patients over three years, with iRBD patients who converted to PD showing the greatest level of nigrostriatal dopaminergic dysfunction at baseline [123I]FP-CIT SPECT greater than 25% in the putamen has been shown to discriminate iRBD patients, with DAT deficits, who converted to a synucleinopathy from iRBD patients who did not convert after three-year follow-up [123I], FP-CIT SPECT had 75% sensitivity and 51% specificity to predict iRBD conversion to a synucleinopathy with a likelihood ratio of 1.54 [99mTC]TRODAT-1 SPECT, in iRBD patients over 5 years with greater DAT deficits in those patients at high risk of progressing to a synucleinopathy [[early PD –44. Fourearly PD –45. Iranbaseline . Furtherollow-up . At a fi of 1.54 . Li and inopathy  therefor99mTc]ECD SPECT study illustrated increased perfusion in the hippocampus of RBD patients who developed a synucleinopathy at a 3-year follow-up compared to those who did not progress [18F]FDG PET scans to measure progressive changes in PD-related brain pattern expression measures as a prodromal PD biomarker to predict phenoconversion in iRBD patients metaiodobenzylguanidine (MIBG) scintigraphy has also been investigated in iRBD patients. While cross-sectional studies have revealed abnormalities [123I]MIBG might not be a sensitive biomarkers for the progression and phenoconversion in RBD patients.Cardiac [malities , 101, a malities . These fStructural and functional MRI techniques have demonstrated changes in deep grey matter, cortical grey matter, microstructural white matter and disrupted functional connectivity networks in patients with RBD which can be associated with clinical symptoms . IsolateDiffusion-weighted MRI has been employed to define longitudinal brain connectome progression scores, using interpretable machine learning algorithm, to evaluate the progression patterns in iRBD patients as a prodromal phase of PD •. The loAs a high-risk population for conversion to synucleinopathies, iRBD offers a valuable therapeutic window for application of early neuroprotective interventions and disease-modifying therapies. Recent longitudinal studies have highlighted a variety of potential biomarkers, including clinical, neurophysiological, genetic, CSF, serum, and neuroimaging, for monitoring disease progression and predicting iRBD conversion into synucleinopathies Fig. . However


PHVMs have been implemented throughout the world; however, their implementation in the United States (US) is a recent phenomenon. In 2017, Trac-B Exchange  installed three PHVMs. In 2019, naloxone dispensation was launched at PHVMs in Clark County. The purpose of this research is to examine the extent to which naloxone dispensation at PHVMs was associated with changes in opioid-involved overdose fatalities.Implementing public health vending machines (PHVMs) is an evidence-based strategy for mitigating substance use-associated morbidity and mortality Monthly counts of opioid-involved overdose fatalities among Clark County residents that occurred from January 2015 to December 2020 were used to build an autoregressive integrated moving averages (ARIMA) model to measure the impact of naloxone dispensation at PHVMs. We forecasted the number of expected opioid-involved overdose fatalities had naloxone dispensation at PHVMs not occurred and compared to observed monthly counts. Interrupted time series analyses (ITSA) were used to evaluate the step  and slope change .p = .0022) and a significant increasing slope change . Forecasts that extended into the COVID-19 pandemic suggested worsening trends in overdose fatalities.During the 12-months immediately following naloxone dispensation at PHVMs, our model forecasted 270 opioid-involved overdose fatalities, but death certificate data indicated only 229 occurred, suggesting an aversion of 41 deaths. ITSA identified a significant negative step change in opioid-involved overdose fatalities at the time naloxone dispensation at PHVMs was launched (B = −8.52, Naloxone dispensation at PHVMs was associated with immediate reductions in opioid-involved overdose fatalities.Communities should consider implementing public health vending machines in efforts to prevent opioid-involved overdose fatalities.The COVID-19 pandemic worsened the overdose crisis.Naloxone dispensation at PHVMs was associated with immediate reductions in opioid-involved overdose fatalities. An ARIMA  model was determined to be the best fit for the time series with no outliers or seasonal trend detected during the months preceding naloxone dispensation at PHVMs. During the 12-months immediately following naloxone dispensation at PHVMs (March 2019 to February 2020), the model forecasted 270 opioid-involved overdose fatalities, but death certificate data indicated only 229 actually occurred during this time, suggesting an aversion of 41 deaths. Forecasting for the 22-month period following naloxone dispensation at PHVMs (March 2019 to December 2020) and partially overlapping with the COVID-19 pandemic, the model estimated that 495 opioid-involved overdose fatalities would have occurred; however, death certificate data indicated that 566 actually occurred, a difference of 71 more deaths than expected. Forecasting for the 10-month period that overlapped with the COVID-19 pandemic (March 2020 to December 2020) estimated that 225 opioid-involved overdose fatalities would have occurred, but in actuality, 337 were observed, reflecting an additional 112 fatalities than expected.Between January 2015 and December 2020, Clark County averaged 23.5 opioid-involved overdose fatalities per month, with fewer on average in the months preceding naloxone dispensation at PHVMs (January 2015 to February 2019) than in the post-naloxone dispensation period (March 2019 to December 2020) [22.5 vs. 25.7, respectively; p=.0022) and a significant increasing slope change .Using the same ARIMA  model, interrupted time series analyses were conducted to examine the immediate and trend change in opioid-involved overdose fatalities following naloxone distribution at PHVMs. Results of these analyses can be found in Our analyses suggest that naloxone dispensation at PHVMs in Clark County, Nevada was associated with immediate reductions in opioid-involved overdose fatalities. However, these reductions were situated within a broader context of worsening trends in overdose fatalities. The worsening trends in monthly overdose fatality counts parallel trends throughout the United States and may be explained by a drug supply that is widely contaminated with potent synthetic opioids and adverse health effects associated with the global COVID-19 pandemic  ,42,43. FOur forecast models demonstrated that in the 12-months following naloxone dispensation at PHVMs (and preceding the COVID-19 pandemic), 41 fewer overdose fatalities occurred than what would have been expected. In contrast, our analyses that examine the 22-month period following the launch of naloxone dispensation at PHVMs (and reflecting 10 months of the COVID-19 pandemic) suggested