Recent technical breakthroughs in genotyping and bioinformatics techniques have greatly facilitated the translation of genomics into clinical care. In particular, advancements in genomics have significantly improved our understanding and treatment of rare genetic diseases. Rare diseases collectively affect approximately 2–6% of the population  and tendNew available genetic data allow real disease prevalence to be established while defining the diseases according to their etiology and not only their phenotypes. The progressive reclassification of diseases has also helped in distinguishing pathologic subtypes according to their genetic cause, better establishing patients’ disease risk and assessing disease severity for personalized medicine and genotype-driven therapies . Indeed,The present collection covers most of the key advancements in this area, with a specific focus on genomics approaches in rare disease research.The clinical relevance of the genomic advances and their specific applications in rare diseases is described in two comprehensive reviews in this Special Issue, in which genomics is identified as a paradigm to understand the pathological and physiological function of genes, pathways, and mechanisms in neurogenetic research ,4.Specifically, Zaghi and collaborators focused their attention on the exploitation of NGS-based approaches for the diagnosis and molecular characterization of the heterogeneity of neurodevelopmental disorders , while KHSPB1 gene. On top of a deep clinical phenotypic characterization, expanding the knowledge on the heterogeneity of the clinical presentations of the disease, the authors performed functional in vitro studies on the newly described variant p.V97L, defining its pathogenicity [An exemplificative study on this topic is presented by Shen et al., describing a case series of three patients with distal hereditary motor neuropathy with variations in the genicity .The understanding of the genetic causes of some rare diseases is poor or still lacking. To meliorate the current knowledge, SNP association studies can be performed by whole-genome or candidate gene approaches.PBX1 gene, and another within the PCCA gene. The authors completed the study with a metabolic screening that revealed a consistently lower concentration of lysophosphatidylcholine a C20:3, indicating a possible role of metabolic alterations in the pathophysiology of AF [The first has been exploited by Emmert et al. in the South Tyrol CHRIS cohort, specifically on 110 cases affected by atrial fibrillation (AF) out of a general population of 10,509. A genome-wide association scan identified two novel loci, one around an SNP next to the gy of AF .The second possible approach was the focus of the work of Alele and colleagues, who investigated the association of SNPs in heat-shock proteins with heat tolerance in members of the Australian military with a history of exertional heat stroke. They identified a clear association between the HSPA1B genetic variant at the g.31829044 locus and heat tolerance . This reCOL2A1 and GLI3 were particularly enriched in the ultra-rare variant, thus constituting candidate genes that may contribute to the individual risk of disease [It is important to point out that genome-wide association approaches may not reveal a significant role of SNPs in rare diseases, such as in the isolated form of nonsyndromic cleft palate. For this, Iovino and coworkers assessed the overlap between the genes harboring ultra-rare variants, detected through whole-exome sequencing of 35 patients, and the enriched gene set implicated in the pathobiology of nonsyndromic cleft palate. They found that  disease .Rare diseases still suffer from a low genetic diagnostic yield.An example of this is in the study by Mazzaccara et al., who described the prevalence of genetic variants in a southern Italian cohort of 133 patients with inherited cardiomyopathies and channelopathies. The relatively low yield of definitive genotyping, due to both the strength of gene–disease association and the identification of variant of unknown significance, as defined by the ClinGen consortia, reinforces the need to continue screening, at least for research purposes, uncommon genes to gain more knowledge and increase the diagnostic sensitivity of the genetic testing of inherited cardiomyopathies and channelopathies .Moreover, it is important to underline that beyond the main causative pathogenic mutations, common variants can be used to better classify a disease through genotype–phenotype studies. Indeed, common variants of the genes associated with cardiomyopathies and channelopathies may better define disease prognosis and the risk stratification of arrhythmogenic cardiomyopathy patients. Interestingly, Lippi and coworkers demonstrated that 28 polymorphisms were associated with an increased risk of arrhythmic events during patient follow-up, 5 of them with increased levels of the inflammation markers, while the others were associated with the right- vs. left-dominant forms of the disease . In addiA genotype–phenotype correlation was performed in the study by Storoni et al. in a cohort of 675 Dutch osteogenesis imperfecta patients, in which they identified that carriers of dominant negative COL1A1 or COL1A2 mis-sense pathogenic variants require less healthcare attention than the other groups . The resImproving the molecular classification often means ameliorating the clinical management of patients, as described by Peretto and collaborators. Indeed, myocardial inflammation is increasingly recognized as both a phenotype and an active modulator of the pathogenesis of genetic cardiomyopathies. The review by Peretto et al.  highlighFinally, advances in genomics have been achieved through the discovery of different categories of noncoding RNA, such as circular RNA (CircRNA), thanks to the development of more sensitive sequencing technologies. This is the topic of the literature review by Caba and coworkers, which elucidates how CircRNAs can regulate transcription, splicing, microRNA action, and protein–protein interactions, modulate the pathogenic mechanisms of some diseases and play a potential role as biomarkers .In conclusion, the present Special Issue provides an in-depth look at insights into rare diseases thanks to ever-improving advances in genomics .


