Dear Editor,The impact of the pandemic on eating disorders: The COVID-19 pandemic, associated with a 15.3% increase of overall incidence of eating disorders, corresponded to an increased demand for eating disorder services in Australia. This resulted in several paediatric services revisiting the way they delivered timely and suitable interventions for anorexia nervosa. This letter describes four such responses, only one of which has been formally evaluated. We also summarise important principles from service providers across Australia to whom these service delivery models were described at a workshop.Innovative service delivery in challenging times: The themes of the four different service models, described in Principles of practice identified across service providers: At the annual meeting of the 2022 Australia and New Zealand Academy of Eating Disorders (ANZAED) a workshop was conducted and facilitated by the authors with 87 registrants , representing consumers and various disciplines across private practice, public service, and non-government organisations. Discussions were held in small groups focusing on the question: ‘What principles do we need to embrace moving forward with service provision?’Five principles were endorsed. First, the importance of immediate availability of a low-resource intervention that was ‘good enough’. The experience of the pandemic suggests that immediate, time-limited online/telephone connection with parents/carers is appreciated by many families, even in the absence of a detailed, multi-disciplinary, face-to-face assessment. Such contact can lead to substantial improvements to those families who participate.Second, the necessity of providing hybrid services to the young person with an important non-negotiable of face-to-face meetings for regular medical monitoring. Given the immense burden anorexia nervosa imposes on families, we must carefully consider which elements of service delivery can be delivered face-to-face or remotely.Third, the immediate importance of enhancing carer knowledge and skills. The usefulness of psychoeducation, presented in digestible units, and tailored to the circumstances and context of the family, was highly valued.Fourth, utilisation of lived experience was especially important for increasing the acceptability and uptake of services, building hope in families, engaging families in treatment, and enabling a greater understanding of the skills needed to refeed one’s child.Fifth, resources for evaluation of service delivery are essential for dissemination of what is working and what is not working so we can continue to respond flexibly in providing the best service delivery to a vulnerable client group.


Despite being one of the most debilitating conditions encountered in the field of toxicology, there is a lack of neutralization measures for the toxins involved in acute corrosive poisoning, and this promotes progressive contact injury of deep tissues after poisoning has occurred. Multiple controversies still surround management strategies during the acute phase of poisoning and the long-term follow-up of the patient. Here, we report a severe case of intentional poisoning with nitric acid complicated by extensive injury of the upper digestive tract, multiple stricture formation, and complete dysphagia. Serial endoscopic dilation and insertion of a jejunostomy feeding tube were necessary, and underlying psychiatric illness negatively affected the outcome of the patient. We conclude that an interdisciplinary approach is necessary to properly reduce the extent of lesions and sequelae induced by corrosion. Early endoscopic mapping of injuries is of major importance to better predict the evolution and possible complications of poisoning. Interventional and reconstructive surgical procedures may significantly improve the life expectancy and quality of life of patients following intoxication with corrosive substances. The curCorrosive poisoning can induce short-term  and long-term  complications, and proper management in both situations is essential ,25.Here, we report a severe case of a patient who attempted suicide by ingesting nitric acid, which was complicated by extensive gastro-esophageal necrosis and complete dysphagia secondary to multiple stricture formation treated with serial endoscopic dilation. The refusal of the patient to proceed with surgical treatment, as well as noncompliance with the instructions received from physicians (due to the patient’s decompensated psychiatric condition), contributed to the fatal outcome.Although severe respiratory effects and/or lethality can occur after the inhalation of gases and vapors originating from nitric acid, this article refers exclusively to the acute toxicity associated with the ingestion of corrosive substances, such as nitric acid ,27.A 46-year-old male was admitted to the emergency department 3 h after the intentional ingestion of an unspecified amount of nitric acid. As part of the Roma ethnic group, the patient worked as a coppersmith, handling concentrated solutions of nitric acid, which he used for the surface cleaning of copper vessels.The patient had a medical history of depression (a bereavement reaction to his wife’s death 6 weeks previously) and chronic alcoholism. Suicidal ideation and deliberate self-poisoning were enhanced by ethanol co-ingestion.2) of 97% in room air, and absence of fever. Two episodes of hematemesis were witnessed in the emergency department.The initial clinical manifestations included dysphagia, retrosternal and epigastric pain, vomiting, and productive cough. The clinical examination showed anxiety and agitation, a Coma Glasgow Scale score of 12, breath alcohol odor, blood pressure of 176/124 mmHg, a heart rate 84/minute, a respiratory of rate 21/min, oxygen saturation (SpO3 with neutrophilia of 90% and increased high-sensitivity C-reactive protein), thrombocytopenia, and increased serum lactate. The otorhinolaryngology evaluation showed mild congestion of the oropharyngeal and laryngeal mucosa, without signs of acute respiratory failure.The biological assessment confirmed the co-ingestion of ethanol, increased pancreatic enzymes suggestive of toxic acute pancreatitis, systemic inflammatory reaction  with careful monitoring in the intensive care unit and then admission to the general surgery unit for surveillance and follow-up in case of immediate complications (such as active hemorrhage or perforation). Complete restriction of oral intake, high-dose proton pomp inhibitors, and parenteral nutrition were initiated. Empiric antibiotic treatment (amoxicillin/clavulanic acid and clindamycin) was administered due to clinical, biological, and imagistic suspicion of tracheobronchial aspiration.On the seventh day after ingestion of the nitric acid, the patient tested positive for SARS-CoV-2 (RT-PCR) and, due to the epidemiological context and the stability of the corrosive lesions, he was transferred to the Internal Medicine Department for the treatment of pneumonia.Eleven days after the ingestion, the patient restarted oral feeding by ingesting small amounts of fluids, which was followed by the persistence of dysphagia and an accentuation of epigastric pain. Although parenteral nutrition was recommended, the patient disregarded the indications and continued to feed himself orally with poor digestive tolerance . On the 13th day after the ingestion, the patient presented hematemesis and melena. An endoscopic evaluation was attempted, but a lack of cooperation on the part of the patient restricted the further continuation of the procedure due to safety reasons. Hemostatic treatment was administered, and remission of the bleeding signs was noted. In the following days, the patient’s clinical state permitted a new attempt to restart oral nutrition (liquids and semi-solid foods) with a favorable clinical outcome, and the patient was discharged on the 22nd day of the evolution of post-corrosive ingestion. Recommendations for gastroenterology evaluation (by esophagogastroduodenoscopy or by barium esophagogram) in an ambulatory setting were made to accurately assess the residual post-corrosive injuries (4 weeks after the exposure to nitric acid).The long-term follow-up revealed the development of multiple esophageal strictures, with dysphagia for liquids and, intermittently, solids. The patient was non-compliant with the indications of the gastroenterologist and only appeared for two of the endoscopic esophageal dilation sessions with a 10–12 mm Controlled Radial Expansion balloon, mentioning that he could feed himself with semi-solid foods at home.Three months after the ingestion, he presented himself again to our hospital for complete dysphagia for liquids. He refused a new endoscopic dilation session, which is why a feeding jejunostomy was inserted.About 5 months after the insertion of the jejunostomy tube, the patient presented himself to our hospital again due to accidental self-suppression of the jejunostomy tube. At this moment, the patient showed a noticeable decrease in weight. Esophageal stripping with esophagoplasty was proposed to him, but he refused the surgical intervention, and a new insertion of the feeding jejunostomy was jointly decided by the medical team.Approximately 10 months after the ingestion event, the patient arrived at the gastroenterology department again, where a new session of endoscopic esophageal dilation was performed, which was complicated by esophageal perforation, pneumomediastinum, minimal right pneumothorax, and right pleurisy. The patient continued to refuse surgical treatment for esophageal stenosis and pleurotomy. His general condition worsened, necessitating admission to the intensive care unit, orotracheal intubation, and mechanical ventilation. During this time, a medical committee consisting of an intensive-care physician, a thoracic surgeon, and a general surgeon was assembled, and it was decided, for the patient’s well-being, to perform a bilateral pleurotomy and drain the pleurisy. Considering his improved condition, the patient was extubated, with the resumption of respiratory function in normal parameters being achieved. Despite psychological counseling and psychiatric evaluation, the patient behaved aggressively, refused the administration of medication, and once again self-suppressed his jejunostomy tube.The patient was supported throughout the hospitalization with parenteral nutrition and was discharged at the request of his family to be cared for at home. The subsequent follow-up  confirmed the death of the patient.An extensive search of the literature was performed with the journal search engines of