overdose fatalities exceeded that which was forecasted, highlighting the far-reaching effects of the COVID-19 pandemic. It is important to be cognisant that there is no evidence to suggest that providing naloxone at PHVMs resulted in escalations in monthly overdose fatalities; indeed, there is widespread scientific consensus that naloxone provision does not encourage or enable substance use ,17–20. Fet al. (2019) found that the implementation of three overdose prevention interventions  in British Columbia averted more than 60% of the overdose fatalities that were estimated to have happened without their implementation [via expanding access to naloxone at PHVMs, throughout the United States.Immediate reductions in overdose fatalities following naloxone dispensation at PHVMs nested in the broader context of worsening trends in overdose fatalities underscores the need for communities to utilise all available evidence-based strategies for overdose prevention. Mathematical modelling studies have found that combination approaches for overdose prevention are most effective ,46. For entation . Future To our knowledge, this is the first study that examined the impact of naloxone dispensation at PHVMs in the United States. However, PHVMs are not novel interventions as they were first implemented in Denmark in the late 1980s and since expanded to more than 14 countries ,25,47. CThroughout PHVM implementation in Clark County, there have been many lessons learned. For example, PHVM placement is a key consideration of implementation. Machines should be located at venues that are easily accessible for clients. Machines also require internet access  and an electrical outlet, potentially limiting the locations where they may be placed. Additionally, organisations may consider partnering with other agencies that provide services (e.g. drug treatment) to people who use drugs to co-locate PHVMs and ensure access is as low threshold as possible. Agencies interested in implementing PHVMs should also carefully consider associated costs, such as: the costs of purchasing PHVMs, day-to-day operational costs , supplies and packaging materials, and insurance. Conducting needs assessments with potential clients prior to PHVM launch may be beneficial for not only informing the type and volume of supplies needed at each machine, but also where PHVMs should be located. Additionally, communities should consider discussing with local populations of people who use drugs what time(s) PHVMs should be accessible. Tailoring when PHVMs are accessible to the times people who use drugs prefer has the potential to enhance their access and utilisation. Before PHVM implementation, stakeholders should also explore community readiness and assess if trainings about harm reduction services are needed.Our study has several limitations. First, our interrupted time series analysis only includes one interruption ; however, we know other events, such as the COVID-19 pandemic, occurred during the time period analysed. We did not include an interruption in our analyses for the onset of the COVID-19 pandemic given that the impact of the pandemic evolved over time. Our analyses also do not account for the implementation of pandemic-related mitigation strategies  and associated service access challenges. It is possible that the extent to which these events (the COVID-19 pandemic and associated mitigation strategies) affected the utilisation of PHVMs varied over the study period and by site. It is also plausible that each PHVM serves a different segment of the population of people who use drugs with potentially different levels of willingness to seek supplies at PHVMs during a pandemic. Future studies should characterise the networks of people who use drugs that access supplies at PHVMs and explore their preferences for where and when machines are located. In light of these limitations, we elected to examine our forecast models for monthly counts of opioid-involved overdose fatalities in three ways: the 12-months following the launch of naloxone dispensation at PHVMs (preceding the COVID-19 pandemic), the 22-months following naloxone dispensation at PHVMs (including 10 months that overlapped with COVID-19), and the 10-months during COVID-19. While we cannot determine causality with the available data, the forecasts suggest that naloxone dispensation at PHVMs was associated with significant and immediate reductions in overdose fatalities and that the COVID-19 pandemic was associated with increased overdose mortality.Another limitation is that our analyses are unable to account for where persons who administered naloxone acquired it. This is an important limitation given that naloxone is available at venues throughout Clark County. Notably, an overdose prevention initiative was launched in 2018 which included efforts to distribute naloxone to community stakeholders at risk for experiencing an overdose or who may be a bystander. Another limitation is that we did not examine shifts in the number of EMS calls for overdose nor overdose-associated hospital visits. It is also plausible that shifts in the drug supply may have differentially affected overdose mortality over the study period. An additional limitation is that we only examined monthly counts of opioid-involved overdose fatalities from 2015 to 2020 due to limitations in data availability. More nuanced analyses may be possible as more recent overdose data become available. Another limitation is that our analyses cannot speak to the totality of interconnected factors that affect overdose fatalities at the community level. Future studies should pair quantitative analyses with complementary lines of qualitative inquiry among people who use drugs to understand the overdose prevention landscape more holistically. Finally, our analyses are limited in that we cannot ascertain the potential impact of simultaneously occurring overdose prevention initiatives; our findings cannot speak to causality. It is conceivable that the reductions in overdose fatalities we identified stem from PHVM implementation in combination with other overdose prevention interventions. Looking ahead, studies should be conducted to determine the constellation of interventions that maximise reductions in overdose morbidity and mortality.In conclusion, naloxone dispensation at PHVMs in Clark County, NV was associated with immediate reductions in opioid-involved overdose fatalities. In the 12-months following naloxone dispensation at PHVMs (and preceding the COVID-19 pandemic), our model forecasted 270 opioid-involved overdose fatalities, but death certificate data indicated only 229 actually occurred, suggesting an aversion of 41 deaths. Future work should be conducted to better understand how to bring PHVMs to scale throughout the United States given that there are sustained increases in opioid-involved overdose fatalities. Communities should work expeditiously to implement evidence-based overdose prevention interventions, including naloxone dispensation at PHVMs.