Community empowerment activities conducted by mothers’ support groups in Sri Lanka played a critical role in COVID-19 outbreak control among communities. During the COVID-19 response, mothers’ support groups (MSGs) aimed to promote community health and well-being through community engagement activities, including sharing information, education, and communication materials about COVID-19; creating a supportive environment for infection prevention and control practices; distributing essential food items and medicine to people in need; and organizing recreational and social support activities.A key strength of using MSGs was the well-established trust and relationships within communities and their direct access to communities. Other facilitating factors were the support received from existing community partnerships and training and capacity-building from district health education officer networks.Key barriers to conducting these activities included reluctance of public health workers to work together with MSGs, competing stakeholder agendas, and lack of support for appreciation of MSG activities from local health authorities.Community empowerment can play an essential role in disease outbreak control activities, and its potential should be further studied.Well-implemented community engagement strategies can support health systems in overcoming pandemics.Health officials can strengthen the skills of community group members to help build more resilient communities during future pandemics. Community empowerment has previously been used to mitigate the effects of health emergencies, such as outbreaks of Ebola virus disease and Zika virus. In Sri Lanka, mothers’ support groups (MSGs) aim to promote community health, well-being, and nutrition practices through community engagement. With the emergence of the COVID-19 pandemic, MSGs were mobilized by the Health Promotion Bureau in response to the pandemic. Key activities MSGs engaged in during the COVID-19 response included establishing communication networks, creating a supportive environment for preventive behaviors, organizing vaccination clinics, distributing essential food and medicine, organizing recreational activities, promoting home gardening, and monitoring community activities. We examine how these community-based empowerment initiatives successfully assisted in the pandemic response. Health officials can help to build more resilient communities that are better prepared for future health emergencies by valuing the community-level methods used in overcoming COVID-19 and further strengthening the skills of community group members. Community empowerment is a key concept of health promotion and is widely practiced worldwide. It was well documented in the Ottawa Charter, the first international conference on health promotion,Community members or voluntary organizations working in partnership with formal organizations when deciding and implementing interventionsMembers of voluntary and community organizations getting things done; fostering community links; and building skills, self-esteem, and networksInformally engaging with the community, involving social support mechanisms based on kinship, friendship, and neighborhood networksAs defined by the World Health Organization, community empowerment is a process of enabling communities to increase control over their lives.The use of community engagement in disease response is not a novel idea. It has been adopted and known to be a key component in responses to past epidemics of Ebola virus disease, Zika virus, Middle East respiratory syndrome, and severe acute respiratory syndrome. Facilitators of and barriers to the success of community engagement in response to disease outbreaks are listed in Communities share a common interest irrespective of their unique connections. Enabling communities to have more control over their lives through empowerment is an essential aspect in the context of health promotion.On January 30, 2020, the World Health Organization declared COVID-19 a Public Health Emergency of International Concern, and it spread to worldwide within a short period of time.The global history of mothers’ support groups (MSGs) began in the 1950s.In Sri Lanka, MSGs aim to promote health, well-being, and nutrition practices through community engagement.Each MSG comprises 5–20 participants from families with children aged younger than 5 years. MSGs seek to improve nutrition-related practices in the communities by being change agents; improve family health in the community by enhancing awareness and practices; encourage the community in local income generation; prevent substance abuse in the community; support early childcare and development; improve parenting skills; contribute to optimizing environmental health; and address any priority health needs within the local communities.Sri Lanka is divided into 26 health administrative districts, and each district is further subdivided into several medical officer of health areas. Within each of these areas, there are further small subdivisions called public health midwife (PHM) areas. Within each PHM area, several MSGs function to improve the health and well-being of people at the village level.From the early phase of the pandemic until the present, the HPB used the MSG approach in communities to