Thompson ISI—Web of Science and PubMed. We used the MeSH terms “suicide”; “nitric acid”; “corrosive”; “caustic”; and “toxicity”, “intoxication”, or “poisoning” in different permutations. The titles and abstracts were initially screened, and relevant studies were selected for full-text evaluations. Additionally, we examined the citations of all resulting articles for any additional relevant references. Given the large distribution of pediatric cases, attentive selection of articles involving this category of patients was carried out to properly extract relevant information for the adult population.The epidemiological burden of acute corrosive poisoning is difficult to estimate given the inhomogeneous distribution of cases worldwide, corroborated by an increased number of undetected and unreported cases. An estimated 5000 to 15,000 new cases of caustic ingestions occur annually in the United States ,29. PrevThe acute toxicity of nitric acid is mainly associated with the extremely corrosive nature of this strong acid. Several factors can reflect the potential toxicity of the corrosive substances and can strongly interfere with the prognosis of the patient, such as the type , the pH level (<2 or >12), the volume, the concentration, the time of contact, the state of presentation (liquid substances produce more extensive injuries than solids), and the intentionality of the poisoning  ,16,21,31Acidic or alkaline corrosive substances also represent a significant variable in determining the anatomical injury site. Acids will mainly affect the lower esophagus and the stomach, while alkaline chemicals will affect the oropharynx and the esophagus. One possible explanation for this could be the partial neutralizing effect that the endogenous gastric secretion might have when exposed to alkali substances ,17,30.Furthermore, repeated episodes of vomiting and/or the repeated passage of the corrosive substance in the first 6 h after ingestion induced by dyskinetic movements of the upper digestive tract may lead to tracheobronchial aspiration, thus further enhancing the potential of toxicity in the acute phase .The ingestion of acidic substances induces acute coagulative necrosis , accompanied by the formation of protective eschar, which explains the delayed risk of perforation that may occur, starting from day 4 ,16,32. ODue to its excellent oxidizing action, nitric acid induces an immediate reaction with any tissue, causing early symptoms such as oropharyngeal pain, dysphagia, excessive salivation, and upper gastrointestinal bleeding ,36,37.Although the clinical diagnosis may become evident in the presence of the patient’s relevant history, the most severe forms of intoxication tend to exhibit a very complex picture. Involvement of respiratory structures may lead to laryngospasm, stridor, dyspnea, hemoptysis, dysphonia, or respiratory distress signs ,40,41,42In the case of esophageal perforation, the location of the pain will indicate the site of perforation in 70–90% of cases. Subcutaneous emphysema may be present when perforation of the cervical esophagus occurs, while hemodynamic deterioration, fever, or signs of multiorgan failure should raise suspicion of infectious complications and septic shock ,44.Even in the absence of these symptoms, potential harm may be considered, indicating the need to still perform endoscopy/bronchoscopy in selected cases . Another misleading element in proper clinical assessment after exposure to corrosive substances may be the different distribution of damaged tissues. A lack of obvious oropharyngeal lesions does not preclude the existence of distal injuries at multiple levels, and nor should it minimize the severity of the poisoning ,45.Moreover, the intensity of the primary complaints may vary according to the different phases of tissue remodeling . Thus, no correlation can be established between the severity of the symptoms and the extent of the injuries . The sevEstimations of the volume of the ingested substance by clinicians seem to be inaccurate, thus making it difficult to estimate the severity of intoxication using this criterion alone. Pre-hospital management should focus on establishing the toxicological context, identifying risk factors  and initiating supportive care measures . Attempts to neutralize acids or alkalis are prohibited since exothermic reactions may occur, increasing the damage .Initial management should carefully assess the extent of injuries. Esophagogastroduodenoscopy remains the gold standard for diagnosis evaluation of corrosive-induced injures of the upper digestive tract. Furthermore, the precise endoscopic mapping of the injuries  represents the most important determinant regarding the prognosis and treatment of the patient .Emergency endoscopy must be performed within the first 48 h after exposure to the toxin, with the optimal interval generally considered to be 12–24 h ,36,49,50Since various gradings of the injuries can be highlighted throughout the length of the upper digestive tract , great bRecent research has involved a series of debates regarding the diagnostic and prognostic importance of computed tomography (CT) imaging as a non-invasive method in the assessment of corrosive-induced lesions ,53,54,55In current practice, endoscopic and imagistic modalities offer complementary information and, in the absence of contraindications, sustain a holistic approach for the acutely poisoned patient. The CT scan is the investigation method of choice when perforation is suspected or when involvement of the mediastinal/abdominal structures needs to be assessed ,58.According to our experience, biological inflammatory markers (high-sensitivity C-reactive protein and white blood cell count) are significantly higher in patients with corrosive poisoning compared to other forms of acute intoxications . There is pathogenic support for this since tissular injuries associated with corrosive exposure involve a sustained systemic inflammatory response that, nonetheless, must be differentiated from other possible etiologies ,60,61.Several clinical and paraclinical findings  should raise the suspicion of complications, such as perforation . The decThe devastating effect that the ingestion of corrosive substances might have on the respiratory tract must also be mentioned. The aspiration of corrosive substances may induce extensive tracheobronchial injuries . Thus, tWhen the presence of extensive lesions in the upper digestive tract is suspected, the authors acknowledge the possible benefits of an initial bronchoscopy (prior to esophagogastroduodenoscopy) given that it provides warnings about the severity of oropharyngeal injuries and given that instruments with a smaller caliber are being used . MoreoveSince one of the major consequences of tissue exposure to corrosive substances implies excessive fibrogenic activity, and since the secondary development of strictures is also a problem, additional therapies should be considered in selected cases. Several experimental corrosive esophagitis animal models have been used to promote new antifibrotic and antiproliferative strategies, such as vitamin E (α-tocopherol), methylprednisolone or EW-7197, and a selective inhibitor of TGF (transforming growth factor) β type I receptor kinase ,68,69. TAnother major goal in the management of both the acute and chronic phases of corrosive substance poisoning is the avoidance of malnutrition . PatientThe accumulated evidence is consistent with the following recommendations assessing several controversial therapies in the management of acute exposure to corrosive substances .According to Katz and Kluger, over 90% of patients with grade 3 injuries and about 30–70% of patients with grade 2B will develop esophageal strictures within 8 weeks after oral exposure to corrosive substances . A smallDilatation of the esophagus is considered a relatively high-risk intervention, and determining the precise moment to perform endoscopic dilatation of the strictures therefore has a major impact on the functional outcome ,72. CompAdditional procedures, such as intralesional steroid injection or topical applications of mitomycin-C, can limit the synthesis of collagen and the excessive development of fibrosis, thus reducing the necessity for serial dilatation maneuvers . The temLate reconstructive surgery should be considered as a last-resort option for refractory or complicated complex strictures or for long strictures that are endoscopically inaccessible .To date, corrosive-substance poisoning remains a therapeutic challenge. The most severe forms of poisoning can lead to mortality or long-term sequelae and can require multiple admissions and prolonged nutritional support .During the long-term follow-up, endoscopic surveillance is recommended to allow early detection of pre-cancerous dysplastic lesions. No consensus has been established regarding the optimum interval to perform endoscopy, but every 2 to 3 years seems to be the most accepted strategy among specialists . NonetheIn the acute phase, the severity of corrosive poisoning may vary, from minor injuries to life-threatening conditions, such as perforation, bleeding, necrosis of the esophagus and stomach, sepsis, and shock ,54,78,79The estimated amount of time needed for esophageal cancer to develop is about 15-to-40 years after corrosive substance exposure and the initiation of the carcinogenesis process ,81. WithThe management of post-corrosive esophageal lesions is a multidisciplinary one that must combat short-term complications, such as perforation and hemorrhage, but also long-term complications, such as stenosis and malignancy. Short-term complications are the prerogative of an interdisciplinary team that must act urgently to save the patient’s life by preventing perforation and hemorrhagic shock. Problems arise in the long-term management for treating the phenomena of fibrosis and stenosis characteristic of esophageal corrosive injuries. The first step is endoscopic dilation of the stenoses, which is followed by a surgical procedure if endoscopic dilation is impossible to perform or has a high risk of perforations. Esophageal stripping with different esophagoplasty techniques depending on the local lesions and the experience of the surgeon is the gold standard for the surgical treatment of post-corrosive esophageal strictures.Although significant legislative limitations have been implemented, potentially corrosive substances are still easily accessed by the population, thus requiring supplementary measures to prevent corrosion-induced injuries. Ultimately, providing the best outcome for patients remains the main challenge.