Falls impose significant health and economic burdens on community-dwelling older persons. Decision modelling can inform commissioning of alternative falls prevention strategies. Several methodological challenges arise when modelling public health interventions including community-based falls prevention. This study aims to conduct a systematic review (SR) to: systematically identify community-based falls prevention economic models; synthesise and critically appraise how the models handled key methodological challenges associated with public health modelling; and suggest areas for further methodological research.The SR followed the 2021 PRISMA reporting guideline and covered the period 2003–2020 and 12 academic databases and grey literature. The extracted methodological features of included models were synthesised by their relevance to the following challenges: (1) capturing non-health outcomes and societal intervention costs; (2) considering heterogeneity and dynamic complexity; (3) considering theories of human behaviour and implementation; and (4) considering equity issues. The critical appraisal assessed the prevalence of each feature across models, then appraised the methods used to incorporate the feature. The methodological strengths and limitations stated by the modellers were used as indicators of desirable modelling practice and scope for improvement, respectively. The methods were also compared against those suggested in the broader empirical and methodological literature. Areas of further methodological research were suggested based on appraisal results.46 models were identified. Comprehensive incorporation of non-health outcomes and societal intervention costs was infrequent. The assessments of heterogeneity and dynamic complexity were limited; subgroup delineation was confined primarily to demographics and binary disease/physical status. Few models incorporated heterogeneity in intervention implementation level, efficacy and cost. Few dynamic variables other than age and falls history were incorporated to characterise the trajectories of falls risk and general health/frailty. Intervention sustainability was frequently based on assumptions; few models estimated the economic/health returns from improved implementation. Seven models incorporated ethnicity- and severity-based subgroups but did not estimate the equity-efficiency trade-offs. Sixteen methodological research suggestions were made.Existing community-based falls prevention models contain methodological limitations spanning four challenge areas relevant for public health modelling. There is scope for further methodological research to inform the development of falls prevention and other public health models.The online version contains supplementary material available at 10.1186/s12962-022-00367-y. The process of ageing encompasses multidimensional changes in physical and psychosocial domains . AssociaThe National Institute for Health and Care Excellence (NICE) falls prevention clinical guideline (CG161) for England and Wales recommends that community-dwelling people aged 65+ are routinely screened for falls risk. High-risk individuals should be referred to multifactorial intervention involving multidisciplinary falls risk assessment, followed by tailored treatments including exercise, home assessment and modification (HAM), vision correction and medication change , 28. TriCommissioning of these community-based interventions should be informed by economic evaluations that consider the costs and consequences of any falls prevention strategy against the next best alternative use of resources . Decisiopublic health rather than clinical interventions [There are methodological challenges which are likelier to arise when economic evaluation is applied to ventions –38. The ventions , 40.Community-based falls prevention could be conceived as a representative public health intervention for several reasons. First, the multidimensional and syndromic nature of falls generates significant heterogeneity in falls risk among the general older population and the associated need for risk screening and multiple intervention pathways as noted. Second, falls are closely associated with frailty , 42, whiA systematic review approach can be used to critically appraise how existing falls prevention economic models have handled the methodological challenges, and thereby assist in the conceptualisation of future models . A previThese findings motivated the current de novo systematic review, the methods and first part of results of which were recently published in a separate article . The latA previous systematic methodological review identified the following four key challenge categories to public health modelling : (1) capPublic health issues and interventions frequently affect non-health outcomes and expend resources outside the public healthcare system , 53–55. The ageing process that encompasses multidimensional changes in physical and psychosocial domains gives rise to high levels of heterogeneity in health status, functioning and healthcare needs . This isGeriatric health behaviours are strongly shaped by individual psychology  and social interaction , 73–75. As highlighted by an international expert panel, healthcare decision-makers face several priority setting criteria beyond cost-effectiveness . These cThe systematic review methods were previously described in the aforementioned article . “SystemThe systematic review protocol is registered on the Prospective Register of Systematic Reviews (CRD42021232147). The review followed the 2021 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline : see cheA study was included if it: (i) targets a population of community-dwelling older persons (aged 60+) and/or individuals aged 50–59 at high falls risk; (ii) evaluates intervention(s) designed to reduce the number of falls or fall-related injuries; (iii) is evaluated against any comparator(s); (iv) reports outcomes of economic evaluation ; (v) useThe methodological features of included models were synthesised by their relevance to the four PHMC challenge categories. Critical appraisal first assessed the prevalence of the given feature across models, then appraised the methods used to incorporate the feature. For example, the proportion of models that accounted for productivity loss associated with falls was assessed. Then, amongst models that accounted for the loss, the range of methods used for doing so were described and compared. The methodological strengths and limitations stated by the models’ authors were used as indicators of desirable modelling practice and scope for improvement, respectively. Where relevant, the methods were also compared against those suggested in the literature informing the PHMC framework in “In total, 15,730 titles and abstracts and 92 full texts were screened from which 46 decision models were identified. See the separate article for the PRISMA flow diagram and the list of studies excluded at the full-text screening stage .Table Exercise was the most evaluated intervention type (n = 17 models), followed by multifactorial intervention (n = 13). There were four model type categories: binary decision (n = 14 models)—comparing the state of the world with and without the intervention and without transition probabilities or time cycles; static (n = 9)—all except one  were decThe critical appraisal results are presented by the four categories of public health modelling challenges.Eighteen models operationalised analyses from the societal perspective  burden of falls under CBA. There may also be intersectoral differences in productive efficiencies , leading to intersectoral variations in cost-effectiveness thresholds [Where outcomes are generated and costs incurred outside the public healthcare system, their valuation methods should change accordingly . Yet onlresholds . Typicalresholds . Hence, resholds . Incorporesholds , 99, 100Overall, comprehensive incorporation of non-health outcomes and societal intervention costs is uncommon among models operationalising analyses from the societal perspective. A pressing issue is