conduct community empowerment activities. In this article, we review the methods that MSGs used to empower communities in overcoming the COVID-19 pandemic.At the beginning of 2020, the HPB sent generic strategies to all MSGs to empower communities in preventing the spread of COVID-19. These guidelines were initially focused on preventive behaviors and later modified to include the promotion of vaccination at the community level upon the availability of the COVID-19 vaccine. However, the MSGs could also adopt other community-level strategies for mitigating the spread of the disease.The outcomes of the activities of the MSGs are usually assessed by physical district reviews conducted by a team of HPB experts that visit each district individually. However, due to COVID-19 restrictions, this was not performed. Instead, the performance of each district and adherence to strategies were monitored through monthly virtual presentations. In addition, the case numbers and new clusters of cases were separately monitored in each district by the Epidemiology Unit within the Ministry of Health. The HPB was also part of this monitoring mechanism.The HPB initially linked MSGs and other platforms at the village and district levels, such as community support organizations and religious leaders.Establishment of communication networksCreation of a supportive environment for preventive behaviorsOrganization of COVID-19 vaccination clinicsDistribution of essential food items to people in needDistribution of routine clinic medicines to patients with noncommunicable diseases (NCDs)Organization of recreational activities for children and adultsPromotion of home gardeningMonitoring and evaluation of the workThe HPB organized a national review in December 2021, and each MSG was asked to present its success stories on December 9–10, 2021. Each district team presented activities conducted by the MSG in the districts. A sample of 26 PHMs was selected to give presentations for the virtual event. The sample was purposive. The entire event was recorded, and the video recordings were transcribed using Microsoft Word by 2 coders. No special software was used for the analysis. We did not quantify the interpretations of the respondents, and the researchers noted their own influence on data to minimize bias. The qualitative data analysis process was data-driven and inductive.In adapting to the “new normal” era, community empowerment required changing old patterns and making new ones. Meeting with the community in person was limited, and new modalities of communicating with the community members were established.One of the key strategies identified in health promotion is the creation of supportive environments.COVID-19 vaccines provided hope for ending the pandemic with the assumptions of equal access and optimal uptake worldwide.The provision of emergency aid has been identified as one of the major activities coordinated through religious leaders and institutions in the community in Sri Lanka.The COVID-19 pandemic resulted in a widespread NCD health service disruption that placed enormous strain on health systems in the South East Asia region.MSG members procured medicines from hospitals for patients with NCDs who were unable to travel during quarantine.COVID-19 affected the psychosocial well-being of many communities. Recent evidence highlights increased mental health problems such as depression and anxiety. Therefore, many recommendations emphasize the importance of allocating time for hobbies and leisure activities, while adhering to COVID-19 guidelines.Home gardening promotion during the pandemic was identified as an intervention to improve self-reported physical and mental well-beingOne of the key recommendations for COVID-19 prevention and control through community engagement approachesCommunities were severely affected during the COVID-19 pandemic and were required to adapt to sudden changes that restricted their freedom; this impacted the communities' potential welfare, leading to a new normal way of living.,Sri Lanka faced 3 prominent waves of COVID-19 .The MSGs have employed many successful community-level methods in overcoming the COVID-19 pandemic in Sri Lanka.We have adapted the themes described by Harden et al.Regarding the quality of existing relationships with the communities, the MSGs were well recognized and villages did not see them as a threat. However, the organizational commitment was at a suboptimal level, with resistance from PHMs and PHIs to share power. Even though the MSG members are empowered in health and well-being activities, PHMs and PHIs primarily provide preventive health services. Therefore, the MSG members mainly play a supportive role in these activities. However, this was challenged during the pandemic, when the PHMs and PHIs needed extensive support from community groups in conducting control activities. Reluctance of these workers to share power with the community groups was identified as a major barrier by many MSGs. Furthermore, since the MSGs fall under the volunteer category, purely working without attachment to local or regional health institutions, many regional health authorities were not committed to their welfare. Therefore, many effective activities conducted by the MSGs were not appreciated or recognized by the local or