The field of gastrointestinal cancer research continues to make significant strides in understanding the complexities of these challenging diseases. In the realm of medical advancements, few areas have witnessed as much progress as the management of gastrointestinal (GI) and hepatobiliary cancer. With groundbreaking research that produces translationally evidence-based innovative treatments in the shortest possible time, the field has transformed, offering renewed hope to patients and healthcare professionals alike.The advent of precision medicine has revolutionized cancer treatment, enabling tailored therapies based on a patient’s unique genetic profile. In GI and hepatobiliary cancer, targeted therapies have emerged as real game-changers. From anti-angiogenic agents to immune checkpoint inhibitors (with or without chemotherapy-backbones), these new treatment options have shown promising results in improving survival rates and quality of life for many patients.In addition, the introduction of minimally invasive surgical techniques, such as laparoscopic and robotic-assisted operations, has equally transformed the landscape. These procedures offer numerous benefits, including an improved rate of R0-resections, reduced post-operative pain, faster recovery times, and the fewest possible functional limitations. As a result, patients can now undergo surgeries with decreased morbidity, empowering them to return to daily activities in a shorter time, as well as making them ready for further interdisciplinary therapeutic approaches.The progress that has been achieved in the management of gastrointestinal cancer is remarkable in many ways. From advancements in screening and early detection to the integration of precision medicine and targeted (immuno-) therapies, patients diagnosed with GI or hepatobiliary cancers have much more promising prospects at present than were available at the beginning of this millennium. In a period that looks like a “blink of an eye” in the history of medicine, the first steps into a development that offers unimagined possibilities have been taken.Impressively completed by minimally invasive surgical techniques and improved radiation therapy, multidisciplinary approaches have transformed the landscape of cancer care, offering patients better outcomes through increased response rates and extended survival times not only with regard to the progression-free survival (PFS), but encouragingly, also the overall survival (OS). All these achievements were out of reach just a few years ago.Cancers aims to shed light on various aspects of the diagnosis, treatment and management of colorectal, gastric, pancreatic and hepatobiliary cancers by illustrating the remarkable progress achieved in GI cancer management and the potential this holds for the future.The series of recent publications in this Special Issue of One noteworthy study, conducted by Rebecca Thonhauser and colleagues, explores the impact of induction chemotherapy with vascular endothelial growth factor (VEGF) inhibition on tumor response in patients with synchronously metastasized, potentially resectable colorectal cancer (mCRC) . The resFocusing on the cellular foundations, the research by Ana Montero-Calle and her team focuses on novel proteoforms derived from the alternative splicing of p53 and p63 proteins in colorectal cancer cells . Their wThe publication by Claudio Gambardella and collaborators delves into the use of biosynthetic mesh reconstruction after abdominoperineal resection for low rectal cancer . The stuCancers. Andrew J. Sinnamon and team introduce the Clockwise Anterior-to-Posterior—Double Isolation (CAP-DI) approach to portal lymphadenectomy in biliary tract cancer [Advances in surgical techniques are also the focus of another recent publication in this issue of t cancer . This inThe newest diagnostic armentarium is the focus of the paper by Lucia Cerrito and coauthors, presenting a comprehensive review about the use of contrast-enhanced imaging in the management of intrahepatic cholangiocarcinoma . Their wAnother notable contribution is an exploratory assessment of nutritional evaluation tools as predictors of complications and sarcopenia in patients with colorectal cancer, conducted by Isabel M. Vegas-Aguilar and a team of dedicated researchers . This stFurthermore, the effect of perioperative blood transfusions and infectious complications on inflammatory activation and long-term survival following gastric cancer resection is a topic of significant importance. Noelia Puértolas and colleagues look into this critical aspect of gastric cancer management, highlighting the complex interplay between surgical procedures, immune response, and patient prognosis . Their rCancers, collectively demonstrate and prove the multidimensional nature of gastrointestinal cancer research. From investigating novel nutritional assessment tools to understanding the implications of perioperative interventions for immune response and survival, research is making unstoppable progress toward improving the lives of cancer patients. The efforts and successes of networked scientific studies impressively and undoubtedly prove the importance of collaboration between researchers, clinicians and patients in the ongoing quest to unravel the complexities of gastrointestinal cancers.All these publications, as well as other contributions to this Special Issue of Cancers aims to provide a glimpse into the exciting research dealing with various aspects of the genesis, nature, treatment, and management of gastrointestinal, hepatobiliary, and pancreatic tumors, and thereby hopes to contribute to the definition and assessment of the current state of modern cancer care in these selected specialties.In summary, this issue of


Despite being a common noncommunicable disease in Nepal, little attention has been paid to it, in terms of formulating national health plans and policies by the concerned authorities. This was a descriptive cross-sectional study in patients diagnosed with cerebrovascular accidents at a tertiary care hospital in Eastern Nepal. We analyzed 128 diagnosed cases of cerebrovascular accidents from February 26, 2023 to June 26, 2023 after taking ethical clearance from the Institutional Review Committee (Reference no. IRC-PA-283/2078–79). Data were analyzed by Statistical Package for the Social Sciences version 23. The objective of this study was to explore the age and sex distribution of CVA, its association with medical co-morbidities, and known risk factors like Type-2-Diabetes Mellitus, hypertension, thyroid disorders, smoking and alcohol. Together with calculating the distribution of ischemic CVA and hemorrhagic CVA we had also staged the disease based on the National Institute of Health Stroke Scale. As of 2019, there were 12.2 million incident cases of stroke, 101 million prevalent cases of stroke. Based on disability-adjusted life years; stroke is one of the major causes of death and is among the top 5 diseases in Nepal. Over the last few decades, 75% of all stroke deaths and 81% of the total disability-adjusted life years lost due to stroke have occured in developing countries. Inadequacy of knowledge and awareness towards the signs and symptoms of the diseases and ignorance at the early stage are few inevitable factors which hinder the timely diagnosis and management of the diseases. Poor accessibility to health care centers and lack of adequate trained neurologists in the country further add to the problem. There is paucity of data on the CVA clinic-epidemiological profile in eastern Nepal. In this study, we aimed to find out age and sex distribution of CVA, association with medical co-morbidities and known risk factors, types of CVA and severity assessment via the National Institute of Health Stroke Scale (NIHSS). This will raise the concern of community health policy makers and the concerned authorities in addressing the burden of the disease at national level.Cerebrovascular accident (CVA) is defined as a rapidly onset clinical sign of focal or global disturbance of cerebral function with no apparent cause other than a vascular origin.This descriptive cross-sectional study included patients diagnosed with cerebrovascular accidents at a tertiary care hospital in Eastern Nepal. We included every diagnosed case of CVA via neuroimaging that was treated on an inpatient or outpatient basis. We analyzed 128 diagnosed cerebrovascular accidents cases from February 26, 2023, to June 26, 2023. We included patients with a clinico-radiological diagnosis of CVA presenting to our center. Participants meeting inclusion criteria and were evaluated on-site (outpatient and inpatient departments) using the structured proforma after taking ethical clearance from the Institutional Review Committee (Reference no. IRC-PA-283/2078–79).All the diagnosed cases of cerebrovascular accidents with the clinical features of global or focal neurological deficits, where no any cause other than vascular was identified on radiological evaluation, were included in this study. We excluded the cases presenting with neurological deficit without radiological evidences of vascular insult to the brain.We included all the diagnosed cases of cerebrovascular accidents meeting inclusion criteria, and evaluated them on-site (Outpatient and Inpatient departments) using the structured proforma. Particulars and general information of the patients was