the balanced incorporation of non-health outcomes and societal intervention costs to prevent models over-estimating (if intervention costs are excluded) or under-estimating (if outcomes excluded) the cost-effectiveness of interventions.Overall, 27 (58.7%) models conducted at least one analysis related to heterogeneity. Table Age and sex were the most common delineators, used in 24 models. The use of social delineators was infrequent: four models from the same research group used ethnicity , 109–111. Likewise, heterogeneity in intervention cost was poorly modelled: only Honkanen et al. [Pega et al.  was uniqn et al.  allowed An issue in several models concerned how evaluation outcomes were compared across heterogeneously sized target subgroups. Specifically, there was a need to compare both incremental cost-per-unit ratios  and aggregate outcomes; an example of the latter is incremental net monetary benefit (INMB) computed by multiplying the total incremental health  gain by the cost-effectiveness threshold to obtain its monetary equivalent and subtracting the total incremental cost. An intervention tailored to a specific subgroup may generate a very favourable cost-per-unit ratio but a low aggregate benefit due to the small subgroup size (p. 118–122) . AccordiTable The time-variant risk factors were grouped into three categories: ‘age’, ‘falls incidence’, and ‘other’ . For the four individual-level Markov models, fracture risks were updated for individuals by age progression in each cycle. For the 13 cohort-level models, accounting for the age-based risk progression would have required tunnel states for each model state, but this was not mentioned or graphed. Tunnel states exist within each pre-specified Markov model state and have differing transition probabilities to other states to reflect the changes in risk that would occur over the time spent in the given model state ; the proOnly two models incorporated dynamic changes to intervention need: Honkanen et al.  allowed All models in Table Additional file Overall, the assessment of heterogeneity was limited, confined primarily to comparisons delineated by demographic factors and binary disease or physical capacity status ; the latter neglects the nature of geriatric health best characterised as a position on a continuous spectrum . LikewisNo model directly parameterised psychological and social causal mechanisms based on individual and social behavioural theories. Nevertheless, 31 (67.4%) models reported at least one implementation level, as shown in Table and applied compliance rates, there was a risk of confounding. For example, OMAS [A notable feature was the frequent reliance on modeller assumptions to parameterise the implementation levels, which was widely acknowledged as a limitation by authors , 121. Ofle, OMAS  specifiele, OMAS , 122. Unle, OMAS  did not Table how the variations in implementation levels were generated, often assessing the variations under deterministic sensitivity analysis  rather than under scenario analysis as distinct intervention strategies ..how the An issue related to implementation is the presence of capacity or budget constraint which defines the feasible levels of implementation ; no modeOverall, the most pressing methodological issue regarding behaviour and implementation concerns parameterising the long-term intervention sustainability using appropriate evidence rather than modeller assumptions. Moreover, there is greater scope for conducting value of implementation (VoIM) analyses and incorporating capacity constraints to improve model credibility , 78.Only seven (15.2%) models, shown in Table higher per-capita QALY gain than the non-Maori group. Hence, the LED problem was identified as the main cause of reduced capacity. But homogenous parameters across ethnic subgroups for intervention cost, efficacy and implementation precluded analysis of the DJ problem. The latter was only narratively discussed, with reference to non-ethnic social delineators. For example, Wilson et al. [Only the four models from the same BODE3 research group incorporated social subgroups delineated by ethnicity (Maori vs. non-Maori) , 109–111n et al.  mentionewithout fear. Nevertheless, the model did not report any subgroup results.Three models incorporated severity subgroups delineated by variables other than age, sex and individual falls risk factors . Eldridge et al.  incorporlower for the dependent, meaning that fracture prevention is less cost-effective for them. The LED likely also contributed via the higher mortality risk faced by the dependent.Honkanen et al.  incorporSmith et al.  operatioNo model conducted analyses that quantified the equity-efficiency trade-off. Except Boyd et al. , the BODThe results of the critical appraisal of the models by the systematic review were translated to 16 suggestions for further methodological research, sub-categorised by the four key challenges. These are shown in Table This systematic review and critical appraisal explored how 46 existing economic models of community-based falls prevention addressed four key methodological challenges associated with public health economic modelling and made methodological research suggestions that may inform future model development. The appraisal results supplement those concerning falls epidemiology, falls prevention intervention, and evaluation methods in the first part of the review results .Although the four challenges were appraised separately, the significant interactions between them should be noted. Incorporation of non-health outcomes would increase the heterogeneity and dynamic complexity in analysis . Wider iThe interactions between the first three challenges and the last , warrant further attention. First, capturing non-health outcomes and societal intervention costs likely exacerbates the inequitable outcome differences between social- and severity-based subgroups. For example, incorporating wider consumption benefits of HAM advantages richer homeowners . IncorpoSecond, there is a close overlap between considerations of heterogeneous intervention need and severity-based equity issues , 119. OnThird, social status and culture are known to influence geriatric health behaviour , and heaConsideration of the above modelling challenges holds relevance to other public health areas. Inclusion of non-health outcomes and societal intervention costs has been identified as a key methodological challenge for all geriatric public health interventions , 55. ModAn important avenue of further research concerns the availability of data required to implement the methodological aspects highlighted by the appraisal. Forthcoming work by the current authors seeks to develop a falls prevention economic model that implements the aspects using publicly available data , specifiA key strength of this critical appraisal is the range of the methodological challenges covered: one previous systematic review covered only the challenge of capturing non-health outcomes , while aAn important caveat is that the methodological appraisals in this article do not exhaust the range of issues relevant to falls prevention modelling but rather focus on those highlighted by the systematic methodological review as being critical for public health economic model’s credibility . FurtherExisting models for economic evaluation of community-based falls preventions contain methodological limitations spanning four challenge areas relevant for public health economic modelling. The appraisal in this work can inform the conceptual modelling of future falls prevention economic models to increase their credibility, as well as highlighting aspects for further methodological research within public health economic modelling. Stakeholders for modelling should explore how the four challenges and their interactions are specifically relevant to their decision-making context.Additional file 1: Table S1. Definitions of analysis types in economic evaluation. Table S2. Dynamic entry and exit patterns for non-binary models with horizons longer than 5 years. Table S3. Implementation levels by demand and supply dimensions.