regional level health authorities. This lack of appreciation and recognition was a major barrier for MSGs in obtaining support from other non-health sector partners.The supportive culture and attitudes that were present at the beginning of the pandemic were lacking later on, which may be due to “pandemic fatigue”However, there were several facilitating factors, such as many initiatives in the communities that were planned well with a joint decision-making process. Furthermore, the MSGs received support from existing partnerships and networks, such as religious leaders and community influencers.Although there is limited literature on COVID-19 community engagements of similar nature (as we have described with MSGs), approaches comparable to the MSG system in Sri Lanka have been documented in many other countries for strengthening maternal and child health. These are called the “Care Groups,” which were developed to support maternal and child health in resource-constrained settings.It is also worth noting that the community engagement initiatives undertaken by the MSGs in Sri Lanka further strengthen the evidence linking the concept of social capital with low mortality, better self-rated health, and the practice of healthy behaviors.The success of the MSG initiatives strengthens evidence linking social capital with low mortality, better self-rated health, and the practice of healthy behaviors.Community engagement initiatives can play a crucial role during disease outbreak control activities. The community-level methods employed by MSGs in Sri Lanka ranged from promoting preventive behaviors to organizing simple recreational activities. Our review showed that adaptation to the sociocultural context of the particular community is important to improve efficiency and overall success in community engagement. Furthermore, it revealed the importance of the continuous development of the knowledge and skills of MSG members, appreciation of MSG activities by the health authorities, and promotion of power-sharing among partners for successful community engagement.


Legumes can fix atmospheric nitrogen (N) and facilitate N availability to their companion plants in crop mixtures. However, biological nitrogen fixation (BNF) of legumes in intercrops varies largely with the identity of the legume species. The aim of our study was to understand whether BNF and concentration of plant nutrients by common bean is influenced by the identity of the companion plant species in crop mixtures. In this greenhouse pot study, common beans were cultivated with another legume (chickpea) and a cereal (Sorghum). We compared BNF, crop biomass and nutrient assimilation of all plant species grown in monocultures with plants grown in crop mixtures.We found beans to exhibit low levels of BNF, and to potentially compete with other species for available soil N in crop mixtures. The BNF of chickpeas however, was enhanced when grown in mixtures. Furthermore, biomass, phosphorous and potassium values of chickpea and Sorghum plants were higher in monocultures, compared to in mixtures with beans; suggesting competitive effects of beans on these plants. Concentration of calcium, magnesium and zinc in beans was higher when grown with chickpeas than with Sorghum.It is generally assumed that legumes benefit their companion plant species. Our study highlights the contrary and shows that the specific benefits of cereal-legume mixtures are dependent on the growth rate of the species concerned. We further highlight that the potential of legume-legume mixtures is currently undervalued and may play a strong role in increasing N use efficiency of intercrop-based systems. Lack of nitrogen (N) is one of the main factors limiting crop productivity worldwide , 2. DeveThe most widespread intercropping systems that incorporate legumes are legume-cereal mixtures, and these are still grown commonly in low-input systems in the tropics . Facilit. In crop mixtures one plant can mobilize otherwise unavailable nutrients for its companion plant. However, the type of nutrients mobilized is dependent on the functional trait of the plant species in the mixture  and week of collection (week five and eight) as fixed effects. To test for the effects of variety identity and identity of companion plant species on our response variables, we split the data and focused on single variety pots . We included variety identity (Variety 1 or Variety 2), presence/absence of companion plant species and week of collection as fixed effects. For %ndfa response variable, only data for week eight was used.Week of collection had a significant effect on all other response variables. Therefore, we further split the data for the different weeks and tested the effects of cropping treatment, bean variety identity and companion crop identity within each harvest time point for our response variables.For all response variables for a specific plant, we only used data where the specific species was present. We first ran a LMER or GLMER model on the whole chickpea or Sorghum data, including cropping treatment [crop mixture and chickpea/Sorghum monoculture] and week of collection (week five and eight) as fixed effects. We further split the data into each harvest time point to investigate the effect of cropping treatment on all response variables.