assessed to find out age and sex distribution. Associated medical co-morbidities of the patients like hypertension, type-2-diabetes mellitus and thyroid disorders were also recorded. Smoking and alcohol history was also taken to show the association with CVA. Similarly, based on neuroimaging findings, we stratify it into ischemic CVA and hemorrhagic CVA. The NIHSS was used to grade the severity of the stroke as: minor stroke, moderate stroke, moderate to severe stroke and severe stroke.The average age of presentation among cerebrovascular accidents cases was 63.35 years and 61.79 years in male and female respectively Table . The med Hypertension, cigarette smoking, alcohol consumption, and diabetes are the main predisposing factors for stroke, and ischemic stroke is more common (63%) than hemorrhagic stroke (37%). Talking about the sex predisposition, Women accounted for 57.1% of stroke deaths in 2019, with stroke accounting for 6.2% of all female deaths, while comprising 4.4% of all male deaths. In total, approximately 55,000 more fatal strokes occur in women each year than men. Most (85%) strokes are ischemic, predominantly caused by small vessel arteriolosclerosis, cardioembolism, and large artery athero-thromboembolism while ischemic strokes in younger patients can result from a different spectrum of causes such as extracranial dissection and approximately 15% of strokes worldwide are the result of intracerebral hemorrhage, which can be deep , cerebellar or lobar. Stroke prevention is all about avoiding modifiable risk factors but management of stroke depends on treating the pathophysiology which is not very well understood. Reperfusion remained the mainstay of treatment; however the efficiency of thrombolytic drugs depends on many factors including the age of the clot, the specificity of the thrombolytic agent for fibrin and the presence and half-life of neutralizing antibodies. The most effective thrombolytic drug recommended by the by the US National Institute of Neurological Disorders and Stroke is recombinant tissue plasminogen activator like alteplase. Unlike, fibrin activators like alteplase, reteplase and tenecteplase which convert plasminogen to plasmin directly, non-fibrin activators like the drugs streptokinase do so indirectly and are relatively less effacious. Apart from the conventional reperfusion techniques, embryonic stem cells, mesenchymal cells and induced pluripotent stem cells has assessed their potential for tissue regeneration, maintenance, migration and proliferation, rewiring of neural circuitry and physical and behavioral rejuvenation.On a global basis, Median age of presentation of CVA is 66 years.Noncommunicable diseases were once regarded to be the diseases of western world but with the change in our lifestyle and dietary measures, these disorders have found their way to low-income countries like Nepal and Cerebrovascular accidents are no exception. Because of sedentary lifestyle and westernization of diets, hypertension, Diabetes and hyperlipidemia are on the rising secular trend which has led to subsequent increased incidence of thromboembolic events. Clinical pictures of CVA are very nonspecific, to begin with, like mild weakness of arms, and are often ignored at an early stage of the disease because of lack of awareness regarding the clinical presentation of the diseases, so these patients always come to us at a very advanced stage. Not only that, lack of accessibility to health care centers in the periphery of the country, limited number of neurologists in the countries and poor patient compliance towards treatment and follow-up are few other inevitable factors which make the management approach even more challenging. Despite such a high burden of the diseases, little attention has been given to noncommunicable diseases in the context of Nepal and our health plans and policies are very much biased towards infectious diseases. Further, the epidemiology of Cerebrovascular accident, age of presentation, sex predisposition as well as relation with comorbid conditions in low to middle-income countries such as Nepal have not been closely analyzed. In this study we have analyzed the socio-demographic aspects and medical co-morbidities associated with cerebrovascular accidents. The clinco-epidemiological picture is similar to international standards, only difference being we found male predominace over female, in terms of sex predisposition. With the evidence-based data presented in this study, it will draw the attention of concerned authorities towards CVA and will help community health policy-maker in addressing the burden of cerebrovascular accidents.Average age of presentation of cerebrovascular accidents in male was slightly lower than that of females. In our settings, males are more likely to have the disease compared to females. Talking about the association with medical co-morbidities, systemic hypertension, Type-2-Diabetes Mellitus and hypothyroidism were the common co-morbidities associated with CVA. Similarly, smoking and alcohol history were also present in many of the sample population. Ischemic stroke was more common than hemorrhagic stroke and major bulk of patients had minor and moderate stroke as per the NIHSS. Appropriate screening techniques in high-risk populations, early diagnosis and treatment of the diseases can lead to significant decrease in national burden of the diseases and subsequent drop in morbidity and mortality due to the diseases.The Authors are grateful to the department of Radiology for providing the needful information.Conceptualization: Sajjad Ahmed Khan.Data curation: Vivek K Rauniyar, Sakshyam Gautam.Formal analysis: Sakshyam Gautam.Investigation: Vivek K Rauniyar, Sakshyam Gautam, Surya Bahadur Parajuli.Methodology: Vivek K Rauniyar, Surya Bahadur Parajuli.Writing – original draft: Vivek K Rauniyar, Sajjad Ahmed Khan.Writing – review & editing: Vivek K Rauniyar, Surya Bahadur Parajuli.


Significant gender disparities have been highlighted in the incidence, aggressiveness, and prognosis of HCC. A different epidemiological distribution of the risk factors of liver damage and, above all, the actions of sex hormones are at the basis of these differences. Accurate knowledge of gender disparities in HCC would lead to adequate surveillance strategies and the potential implementation of current treatment schemes.Several chronic liver diseases are characterized by a clear gender disparity. Among them, hepatocellular carcinoma (HCC) shows significantly higher incidence rates in men than in women. The different epidemiological distribution of risk factors for liver disease and HCC only partially accounts for these gender differences. In fact, the liver is an organ with recognized sexual dysmorphism and is extremely sensitive to the action of androgens and estrogens. Sex hormones act by modulating the risk of developing HCC and influencing its aggressiveness, response to treatments, and prognosis. Furthermore, androgens and estrogens are able to modulate the action of other factors and cofactors of liver damage , significantly influencing their carcinogenic power. The purpose of this review is to examine the factors related to the different gender distribution in the incidence of HCC as well as the pathophysiological mechanisms involved, with particular reference to the central role played by sex hormones. Hepatocellular carcinoma (HCC) is the sixth most common neoplasm in the world, the third in order of mortality, with 906,000 cases and 830,000 deaths per year . ChronicThe purpose of this review is to examine the factors related to the different gender distribution in the incidence and prognosis of HCC, as well as pathophysiological mechanisms involved, and the clinical implications that this heterogeneity determines.HCC accounts for over 80% of primary liver tumors. Its incidence is 2 to 3 times higher in men than in women, depending on region and clinical trial . This dip < 0.001) and the latter had higher proportion of early-stage tumors at diagnosis. In multivariable analysis, female sex was independently associated with lower mortality rate, early tumor detection, and response to first HCC treatment.In addition to significant epidemiological differences, there are relevant clinical and prognostic differences between the two sexes. Significant gender differences in course and prognosis have already been demonstrated in other types of neoplasms  ,9,10. AsThe lesser aggressiveness of liver tumors in women seems to be related to the reduced size of the tumors ,14. The p = 0.02), the two sexes show similar rates of OS over 65 years  . It. It43]. A careful analysis performed by Sung et al.  for 2012Viral hepatitis resulting from chronic infection with HCV, HBV, and hepatitis D virus (HDV) are among the main determinants of liver cirrhosis and HCC . If all Although historically there has been a predominance of the male gender in the prevalence of viral hepatitis, the secondary intrafamilial diffusion and the increase in the number of people who use drugs (PWUD) among women has in fact reduced the disparity in gender distribution . DespitePrimary biliary cholangitis and autoimmune hepatitis are rare causes of chronic liver injury potentially progressing to liver cirrhosis and HCC. These etiologies are clearly prevalent in the female sex, with a female/male ratio up to 9/1  53]. Ho. Ho53]. Smoking is associated with de novo