As the principal means of acquiring nutrients, feeding behavior is indispensable to the survival and well-being of animals. In response to energy or nutrient deficits, animals seek and consume food to maintain energy homeostasis. On the other hand, even when animals are calorically replete, non-homeostatic factors, such as the sight, smell, and taste of palatable food, or environmental cues that predict food, can stimulate feeding behavior. These homeostatic and non-homeostatic factors have traditionally been investigated separately, but a growing body of literature highlights that these factors work synergistically to promote feeding behavior. Furthermore, recent breakthroughs in cell type-specific and circuit-specific labeling, recording, and manipulation techniques have markedly accelerated the discovery of well-defined neural populations underlying homeostatic and non-homeostatic appetite control, as well as overlapping circuits that contribute to both types of appetite. This review aims to provide an update on our understanding of the neural circuit mechanisms for promoting homeostatic and non-homeostatic appetites, focusing on the function of recently identified, genetically defined cell types. Research on the neural circuit mechanisms underlying feeding behaviors is critical to identifying therapeutic targets for food-related disorders like obesity and anorexia. Sung-Yon Kim and colleagues at Seoul National University, South Korea, reviewed the current understanding of neural circuits promoting feeding behavior, which is regulated by homeostatic and non-homeostatic appetites. In response to deficits in energy  or nutrients, specific populations of neurons sensitive to hormones leptin and ghrelin generate homeostatic appetite and promote feeding. In addition, diverse neural populations stimulate non-homeostatic appetite in the absence of immediate internal needs and are thought to drive overconsumption in the modern obesogenic environment. These appetites extensively interact through overlapping neural circuits to jointly promote feeding behaviors. While self-evident in our daily lives, the importance of this vital function is further emphasized by the fact that inappropriate regulation of feeding behavior is a hallmark of serious metabolic and psychiatric conditions, such as obesity and anorexia5. As such, decades of research have delved into the neural circuit mechanisms for appetite—the motivation to eat.Food intake is essential to the survival of animals as a critical contributor to energy homeostasis9. Information on energy stores and nutrient availability is thought to be primarily conveyed by peripherally produced hormones to certain central neurons9. These interoceptive hormones can directly reach central neurons behind the blood–brain barrier (BBB) via several mechanisms within circumventricular organs  that permit passive transport of hormones to these neurons10. In addition, these hormones can indirectly signal the energy state to hindbrain neurons by acting on vagal afferent neurons8. Upon direct and indirect exposure to peripheral signals of energy or nutrient deficit, central neurons that support homeostatic appetite are activated and drive feeding11.In response to caloric deficiency, animals seek and consume food to defend energy homeostasis13. For example, the sight, smell, and taste of palatable foods, as well as contextual cues that predict food reward, can all stimulate appetite even when animals are calorically replete12. Diverse neural populations mediating this non-homeostatic appetite have been identified and characterized thus far13. Some of these neurons drive feeding behavior specific to palatable foods regardless of the internal state13, while some populations are shown to promote food intake in response to conditioned sensory cues even in a sated state13. This mode of appetite is thought to encourage overconsumption beyond current physiological needs, possibly as a preventive mechanism against anticipated energy deficit12. However, in the modern obesogenic environment where we face an abundance, rather than a scarcity of food, this non-homeostatic appetite is considered to underlie the etiology of obesity, highlighting its clinical relevance11.Feeding behavior can also be initiated in the absence of apparent homeostatic needs6. However, it has continuously been noted that these appetites frequently interact with each other to promote feeding behavior; for one example, energy deficits increase the incentive salience of food-predictive cues13. Accordingly, recent studies have found that the activity of neural populations that are well established to promote non-homeostatic appetite is also modulated by the hunger state and that the neurons essential to homeostatic appetite also respond to non-homeostatic factors14. In addition, many neural populations that play a pivotal role in both homeostatic and non-homeostatic appetite regulation have been identified11.Much research has described these different appetites in isolation, with the predominant assumption that homeostatic and non-homeostatic appetites are mutually exclusive entities16. Here, we review the body of knowledge on the neural mechanisms promoting feeding, focusing on the latest progress under the following three sections: (1) Brain circuits for homeostatic appetite, (2) Brain circuits for non-homeostatic appetite, and (3) Interactions between homeostatic and non-homeostatic appetites. We also discuss future directions that would provide further insights into a comprehensive understanding of the neural mechanisms underlying the generation of appetite and feeding behavior.Recent advancements in techniques enabling anatomical and functional interrogation of genetically defined neuron types have markedly facilitated the disentanglement of well-defined neural circuit components mediating the control of homeostatic and non-homeostatic appetites8. A representative example is leptin, which is an anorexigenic hormone released by adipocytes into the blood circulation17. Plasma levels of leptin largely correlate with the body’s fat stores17. Systemic administration of leptin decreases food intake and induces weight loss, whereas in animals lacking the leptin gene, food consumption and body mass are dramatically increased, and this phenotype is fully reversed by leptin treatment17. Another example is ghrelin, which is an orexigenic hormone secreted by enteroendocrine cells in the stomach1. The levels of ghrelin peak before a meal and drop to baseline levels in less than an hour after eating18. The levels of plasma ghrelin increase following prolonged caloric restriction, whereas the extent to which ghrelin levels drop after a meal correlates with caloric load18. Curiously, while ghrelin administration sufficiently increases food intake, ghrelin-deficient mice exhibit no significant differences in standard chow intake18, perhaps due to other orexigenic mechanisms that prevent malnutrition in animals.Several hormones produced from peripheral metabolic organs primarily transmit information on energy stores and nutrient availability10. Most prominently, neurons expressing the gene encoding agouti-related peptide  in the arcuate nucleus (ARCAgrp neurons), which reside near the BBB-lacking median eminence, detect changes in both leptin and ghrelin levels19 , lateral hypothalamus (LH), bed nucleus of the stria terminalis (BNST), and paraventricular thalamus (PVT)36, but which of these projections are required for the orexigenic effect of ARCAgrp neuron stimulation remains to be determined. Furthermore, ARCAgrp neurons are critical for the orexigenic effect of ghrelin and the anorexigenic effect of leptin. Genetic ablation of leptin receptor (LepR) in ARCAgrp neurons via the CRISPR–Cas9 system increases food intake and body weight to a similar extent as mice lacking LepR completely37. These striking findings imply that leptin predominantly acts on ARCAgrp neurons—among its many potential targets—to maintain energy balance37. In addition, ARCAgrp neurons at least partially mediate ghrelin-evoked