Direct oral anticoagulants against activated factor X and thrombin were the last milestone in thrombosis treatment. Step by step, they replaced antivitamin K and heparins in most of their therapeutic indications. As effective as the previous anticoagulant, the decreased but persistent risk of bleeding while using direct oral anticoagulants has created space for new therapeutics aiming to provide the same efficacy with better safety. On this basis, drug targeting factor XI emerged as an option. In particular, cancer patients might be one of the populations that will most benefit from this technical advance. In this review, after a brief presentation of the different factor IX inhibitors, we explore the potential benefit of this new treatment for cancer patients. From the beginning of the 20th century to the present day, we have experienced significant advancements in antithrombotic drugs . The firSeveral FXI inhibitors are under development. These include the following: I/small molecules that bind to the active site of activated FXI (FXIa) and inhibit its activity (Asundexian and Milvexian), II/antibodies directed against FXI that inhibit the activation of FXI or the activity of FXIa , III/antisense oligonucleotides  which reduce the synthesis of FXI by binding to the messenger RNA of FXI in hepatocytes and induce its degradation, and IV/natural inhibitors . This reIn the classic portrayal of the coagulation cascade, which consists of the intrinsic, extrinsic, and common pathways, FXI is positioned within the intrinsic or contact activation arm of coagulation . Given tIxodes ricinus contact phase inhibitor) appear to be the least-viable therapeutic option due to their slow onset and offset, coupled with a relatively high risk of adverse side effects. The impact of antibodies and ASOs on FXI differ in their time to effect; monoclonal antibodies reduce FXI function within hours post administration, whereas the effect of ASOs only becomes noticeable after several weeks .,65.25,65In a canine model of veno-venous extracorporeal membrane oxygenation (ECMO) using EP-7041, Pollack et al. demonstrated a prolongation of the aPTT and a reduction in bleeding associated with ECMO in this model . UnsurprAn increasing number of studies have examined the link between VTE events and atherothrombosis, including in patients with cancer ,68. As wAlthough we are able to effectively prevent deaths post VTE, there is currently no therapeutic arsenal to prevent sequels such as chronic thromboembolic pulmonary hypertension (CTEPH) or post-thrombotic syndrome (PTS) . From a The pathophysiologic approach to the inhibition of FXI make it a promising target to solve the prothrombotic situations encountered with patients with a cancer-mediated procoagulant state . Subject to the results of ongoing trials, the factor XI inhibition pathway appears to be an encouraging way of improving the management of patients suffering from cancer-associated thrombosis.