malignancies, including lung, oropharyngeal, esophageal, and laryngeal cancer, among others. However, cigarette smoking also contributes to carcinogenesis in HCC . It is eThe cigarette smoking habit is predominant in the male gender in all regions of the world, although this disparity is greatest in Asia and Africa  3]. Glo. Glo3]. Beyond the different gender distribution of modifiable risk factors, a series of non-modifiable risk factors for HCC linked to individual genetic predispositions and differences between male and female sexes have been hypothesized. However, the knowledge of the different genetic predispositions between the two sexes in the development of HCC is still very limited.Although few protein-coding genes are present in the male-specific region of the Y chromosome, Y chromosome genes may play a role in the different incidence and aggressiveness of HCC between the sexes. The sex-determining region Y (SRY) is a gene located on the Y chromosome that encodes for the protein testis-determining factor (TDF), an important transcription factor implicated in male sexual differentiation . In addiAlthough unable to encode proteins, long noncoding RNAs (LncRNAs) are RNA transcripts able to significantly influence gene expression and regulate processes of cell differentiation, proliferation, and migration . LncRNA Beyond the direct role played by some genes in determining a greater male predisposition to the development of HCC, the level of gene expression can be significantly influenced by other factors (for example sex hormones), modulating the oncogenic risk. Such pathways will be discussed below.In the liver, the presence of estrogen and androgen receptors has been demonstrated for several decades . These hEstrogens are steroid hormones mainly produced in the ovary, placenta, corpora lutea, adrenal glands, and adipose tissue and are responsible for the development of the female reproductive system and secondary sexual characteristics ,72. FourEstrogens play a role in numerous functions, including the development of primary and secondary female sexual characteristics, the regulation of reproductive mechanisms and the menstrual cycle, bone metabolism, cholesterol mobilization, and inflammation control, also influencing the function of other systems  ,78,79. IFinally, growing evidence is available about the impact of estrogens on the development of HCC. Both healthy livers and HCC livers express estrogen receptors. In animal models, the administration of estrogens can modulate cell proliferation and the risk of HCC development . The infThe receptor-type tyrosine-protein phosphatase O (PTPRO) is a member of the protein tyrosine phosphatases (PTPs) family that acts as a mediator of cell signaling pathways by inhibiting tumor proliferation and degeneration . The PTPForkhead box (Fox) transcription factors are a family of transcription factors derived from the Fox genes and involved in hormonal and immune system regulation, embryogenesis, cell proliferation, and growth through the regulation of the epithelial-mesenchymal transition . In oncoAs already mentioned, GPER is a more recently discovered membrane estrogen receptor . In addiThe development of HCC is closely related to tissue inflammation . In factInterleukin 6 (IL-6) is a multifunctional inflammatory cytokine involved in the development of inflammation and cell proliferation . In the Within the tumor microenvironment, tumor-associated macrophages (TAMs) have an active role in the genesis and progression of the tumor . MacrophThe NLRP3 inflammasome is an intracellular multiprotein complex mediating innate immunity that assembles in response to cellular insults . When asAndrogens are steroidal sex hormones essential for both sexes, however the serum concentration is significantly higher in men than in women . These hAlthough they have a less defined role than estrogens, androgens also play important functions in the pathogenesis of HCC . Indeed,In addition to the role directly played by male sex hormones and RA in the pathogenesis of HCC and its male predominance, androgens are also able to significantly enhance the oncogenic power of HBV infection . The rolIn light of the male predominance in HCC incidence and the role of androgens and AR in oncogenic proliferation, anti-androgen and anti-AR therapies have been tested in the treatment of liver cancer. However, the results obtained were unsatisfactory . DespiteIn addition to acting directly on the risk of developing HCC, sex hormones are also able to modulate the action of other factors and cofactors of liver damage, significantly influencing their carcinogenic potential.Beyond the epidemiological differences in gender distribution, some evidence suggests that both chronic HCV and HBV infections are associated with a greater probability of developing HCC in males rather than in females. The gender difference in the risk of developing HCC during HBV infection appears to be extremely relevant. Indeed, the male-to-female ratio for HBV-related HCC is significantly higher than that for HCV-related HCC . OverallSimilar to what occurs during HBV infection, in chronic hepatitis C, male gender has been shown to be an independent risk factor for faster progression rate towards cirrhosis and consequently for HCC . SimilarObesity is an independent risk factor for malignancies, including HCC. As already discussed, to date it is the cause of about 9% of HCC cases worldwide , increasSimilar to leptin, adiponectin is another hormone produced by adipose tissue and its role is crucial in the mechanisms of metabolism regulation, sensitivity to insulin action, and inflammation . In the Gender differences in the expression of microRNAs have recently emerged (miRNAs) in the context of HCC and in the influence exerted on them by sexual hormones. MiRNAs are small, noncoding, single-stranded RNAs that play the role of posttranscriptional regulators of protein encoding genes . They inRecently, significant gender differences in miRNA expression have emerged in patients with HCC, with close correlation with sex hormones. Among others, miR-216a appears significantly upregulated in HCC cells, particularly in male patients . ThroughA similar action is also performed by miR-22 . This miZhao et al.  finally Since sex hormones play a central role in the development of HCC, numerous attempts have been carried out to identify an estrogenic or anti-androgenic therapy able to improve its prognosis. In the 1990s, on the back of other therapies for estrogen-dependent tumors, many studies focused on the use of tamoxifen, a selective estrogen receptor inhibitor (SERM), in the HCC setting. Hypothesizing that estrogens promote hepatocyte proliferation and hepatocarcinogenesis, Martínez Cerezo  and FariNumerous studies have focused on the potential role played by menopausal hormone therapy (MHT) in the occurrence of HCC in women. McGlynn et al.  showed iIn addition to estrogenic therapies, the use of anti-androgen therapies has also been evaluated in the treatment of HCC. In this regard, the use of the anti-androgens flutamide  and cyprDespite the significant epidemiological and prognostic differences, clinical and therapeutic applications in the HCC setting are still scarce. In fact, although preclinical research has shown that several mechanisms are involved in gender differences, gender-specific therapies are not yet available. It seems promising that everything known about gender differences in HCC could be applied in clinical setting. In fact, compared to other sectors, gender medicine is still underdeveloped today. In the HCC setting, significant gender differences and underlying mechanisms could be used to improve anti-cancer therapies available today. In fact, because of the low efficacy of current treatments for HCC and the central role played by sex hormones in hepatocarcinogenesis, hormonal therapies could be part of combination therapy schemes  potentially able to improve objective treatment response and OS and reduce the risk of recurrence. Specific clinical trials are missing and therefore mandatory.The liver is a sexually dimorphic organ with large differences in gene expression, cellular function and composition, and immune response. Large disparities are consequently found in the organ’s responses to pathogenic noxae. In women, estrogens play a protective role, limiting liver inflammation and fibrogenesis and counteracting the development of HCC. They are also partially responsible for the lesser aggressiveness of liver cancer, as well as better response to treatments, lower recurrence rates, and an overall better prognosis. Conversely, androgens promote cell proliferation and hepatocarcinogenesis, elevating the risk of developing HCC. In addition to direct action, sex hormones influence oncogenic risk by modulating other risk factors’ activity . Hence the need for even closer and more effective surveillance in the male gender, which is at greater risk of occurrence and recurrence of HCC. However, more research on gender is needed to investigate mechanisms underlying differences in the pathogenesis of HCC. To date the use and/or manipulation of sex hormones has not demonstrated efficacy in the treatment of HCC despite their central role. A more in-depth knowledge of the mechanisms linking sex hormones to hepatocarcinogenesis could also mean significant progress in the treatment of liver cancer.