feeding. Ablating ARCAgrp neurons abrogates the increase in feeding that follows both oral administration of a ghrelin receptor agonist and subcutaneous injection of ghrelin38. In mice lacking Ghsr, the gene encoding growth hormone secretagogue receptor (GHSR), however, reinstating Ghsr specifically in ARCAgrp neurons only partially restores the orexigenic effects of subcutaneously injected ghrelin39. These results collectively suggest that ARCAgrp neurons are required but not sufficient for ghrelin-evoked feeding.ARCPomc) (ARCPomc neurons) are another key population that responds to hormones signaling the energy state, and that plays an important role in homeostatic appetite42. In contrast to ARCAgrp neurons, the activity of ARCPomc neurons decreases upon fasting and ghrelin injection and increases upon food intake and leptin treatment41, although recent single-cell RNA sequencing and electrophysiological experiments have revealed substantial heterogeneity in the responses of ARCPomc neurons to leptin43. This antagonistic activity of ARCPomc and ARCAgrp neurons appears to be shaped by a mechanism analogous to the flip-flop model from digital electronics44. When mice are calorically replete, ARCPomc neurons are activated, which in turn decreases the activity of glutamatergic terminals presynaptic to ARCAgrp neurons by releasing β-endorphin, leading to reduced ARCAgrp neuronal activity 44. Conversely, when mice are energy deficient, an increase in ghrelin levels activates Ghsr-expressing upstream glutamatergic terminals by activating an intracellular positive feedback loop involving AMP-activated protein kinase44. When the intracellular loop is initiated, ARCAgrp neurons are activated and maintain their elevated activity even after ghrelin is washed out, which inhibits ARCPomc neurons by the release of GABA44. This elevated activity remains persistent until ARCPomc neurons are activated—one suggested mechanism is via leptin, although this might not be physiologically relevant given that the leptin level does not acutely increase after food intake. This interesting study illustrates a neural mechanism by which ARCPomc and ARCAgrp neurons maintain their sustained activity in a bistable manner that is flipped by an energy excess and deficit, represented by leptin and ghrelin44.ARC neurons expressing the pro-opiomelanocortin-encoding gene , a peptide product of the Pomc gene, acts as an agonist of melanocortin 3 and 4 receptors , whereas agouti-related peptide (AgRP) acts as an inverse agonist of these receptors47. Key convergent sites for these neurons are Mc4r-expressing neurons in the PVH (PVHMc4r neurons), of which the expression of MC4R is both necessary and sufficient for the control of feeding48. Application of α-MSH and AgRP to PVHMc4r neurons ex vivo increases and reduces their firing activity, respectively46.In addition to their activity dynamics, the effects of ARC50. One example is the neurons marked by the expression of tyrosine hydroxylase (encoded by the Th gene) in the ARC, which are distinct from ARCAgrp and ARCPomc neurons. Optogenetic stimulation of this population robustly increases food intake, whereas tetanus toxin-mediated silencing of these neurons induces body weight loss49. In addition, these neurons show increased firing rates in the fasted state, as well as in response to ex vivo application of ghrelin49. These neurons inhibit ARCPomc neurons and neurons in the PVH, likely through the corelease of dopamine (DA) and GABA49; the genetic identity of PVH neurons postsynaptic to ARCTh neurons remains to be determined.Within or proximal to the ARC, several other neural populations are found to be orexigenic and activated by hunger and ghrelinSst) (TNSst neurons) are activated by ghrelin both ex vivo and in vivo50. When activated, these neurons promote food intake, as chemogenetic activation of this population dramatically stimulates food consumption . In contrast, chemogenetic and optogenetic inhibition of these neurons reduces food consumption , and ablation of these neurons attenuates body weight gain over ten weeks compared with controls. Optogenetic stimulation of the projection from the TNSst neurons either to the BNST or PVH was sufficient to stimulate appetite50.As another example, in the subregion of the hypothalamus residing lateral to the ARC called the tuberal nucleus, inhibitory neurons expressing the somatostatin gene (Dbh or Th gene) have been implicated in promoting homeostatic appetite. These neurons are activated following food deprivation51, and the level of Dbh mRNA in the NTS is increased upon peripheral ghrelin injection52. Optogenetic and chemogenetic activation of Dbh-expressing NTS neurons potently increases food intake, while optogenetic inhibition of these neurons suppresses feeding51. Some of the Th-expressing NTS neurons project to the ARC, and activation of this projection stimulates appetite while inhibiting this pathway impairs feeding elicited by low blood glucose levels53. Moreover, ablating ARC-projecting, Dbh-expressing neurons throughout the brain, which is also found to ablate most of the catecholaminergic neurons in the NTS, abolishes feeding evoked by peripheral injection of ghrelin52. The appetite-promoting effect of ARC-projecting NTS catecholaminergic neuron stimulation is mediated by norepinephrinergic transmission in the ARC, as this effect is abolished by pharmacological blockade of α-adrenergic receptors53 . Together with the observation that bath application of norepinephrine activates ARCAgrp neurons54, these results suggest that NTS catecholaminergic neurons induce feeding by recruiting ARCAgrp neurons. Given that ARCPomc neurons are also inhibited by norepinephrine in the presence of synaptic blockers54, it is likely that norepinephrine release in the ARC elicits a strong orexigenic effect via concurrent activation of ARCAgrp neurons and inhibition of ARCPomc neurons54.In addition to these key neural populations in the hypothalamus, catecholaminergic neurons in the nucleus of the solitary tract (NTS) that express dopamine β-hydroxylase or tyrosine hydroxylase  into the bloodstream64. Systemic administration of FGF21 decreases the preference for sugar against water65, and in mice presented with a choice of diets differing in protein composition, intracerebroventricular (i.c.v.) injection of FGF21 increases the preference for diets with a higher protein content66. Critically, the reduced carbohydrate preference upon increased FGF21 levels requires the expression of FGF21’s cognate receptor β-klotho in the brain66, specifically within the neurons in the ventromedial hypothalamus (expressing the region-specific marker Sf1), a region adjacent to the third ventricle and the ARC67.Recent investigations have also identified specific circuits in the hypothalamus that drive nutrient-specific appetites in response to internal signals indicating the deficit of certain nutrients—thereby contributing to the maintenance of the levels of individual nutrients, in addition to the mechanisms for defending the homeostasis of the overall energy levelVgat gene) (LHVgat neurons) comprise a key circuit node for non-homeostatic appetite 69. Notably, activation of ARCAgrp neurons did not yield contextual feeding conditioning69.Mounting evidence suggests that inhibitory neurons in the LH expressing vesicular GABA transporter  of the basal forebrain, ventral tegmental area (VTA), and peri-locus coeruleus (peri-LC) are all capable of driving feeding behavior77. Among these, fibers projecting to the VTA, a midbrain dopamine center critical to reward processing6, represent a crucial connection through which LHVgat neurons engage the mesolimbic dopamine system to support feeding behavior76. Activating projections from LHVgat neurons in the VTA increases feeding accompanied by maladaptive gnawing behavior; this aberrant behavior was largely absent during bulk stimulation of LH to VTA projections, which suggests that LHVgat neurons act in coordination with excitatory signals across the LH-VTA pathway to promote appropriate feeding behavior73. Bulk stimulation of LH neuronal projections terminating in the VTA increased food consumption even when mice were required to cross an electric shock grid to obtain the food reward, indicating that these projections potently drive compulsive feeding behavior that persists even in the face of punishment73. Notably, activation of LHVgat neurons increases dopamine levels in the nucleus accumbens (NAc)76, a forebrain region densely innervated by the VTA that shows increased dopamine activity during food-seeking behavior78. Activation of LHVgat axons innervating the VTA inhibits GABAergic neurons in the VTA, which then disinhibits dopaminergic VTA neurons projecting to the NAc, thereby increasing dopamine levels in the NAc76. This increase in dopamine levels in the NAc may play a key modulatory role in promoting the intake of palatable foods9.Multiple projection arms of LHVgat neurons is Vgat-expressing neurons in the peri-locus coeruleus (peri-LCVgat neurons); these neurons medially appose the locus coeruleus (LC). Activation of the projections from LHVgat neurons to the peri-LC, as well as activation of peri-LCVgat neurons, evokes voracious feeding behavior77. Remarkably, lesions of peri-LCVgat neurons completely block feeding driven by the activation of axons projecting from LHVgat neurons to the peri-LC, indicating that the peri-LC neurons that LHVgat neurons recruit to promote feeding are GABAergic. In contrast, VTA GABAergic neuron lesions did not alter feeding stimulated by activation of LHVgat projections to the VTA77. Considering that axons from LHVgat neurons to the peri-LC bypass the VTA, it was suggested that feeding evoked by LHVgat-VTA projection stimulation is attributable to activation of LHVgat axon fibers that pass the VTA and terminate in the peri-LC77.Another significant population downstream of LHVgat-DBB projections also induces feeding. In particular, when mice are provided with both normal and high-fat chow, optogenetic stimulation of the projections evokes indiscriminate feeding toward both normal and high-fat diets74. In the DBB, the majority of projection target neurons innervated by LH neurons express the cholinergic marker gene encoding choline acetyltransferase (Chat)74. In line with the notion that LHVgat neurons inhibit DBBChat neurons to drive feeding, optogenetic activation of DBBChat neurons reduces food intake, whereas ablation of these neurons or conditional Chat knockout in the DBB increases feeding and body weight79. Intriguingly, optogenetic activation of the projections from DBBChat neurons to the ARC reduces feeding, and ablation of cholinergic neurons in the DBB lowers Pomc gene expression in ARCPomc neurons79. As ARCPomc neurons are activated by acetylcholine, it seems plausible that LHVgat neurons inhibit ARCPomc neurons through DBBChat neurons to promote overconsumption79.Activation of LHVgat neurons and their downstream pathways, several populations in the forebrain and hindbrain regions have also been implicated in non-homeostatic appetite, as activation of these populations selectively increases the intake of palatable foods without affecting that of ordinary food or drives feeding even in a sated state. For example, the projection from the anterior PVT (aPVT) to the NAc preferentially drives the intake of palatable high-fat food over standard chow food80. Activation or inhibition of aPVT-NAc projections promotes or suppresses consumption of a high-fat diet, respectively, without affecting standard chow feeding80. Within the ventral subdivision of the basal forebrain (vBF), defined as the region including the DBB, the substantia innominata, and magnocellular preoptic nucleus, Sst-expressing neurons (vBFSst neurons) promote the intake of palatable food81. Activating these neurons in mice specifically increases high-fat chow intake and sucrose preference without affecting the consumption of standard chow81. Interestingly, activating vBFSst neuronal projections to the LH significantly increases the intake of high-fat chow but does not affect sucrose preference, revealing a putative dissociation of preference for fat and sugar within the category of palatable food81.In addition to LHPnoc gene (which encodes prepronociceptin) (ARCPnoc neurons) are also important in driving palatable food intake82. These neurons are distinct from ARCAgrp, ARCTh, and ARCPomc neurons, and these neurons are activated upon high-fat food intake but not upon standard chow intake82. Activation of these neurons or their projections to the BNST increased standard chow intake in animals maintained on a standard chow diet, and stimulating these neurons in high-fat-fed animals increased consumption of a high-fat diet. In addition, activating these neurons elicited direct GABAergic inhibition of neighboring ARCPomc neurons82. Conversely, selective ablation of these cells reduces high-fat feeding and body weight gain in mice maintained on a high-fat diet for three days, but it does not affect food intake or body weight under standard chow consumption82. On the other hand, activation of TNSst neurons in sated mice and inhibition of these neurons in hungry mice increased and decreased the intake of palatable food, respectively, without affecting standard chow consumption69. Chemogenetic activation of these neurons elicits a preference for the stimulation-paired chamber50.Some hypothalamic neurons within and proximal to the ARC also drive palatable feeding. Inhibitory neurons in the ARC expressing the Vglut2) in the hindbrain peri-LC (peri-LCVglut2 neurons) have been implicated in palatability-driven feeding83 . Recording of peri-LCVglut2 neurons in vivo revealed that the majority of these neurons are inhibited during food consumption, and this inhibition was stronger during the consumption of more palatable substances83. Inhibition of these neurons promotes feeding and conditions place preference83. Interestingly, optogenetic inhibition of peri-LCVglut2 neurons increases food intake by sustaining food consumption only when light delivery is temporally coincident with spontaneously initiated bouts, rather than by triggering a bout. It was concluded that this circuit node supports a palatability-guided double-negative feedback model, where consumption of palatable substances inhibits these neurons, which in turn serves to prolong consummatory action83.Recently, neurons expressing vesicular glutamate transporter 2  revealed that these neurons are required for the preference of nutrient-paired flavor84. When bitter-sweet mixture solution was paired with intragastric infusion of nutrients and sweet solution was paired with the infusion of sucralose, mice with ablated DSD1r neurons preferred sweet solution over bitter-sweet mixture, whereas neither wild-type mice nor mice with ablated dopamine D1 receptor-expressing ventral striatum neurons (VSD1r neurons) preferred sweet solution84. Conversely, optogenetic activation of DSD1r neurons, but not VSD1r neurons, robustly increased the intake of both sweet and bitter solutions, as well as another nonnutritive sweetener that was previously associated with visceral malaise84. Taken together, these results indicate that dopamine in the dorsal striatum is a key signal that underlies flavor-nutrient conditioning.In the ventral striatum, dopamine levels rise upon sucralose (a nonnutritive sweetener) licking alone but not upon licking of sucralose mixed with bitter tastants85. Anterograde and retrograde transsynaptic tracing experiments have revealed an anatomical polysynaptic pathway originating from the gut and spanning across the right vagus nerve to the NTS, PB, substantia nigra pars compacta (SNc), and dorsal striatum85. Interestingly, between the right and left vagus nerve, the right one appears to carry fat signals that have positive valence and are reinforcing; the stimulation of the right, but not the left, nodose ganglion neurons that project to the NTS elicited a preference for place paired or conditioned with stimulation, sustained self-stimulation behavior and induced dopamine release upon intragastric fat infusion in the dorsal striatum85. Consistent