The networks of factor flows in rural areas are the main support for rural revitalization, which has become one of the research trends in rural geography. Taking a typical industrial town in China as an example, the study explored the operating characteristics of rural factor flow networks and the relations of multi-factor flows based on the social survey method and fine-grained flows data. Results showed that population flows, capital flows and policy flows increased significantly in rural areas. Thereinto, population flows, especially labor flows, mainly ran into the townships and industrial cluster villages, so did capital inflows and outflows, while policy flows ran around the township. The villages with dense population and capital flows formed the "central villages", which had exceeded the township in the two flow networks. Policy flows and capital flows played a guiding role in population flows, so did the policy flows on the capital flows. Meanwhile, the population flows and the capital flows could reinforce each other. In conclusion, a multi-center structure network with the separation of economic center and administrative center had been formed in rural areas. And there was a close interaction between these factor flows. Furthermore, the theoretical model of town-village symbiotic network was constructed. Since the 1990s, globalization and information technology has developed rapidly, and the global flows of a large number of physical and virtual factors have increased significantly, which leads to the fact that mobility has become an important field in geography and formed a "new flow paradigm" that emphasized dynamic research . With thSince 21st century, the big data and data science developed vigorously, providing a number of relational data and methods that can directly measure traffic flows, information flows, population flows and knowledge flows for geographers, and promoting the study of regional network of factor flows –24, as wChina is a developing country with large population and little arable land, and rural development is facing the dilemma of low per capita resources and the large gap between urban and rural areas. The National 14th Five-Year Plan clearly stated that "fully implement the rural revitalization strategy and encourage more production factors to flow towards rural areas to comprehensively improve the efficiency of rural operations". Moreover, the operating efficiently of rural factor flow networks plays a crucial role in promote rural revitalization, which has currently become a scientific problem to be solved for rural geographers. Therefore, taking a typical industrial town in traditional agricultural areas in Hebei Province, China, as an example, this article aimed to analyze the operating characteristics of the factor flow networks and the relationship of multi-factor flows based on the theory of “space of flows”, and to explore the influencing elements and theoretical model of factor flow networks in Chinese traditional rural areas, in order to provide scientific references for rural revitalization.2, implying the prominent contradiction between man and land, and insufficiency of agricultural development in supporting rural revitalization. Therefore, rural revitalization in traditional agricultural areas needs theoretical and methodological guidance.Traditional agricultural area is one of the most important research areas of rural geography, as well as the main practical object of rural revitalization. Thereinto, the south of Hebei Province is a typical representative with underdeveloped economy, while it plays a crucial role in agricultural production. Because of rural settlements overloaded in number and density, the per cultivated area is less than 0.12 hm2, with 21 administrative villages under its jurisdiction. The town government is located in Jiajiakou village (township). At the end of 2020, the total number of households in Jiajiakou Town has reached 18,869, with a registered population of 59,192 and a permanent resident population of 54,622. Provincial Road 393 runs through the town from east to west, and Highway 20 establishes an entrance and exit in the town at the intersection with Provincial Road 393. Thus, regional transportation is very convenient. Since the 1990s, Jiajiakou town has developed gradually from a traditional grain-producing region into a national production base of wire and cable, and has been awarded the titles as "Famous Town of Chinese Economy and Culture" and "Important Town of Chinese Wire and Cable Production". There are 1,040 private enterprises and 10,833 workers in the town, creating an output value of 22.7 billion yuan and a profit of 2.4 billion yuan annually. Of the 1040 industrial enterprises, 45 have fixed assets over 20 million yuan, which are all wire and cable enterprises.The Jiajiakou town, located in Ningjin County, Hebei Province, is a typical industrial town in the traditional agricultural areas. The town covers an area of 94.3 kmIn short, Jiajiakou town has realized the transformation and upgrading of rural industries, taking into account the task of grain production, and promoting the sustainable development of rural economy and society. Currently, the rural development level ranks the first in the county, becoming one of the economically-developed industrial towns in China, and is representative and demonstrative in Chinese traditional agricultural areas. It is rated as "China’s Rural Revitalization Demonstration Area" and "China’s economic and cultural Town".Therefore, this paper took Jiajiakou town as an example to study the operation characteristics of rural factor flow networks, and to provide certain reference for rural revitalization in traditional agricultural areas. In addition, the Yaotai 1 village, the Yaotai 2 village and the Yaotai 3 village are combined into a natural village named the Yaotai village, since they are adjacent to each other in geographical space and are highly integrated in economy, society and culture. Similarly, the East Huangerying village and West Huangerying village were merged into a natural village named Huangerying village. This study taked the 18 villages (township) that make up the Jiajiakou town as the research objects. Thereinto, Jiajiakou village/township is the administrative center in the town.The data in this study involved three parts: population flows, capital flows, and policy flows. (1) The registration forms of primary school students in 2020 were collected from Jiajiakou town government. (2) The sample size of the survey was calculated based on the stratified sampling method and was composed of 5% of all households in each village. The data on income and consumption capital flows of rural residents in 2020 were collected by questionnaires and semi-structured interviews. A detailed questionnaire containing 60 items was designed and the items were classified into three categories, including the flows of households’ income, the flows of consumption, and the infrastructure and public services. A total of 1000 questionnaires were issued in the participatory survey and 987 were collected, among which 951 were valid. (3) The data of administration district referred to “Ningjin County statistical yearbook” –55 were This paper combined qualitative and quantitative methods to study the operating characteristics of the factor flow networks in rural areas. Through the social survey and spatial analysis method, the operating process of population flow network, capital flow network and policy flow network in rural areas were revealed, as well as the relationship of multi-factor flows in rural areas. The social survey method was used to explore the influencing elements by analyzing the rural endowments and the regional environment. Combined with social investigation and qualitative analysis, this paper further constructed the theoretical model of town-village symbiotic network.Before the 1990s, the daily activities of the rural residents were mainly around agricultural production. Market transactions and social communication were concentrated insides villages and towns, without frequent movements of population . In the Based on the information about the residence and domicile places of all students in Jiajiakou town, the spatial flows matrix of rural students was obtained , Fig 1. Factually, in the population flow network, most rural population flowing was due to employment, thus forming the labor flow networks, which could more objectively reflect the situation of rural transformation and development. Before industrialization, rural labor force was mainly engaged in agricultural production or handicraft activities, mainly flowing inside the village. With the development of industrialization and urbanization, rural labor force generally turned to non-agricultural production activities. Part of the labor force flowed out to the urban areas, and part flowed to the villages where industrial enterprises gathered, such as Huangerying village, Jiajiakou village and Yaotai village. The mobility of rural labor force increased significantly. Therefore, the operation of rural labor flow network was closely related to economic production. The inflow nodes were the settlements with abundant non-agricultural jobs, and the outflow nodes were the general villages.Before the 1990s, the income of rural residents was mainly from the family agricultural production and their daily consumption was insides their own villages, leading to the weak liquidity in rural areas . Since tThe proportion of income source sites of the households from Jiajiakou town in 2020 was surveyed and presented in The data of daily living and large-item consumption sites of households in Jiajiakou town were obtained through related surveys  and 4. TIn a word, rural capital flows showed obvious cluster characteristics, and the capital inflow and outflow were concentrated in Jiajiakou, Huangerying and Yaotai villages.Rural policy flows include administrative order communication, examination and approval, supervision activities and feedback of management, which were implemented and accomplished by the township government and the relevant functional departments Therefore, The operation of policy flows is around the station of township government and the relevant functional departments (administrative center) rather than among general villages. To be specific, policy flows such as administrative orders and supervision activities flowed from Jiajiakou township to all villages, while administrative examination