with the anatomical tracing results, activating SNc-projecting PB neurons also recapitulated these effects85. Ablation of either ascending fibers from the right nodose ganglion or SNc-projecting PB neurons impaired the preference for flavor paired with intragastric fat infusion and abolished the increase in dopamine evoked by intragastric fat infusion85.Furthermore, a remarkable recent study proposed the pathway from the gut to the dorsal striatum that signals the presence of fat in the gut86. This increased VTA dopamine neuron activity is impaired by transection of the hepatic branch of the vagus nerve , whereas optogenetic stimulation of the neurons in the left nodose ganglion increases VTA dopamine activity86.In the case of intragastric infusion of sucrose, VTA dopamine neurons were found to be activatedSst neurons as well as that of LHVgat neurons is sufficient for establishing contextual feeding conditioning69. However, only activation of TNSst neurons, but not LHVgat neurons, is necessary for context-driven overconsumption of palatable foods69. Both neural populations receive monosynaptic inputs from the ventral subiculum (vSub), a hippocampal region shown to transmit contextual information69. Interestingly, the amplitude of postsynaptic currents in TNSst neurons evoked by activation of vSub-TN axons was elevated in animals subjected to contextual conditioning for palatable food, whereas no conditioning-dependent synaptic plasticity was observed in LHVgat neurons69. Inhibition of TNSst neurons, but not ARCAgrp neurons or LHVgat neurons, reduces the intake of palatable food in a conditioned context, highlighting the necessity of establishing contextual feeding conditioning driven by palatable food69.The presence of food-predictive environmental cues sufficiently triggers feeding behavior in the absence of hunger, and recent studies have identified genetically defined neural populations necessary for overconsumption in a conditioned context. Within the hypothalamus, activation of TNNos1 gene) (InsCtxNos1 neurons) that project to the central amygdala (CeA) are required for overconsumption of chow food in a conditioned context87. Curiously, while InsCtxNos1 neurons projecting to the CeA are primarily glutamatergic, these neurons provide net inhibition of anorexigenic neurons expressing PKCδ (encoded by the Prkcd gene) in the CeA, possibly by recruiting inhibitory interneurons within the CeA88.Context-dependent overconsumption also relies on a top-down circuit extending from the cerebral cortex. In the insular cortex (InsCtx), neurons expressing nitric oxide synthase 1  of ghrelin potentiated food-evoked dopamine release in the NAc89, whereas leptin blunted the food cue-evoked activity observed in VTA dopamine neurons in hungry animals91. Moreover, chemogenetic activation of ARCAgrp neurons potentiates dopamine responses upon food presentation in the NAc92. Significantly, ARCAgrp neuron stimulation without food presentation did not change the baseline dopamine level in the NAc92.It is well known that hunger increases the reward value of food93. In contrast, how dopamine signaling modulates the orexigenic effect of ghrelin is unclear, as both agonism and antagonism of central D1R or D2R/D3R receptors attenuated the orexigenic effects of i.c.v. ghrelin injections94, whereas the hyperphagic effects of peripheral ghrelin administration were not affected by systemic injection of D1R or D2R antagonists93. Remarkably, blockade of dopamine receptor signaling by systemic injection of D1R and D2R antagonists attenuates the response of ARCAgrp neurons to nutrients92. Moreover, systemic injection of a dopamine reuptake inhibitor in mice lacking ARCAgrp neurons can restore standard chow intake28, implying that dopamine signaling can override the absence of ARCAgrp neurons and promote standard chow intake.Conversely, dopaminergic reward signaling plays a causal role in homeostatic appetite. Systemic injection of a D2R antagonist or genetic knockout of D2R blunts the hypophagic effect of systemic leptin injectionSst neurons, a single population can also be involved in homeostatic and non-homeostatic control of appetite69. These neurons are activated in the hunger state, as well as by ghrelin signaling an energy deficit, and activation of these neurons promotes chow food intake50. At the same time, these neurons are necessary for food consumption beyond the energy need that occurs in the context paired with high-fat food69. This notable case exemplifies that neural circuits for homeostatic and non-homeostatic appetites are not entirely dissociable.As in the case of TNRecording the activity of neurons during energy deficit and surfeit, or in response to the changes in humoral signals such as hormones or nutrients, would reveal their possible role in sensing physiological energy states.Assessing the effects of stimulating a neural population on the intake of diets of different nutritional compositions  may uncover their causal role in nutrient-specific appetites.Investigating the activity of a neural population during ingestion of nonpalatable and palatable foods will help determine its role in palatability-driven feeding.Testing if these neurons are activated by food-predictive cues, if these cues are sufficient or necessary for the learning of food-cue associations, and if this neural population promotes overconsumption in the presence of learned cues can verify their involvement in cue-evoked conditioned overconsumption.Detailed analysis of meal structure  following perturbation of a neural population can help pinpoint where its orexigenic or anorexigenic effect is exerted along the sequence of feeding behavior  and aid in the identification of their specific role in regulating ingestive behaviors .Observing the long-term  effects of ablating or stimulating specific neurons would be informative in determining their necessity or sufficiency in promoting feeding behavior in the long term, which may bear higher clinical relevance.Here, we reviewed studies on the neural circuit mechanisms driving homeostatic and non-homeostatic appetites, with an emphasis on recent findings. We also discussed that the neural systems supporting the two modes of appetite interact with each other and share common circuit nodes. A key objective in the study of neural circuit mechanisms underlying appetite regulation is identifying specific roles played by a particular neural population. Diverse experimental paradigms have illuminated how individual neural populations mediate particular aspects of feeding behavior. Employing the relevant methodologies to characterize neural populations affecting feeding behaviors would aid in the comprehensive elucidation of their functional significance. Among the numerous approaches, we summarize some notable examples and the possible interpretations that can result:97.In addition, multiple neuropeptide systems  are heavily involved in the control of appetite and should thus be taken into account in this research. Beyond studying each circuit one at a time, elucidating the cooperative workings of the many circuit components in a network context remains a salient future task for revealing a diagram of the full neurocircuitry that drives food intake. Cutting-edge techniques enabling interrogation of neural circuit elements in intact brain tissues would further accelerate this research endeavor101. Furthermore, identification of the neural circuits responsible for such disorders and subsequent screening of druggable targets specific to these neurons by means of single-cell RNA sequencing holds great promise in opening novel avenues for the treatment of feeding pathologies105.From a clinical perspective, it would be critical to examine how neural activity, synaptic connectivity, or transcriptomic profiles of each orexigenic population are affected in disease conditions such as obesity or anorexia nervosa. It is equally important to investigate how pharmacological  or surgical interventions  for such diseases affect appetite-promoting circuit nodes, which would lead to crucial translational insights