and approval, and management feedback flowed from each village to Jiajiakou township, which showed that the rural policy flow network was with a single center structure.In conclusion, according to the quantity and direction of rural population flows and capital flows, Huangerying and Yaotai could be regarded as economic central villages. Similarly, Jiajiakou, as the administrative township, was the center of rural policy flow network. And they were the three central nodes of factor flow networks in rural areas.Rural policy flows ran around the administrative township. In China, public service resources such as education, medical care and transportation were mainly allocated from top to bottom according to the administrative levels, and the township was the key node of basic commodities and services supply in rural areas. Rural residents need access to township in order to obtain necessary administrative approvals, public services and goods, which promoted the flowing of population and capital into the township. Therefore, policy flows had a guiding effect on the population flows and capital flows, making the township becoming the central node of the rural factor flow networks .There were certain similarities in the trajectories of population flows and capital flows in rural areas, and they both were mainly around the economic and administrative centers, and the quantity of the former exceeded that of the latter. Due to the high industrialization in Huangerying and Yaotai villages, more non-agricultural jobs were created compared with the township, which were the main income sources of households and attracted a large number of population and capital inflow from the surrounding villages. With the agglomeration of industry and capital, economic central villages developed and improved the living consumption and public service functions, and then became the central nodes of the consumption flow networks of rural residents, which further enhanced the attraction of the rural population flows. This suggested that population flows and capital flows reinforced each other, and capital flows had a guiding effect on population flows, while there was certain competition between capital flows and policy flows.In short, rural production activities and household livelihood depended on the economic centers, and rural daily life and public services depended on the administrative center. The two centers were separated in rural areas, thus forming the rural factor flow networks with multi-center structure. Moreover, the factor flows of the central villages have exceeded those of the township, which indicated that capital flows were more competitive than policy flows for attracting population flows, and the comprehensive competitiveness of the central villages has exceeded that of the township in rural areas.In the operating process of rural factor flow networks, the multi-center structure had obvious advantages than the single-center structure. On the one hand, there was a cooperative relationship between the economic center and the administrative center. Because the comprehensive carrying capacity of the central town was limited. The separation of economic and administrative centers helped to reduce the carrying capacity and pressure of resources and environment in the township, to improve the accessibility of employment, goods and public services in ordinary villages, and to improve the stability of network operation. On the other hand, there was a competition relationship between economic and administrative centers for population and capital flows. Moderate competition could stimulate the vitality of rural development and improve the efficiency of regional factor mobility in rural areas, but excessive or malicious competition should be prevented.In the operating process of rural factor flow networks, the multi-center characteristics showed that rural units played different roles in the network, which was determined by rural endowments . Rural eThe rural factor flow networks were an open and dynamic system, which was constantly transmitting or exchanging material, information and energy with the regional environment. Natural environment was a relatively stable geographical condition, which had few effect on the change of rural factor flows in short time. Humanistic environment was a dynamic social condition, including economic, social, and institutional environment, which regulated the operation of rural factor flow networks.First, the development of rural industry in the central villages and township drove the upstream and downstream industrial chain, and created a large number of jobs, which attracted a large number of production and living factors flowing into. Therefore, the non-agricultural economic environment could promote the flowing of rural factors. Second, regional social environment still had relatively obvious characteristics of traditional agricultural society, such as the satisfaction with current situation, cultural conservatism, and acquaintance relationship orientation, which constrained rural population and capital flowing. Third, institutional environment could regulate the flowing trajectory of multiple factors in rural areas, and then affect the operation of rural factor flow networks. For example, since 1992, rural development policies in China had mainly experienced the reform of socialist market economy system, household registration and land system, new rural construction, new urbanization and rural revitalization. These policy reforms had removed institutional barriers to the factor flowing, significantly activated the inter-regional flowing of rural factors such as land, population and capital, pushed urban factors into the countryside, and expanded the scope, intensity and direction of rural factor flows. In addition, there were always mutual feedback of elements between rural factor flow networks and external urban environment. Since the 21st century, with the comprehensive promotion of the rural revitalization strategy, urban capital, population, technology and public services had accelerated the reversed flowing into the countryside, especially to the central villages and township, further promoting the formation and development of the multi-center structure of the factor flow networks in the rural areas.In addition, the influence of technology and energy on rural factor flow networks was also remarkable –62. TechRural endowments, factor flows and regional environment played different roles in the operating process of the rural factor flow networks. Central villages, township and other villages interacted closely, forming a new integrated development relationship. Based on the theory of symbiosis –65, thisThe theoretical connotation is that, in the regional symbiotic environment, central villages and township constitute a new type of town-village symbiotic development network through the close interweaving of factor flows and spatial interaction. The theory takes into account the endowments of central villages, township and general villages, as well as the sustainable development goals on food production, economic productivity and sharing of social services, which will be expected to be the main theoretical basis to guide the rural revitalization in Chinese traditional agricultural areas.The paper was the first to use the fine-grained flows data to analyze the operational characteristics of population flow network, capital flow network and policy flow network and the relations of multi-factor flows in rural areas. However, this paper did not take the rural information flows into account, nor the complex relationship between the rural factor flow networks and the network outside the region, which would be further studied in the future work. In addition, this paper initially revealed the disunity and competitive-cooperative relationship between the economic center and the administrative center. Compared with the single-center structure, the multi-center structure of flow networks was more conducive to the accessibility of ordinary villages to obtain employment, commodities and public services, and also helped to improve the stability of network. Then, what is the changing threshold and theoretical model of the competitive-cooperative relationship between economic center and administrative center in rural areas, and whether it is affected by scale? These problems need to be deeply explored in the study of rural revitalization.Taking a typical industrial town in China as an example, the study explored the operating characteristics of rural factor flow networks from three dimensions, including population flow network, capital flow network and policy flow network, and the relationship of multi-factor flows. On one hand, population flows, capital flows and policy flows had increased significantly in rural areas. Thereinto, population flows, especially labor flows, mainly ran into central towns and industrial cluster villages, so did capital inflows and outflows, and policy flows ran around the township. The villages with dense population and capital flows formed the "central villages", which had exceeded the township in the two flow networks. In short, a multi-center structure network with the separation of economic center and administrative center had been formed in rural areas. On the other hand, there was a close interaction between these factor flows. specifically, Policy flows and capital flows played a guiding role in population flows, so did the policy flows on the capital flows, as a result, there was both guidance and competition between the two flows. Meanwhile, the population flows and the capital flows could reinforce each other.This paper discussed the main elements influencing the formation of the multi-center structure of the rural factor flow networks, including rural endowments, regional environment, energy flows and technological advancements, and summarized the advantages of this operating characteristics. Furthermore, the theoretical model of town-village symbiotic network was constructed. That is, in the regional symbiotic environment, central villages/township and general villages constituted a new type of town-village symbiotic development network through the two-way flowing of factors, which taken into account the multiple functions and diversified development goals of rural areas, and would provide theoretical and methodological reference for rural revitalization in traditional agricultural areas in China.S1 Table(DOCX)Click here for additional data file.


An increasing interest in machine learning (ML) has been observed among scholars and health care professionals. However, while ML-based applications have been shown to be effective and have the potential to change the delivery of patient care, their implementation in health care organizations is complex. There are several challenges that currently hamper the uptake of ML in daily practice, and there is currently limited knowledge on how these challenges have been addressed in empirical studies on implemented ML-based applications.The aim of this systematic literature review is twofold: (1) to map the ML-based applications implemented in health care organizations, with a focus on investigating the organizational dimensions that are relevant in the implementation process; and (2) to analyze the processes and strategies adopted to foster a successful uptake of ML.We developed this protocol following the PRISMA-P  guidelines. The search was conducted on 3 databases , considering a 10-year time frame (2013-2023). The search strategy was built around 4 blocks of keywords . Based on the detailed inclusion criteria defined, only empirical studies documenting the implementation of ML-based applications used by health care professionals in clinical settings will be considered. The study protocol was registered in PROSPERO .The review is ongoing and is expected to be completed by September 2023. Data analysis is currently underway, and the first results are expected to be submitted for publication in November 2023. The study was funded by the European Union within the Multilayered Urban Sustainability Action (MUSA) project.ML-based applications involving clinical decision support and automation of clinical tasks present unique traits that add several layers of complexity compared with earlier health technologies. Our review aims at contributing to the existing literature by investigating the implementation of ML from an organizational perspective and by systematizing a conspicuous amount of information on factors influencing implementation.DERR1-10.2196/47971 After a period of so-called artificial intelligence (AI) winter, AI has re-emerged into the scientific and public consciousness by virtue of new technological breakthroughs and marketed solutions . Recent Regulatory science has tried to keep up with these advances by adopting a permissionless innovation approach with low barriers for the entry of new algorithms . DespitePrevious literature has well documented the implementation of expert systems and knowledge- or logic-based applications , all incRecent scholarly contributions have shown that a theoretical understanding of the dimensions and dynamics associated with the implementation of AI in health care organizations is still in its infancy . EmpiricResearch on ML implementation has been predominantly conceptual in nature, with the identification of distinguishing issues in the development and dissemination in clinical practice, such as the opacity or black-box effect, and concerns surrounding equity, data privacy, and security ,18. ConvGiven the potential disruptiveness of recent developments of ML in health care and the lack of knowledge about how to overcome the organizational challenges associated with their implementation, our research objectives are to identify and explore cases of real-life implementation of ML within health care organizations as documented in the literature and to synthesize the processes adopted to foster a successful implementation of ML. We plan to conduct a systematic literature review with the following goals in mind:To examine the stages and characteristics of implementation processes described in empirical studies on ML under the lens of implementation science, namely the scientific study of methods to promote the uptake of evidence-based innovations into routine practice . SpecifiTo analyze the observed or suggested determinants of successful uptake of ML, thereby identifying the implementation processes and strategies currently adopted by health care organizations.This systematic review protocol follows the PRISMA-P  statement ,23 and wThis review will be focused on studies that investigate aspects related to the implementation of ML-based applications in health care organizations. For the purposes of this review, by implementation, we define the “active and planned effort to mainstream innovation within an organization” , while tInclusion criteriaStudy design: empirical studies based on implementation research designs Intervention: implementation of machine learning (ML)–based applications including considerations on the inner setting and/or implementation process domainsStakeholder groups: ML-based applications used at least by health care professionalsSettings: hospitals, outpatients, and other community care settingsExclusion criteriaStudy design: effectiveness research study designs, literature reviews, commentaries, editorials, opinion articles, study protocols, studies collecting perceptions on implementation, and unrelated to specific ML-based applicationsIntervention: implementation of knowledge-based applicationsStakeholder groups: ML-based applications targeting patients and other nonclinical stakeholders  onlyWe will select peer-reviewed empirical studies documenting the implementation of ML-based applications, thereby including experimental or quasi-experimental, observational, hybrid, and simulation study designs . In the Studies will be considered eligible if they analyze the implementation of tools based on ML in health care organizations and discuss the associated processes, context, barriers, or facilitators. As part of ML, we will include both DL techniques, unanimously considered as a subset of ML , and natBased on the constructs of the updated CFIR , only arWe will include studies focused on ML-based applications available for use by health care professionals. Applications used by patients, caregivers, health care administrators, and policy makers will only be included if they are also used by clinicians and other health care professional groups.We will include studies with a spotlight on the implementation of ML-based applications in clinical practice, biomedical research, and public and global health, as per the classification provided by the European Parliament . All posConsidering the rapid evolution and changes in ML-based applications, we will only consider studies published in the past 10 years (since 2013).Literature searches were conducted in MEDLINE (PubMed), Scopus, and Web of Science and replicated in top-tier management journals . In addition, the reference list of all included studies and of the reviews identified will be scanned to ensure that any relevant work is captured. Gray literature was not considered.The search strategy was developed, including a combination of keywords around four main concepts: (1) AI, (2) implementation, (3) health care, and (4) study type.The list of search concepts and associated terms used is provided in The exact search stream was developed by the research team following an iterative process. The general term “artificial intelligence” has been used to encompass studies that address the terms AI and ML as synonymous. The search strategy was initially finalized for PubMed and then adapted to the syntax and subject headings of the other databases. The initial search was performed in April 2023.Main search concepts, to be combined using “AND”Artificial intelligenceImplementationHealthcareStudy typeSearch concepts synonyms, to be combined using “OR”Artificial Intelligence, Machine Learning, Deep Learning, Natural Language ProcessingImplementation, Adoption, Diffusion, UptakeHealthcare, Health*, Therap*, Patient*, Clinic*, Care, Professional, Medic*, Doctor, Hospital, Life Science, PharmaEmpirical, quantitative, trial, qualitative, interview*, case stud*, case report, field stud*, field research, mixed-method*, mixed method*, focus group*, observational stud*, hybrid design, hybrid stud*, trialThe records retrieved from the literature search were uploaded and merged into RefWorks, a reference management tool that simplifies the process of research and collaboration among the review team. Duplicates were removed, and the identified list of records was extracted into an Excel (Microsoft Corp) spreadsheet for title and abstract screening.A total of 2 researchers (VA and LMP) screened the first 100 retrieved articles based on titles and abstracts. Interrater agreement was measured using kappa statistics . Once alThe data collection process will be performed by 3 reviewers . Data will be extracted using an ad hoc Excel (Microsoft Corp) spreadsheet, preliminarily developed by the research team. To ensure consistency across reviewers, the extraction sheet will be tested by each reviewer and possibly recalibrated before starting the data collection process. Disagreements will be resolved by discussion, and 1 of 2 arbitrators (GC and AC) will adjudicate unresolved disagreements. Information on the implementation process of ML-based applications will be collected, as specified in the following section.Data items to be extracted from the selected studies will include the following fields, based on preexisting, established classifications or schemes, where possible:Demographic information: study identifiers, authors, journal outlet, publication year, and keywords.Methodology: study design.Setting: country, organizational setting , organizational nature , and unit of implementation of the ML-based application.Implementation stages: stages of the implementation process described in the study, adapted based on Aarons et al .Intervention: name and description of the ML-based application, level of integration with other technologies, main practice  , steps oIndividuals: actors involved in the development and implementation of the ML-based application.Inner setting: factors related to the organizational context in which the innovation is implemented, including both persistent general characteristics of the organization and properties specific to the delivery of the innovation. These include implementation capacity and readiness, as well as ML-specific domains such as the consideration of ethical concerns  and compOuter setting: considerations on the setting in which the inner setting exists, such as legislative, regulatory, accreditation, and reporting authorities and aspects , partnerImplementation process, including activities and strategies used to implement, assimilate, and routinize the innovation, encourage participation, and collectively discuss the success of the process.Barriers and facilitators explicitly cited in the study.Outcomes: observed, measurable outcome domains and metrics associated with the implementation process.A narrative analysis will be adopted to synthesize the findings from the included studies, as the characteristics of the implementation processes will be tabulated and summarized through descriptive statistics according to the implementation-science domains selected for data collection. Given the objectives of this systematic review, the wide variety in the study designs and outcome domains considered, and the prospected predominance of qualitative studies, no quantitative synthesis of the results will be performed.The systematic review is ongoing. As of June 1, 2023, we have finalized the identification of records and the title and abstract screening of the 3520 records that met our search criteria. A full-text review is currently underway and will be completed by September 2023. After data synthesis, we plan to disseminate the study results by submitting the corresponding manuscript to a peer-reviewed journal in November 2023.ML-based applications have proliferated exponentially in recent years and demonstrated to have high potential both to streamline the clinical workflows and to improve patient outcomes. Yet, available studies have focused mainly on the technical components of ML-based applications and on their clinical efficacy, while the organizational preconditions or determinants needed to facilitate or sustain their implementation have been overlooked, emphasizing the need to identify effective strategies and foster the use of theories, models, and frameworks to facilitate implementation .Therefore, our research will systematically review and synthesize the evidence of empirical studies reporting on implemented ML-based applications that are used in the real world. To comprehensively investigate implementation factors at the organizational level, ML-based applications that impact the activities of health care professionals at large will be considered.In this context, the domains of the updated CFIR will be used as a practical tool to guide the data extraction and interpretation of the organizational factors that drive implementation, adopting the theoretical lens of implementation science. As such, we expect that our review will contribute to the field of implementation science research, a field that seeks to systematically close the gap between what we know and what we do  , adding The strengths of our prospective literature review are that it will follow a standardized methodological approach by adhering to systematic review guidelines   and thatThis work is part of larger research whose overarching aim is to develop a conceptual framework for the implementation of ML in health care organizations in an effort to support the adoption and deployment of health care innovations. In perspective, the theoretical basis of this work will therefore pave the way for the later conceptualization of an implementation framework that will stem from the available implementation science frameworks, but will be tailored to also account for the distinctive features of ML. This process will be additionally informed by the engagement of expert stakeholders employed in health care organizations, who will provide qualitative inputs based on their real-life experience with ML to fine-tune and finalize the framework. All in all, starting with the current review, the aim of our research is twofold: building a practical tool for health care practitioners while transitioning toward the use of ML-based applications within their organization, while also contributing theoretically to management and innovation theories.