The use of inferior vena cava (IVC) filters has been increasingly prevalent. Although they are relatively safe with clear indications, they are not without complications. Late-onset complications include IVC filter migration, IVC wire fracture, wire strut penetration, and perforation of organs in its vicinity. In this report, we present the case of a patient with small bowel volvulus secondary to an IVC wire strut migration, causing tethering of the mesentery and vascular compromise to the small bowel. The use of inferior vena cava (IVC) filters to prevent pulmonary embolism and deep vein thromboses has been popularized since the 1970s and 1980s . With th9/L). The rest of the labs were nonremarkable.We present a case of a patient in his mid-40s with a past medical history of placement of an IVC filter in the mid-1990s after a motor vehicle crash; he was lost to follow-up and without prior history of any other surgeries. This patient presented to the emergency department with multiple episodes of gradually progressing diffuse abdominal pain, nausea, and vomiting of several weeks’ duration. The patient's medical history was significant for placement of an IVC filter in the mid-1990s after a motor vehicle crash. He had no history of prior abdominal surgery and was lost to follow-up many years ago after placement of the IVC filter. The patient ascribed pain as shooting and stabbing, which was exacerbated with movement and relieved by remaining still. He reported having a similar uncomplicated episode of pain that resolved spontaneously at home few weeks prior to arriving to the Emergency Department. Upon physical examination, there was abdominal tenderness on palpation with guarding and signs of peritonitis. The patient was afebrile and hypertensive into 140s/60s with regular heart rate and regular respirations, and his oxygen saturation was above 95% on room air. Given the significance of the physical examination, the patient was urgently taken for radiological evaluation of the abdomen with computed tomography (CT). CT scan with intravenous contrast of the abdomen and pelvis demonstrated small bowel volvulus with possible internal hernia Figures . The rooGiven the patient’s small bowel volvulus findings on CT images with swirl sign and physical examination findings of peritonitis, the patient was taken emergently to the operating room for open abdominal exploration. Intra-operatively, an internal hernia created by mesenteric twisting from IVC wire strut was identified with the jejunal portion of the small bowel looping within its mesentery Figures -3D. ExtePlacement of vena cava filters is a surgical intervention performed to prevent pulmonary embolism and deep vein thrombosis, specifically in certain circumstances where medical anticoagulation is contraindicated -5. AlthoMany late-onset complications of IVC filters are uncommon and are reported in individual case reports ,6-16. ThTo date, literature review shows one case report from 1996, demonstrating a similar case of an IVC filter strut causing small bowel volvulus [There are no conclusive study results that support significant safety, efficacy, and complications differences among various types of vena cava filters . The PRERegarding the patient in our case report, the specific type of filter he had was not known. The permanent IVC filters have been around since the 1980s, and the first retrievable filter was approved by the FDA in 2003 [Even though the overall incidence of very late-onset complications from IVC filters are uncommon, complications from IVC migration pose a great risk of injury of nearby and distal anatomical structures and can lead to devastating clinical outcomes, especially considering that placement of an IVC filter is done for prophylactic indications. Current IVC filters are designed to be explanted at some time in the future. However, there remains an unknown number of people with IVC filters that were lost to follow-up. The clinical significance of this case report outlines the importance of adequate long-term follow-up of patients after IVC filter placement, consideration of repeat imaging, and further consensus guidance on the management of permanent IVC filters.


Their low solubility and short half-life, however, limit their use. Currently, phytonanotechnology is being developed to offer the advantages of increased solubility and availability of phytochemicals. Phytochemicals can reach cancer cells after being attached to nanovehicle surfaces or combined with substances that target tumors. Micelles, liposomes, and nanoparticles are examples of nanoformulations that have the potential to be highly loaded with phytochemicals, including weakly soluble and poorly stable phytochemicals. It will boost the phytochemical bioavailability to local tumors and lower the chances of unfavorable side effects in neighboring or distant organs.A significant problem in medical oncology is chemoresistance. Resistance developed during treatments is a major cause of fatalities in cancer patients. Conventional chemotherapeutic agents have also been revealed to cause damage to normal cells in addition to resistance, suggesting that treatment interruption may be necessary. Phytochemicals might protect healthy tissues Singh et al. offer an insightful overview of clinical updates on tyrosine kinase inhibitors in HER2-positive breast cancer, with a focus on therapeutic advancements such as the use of nanotechnological interventions. To overcome drug resistance and limited efficacy in current treatment options, nanoformulations can be used in patients receiving HER2+ BC treatment. Anti-HER2 ligands can be used in various nanoformulations to target HER2 receptors. Here, the authors discuss targeted TKIs in patients with HER2+ BC, clinical studies of HER2+-targeted TKIs, mechanisms of resistance to HER2-directed therapies with new implications of TKIs in HER2+ MBC (metastatic breast cancer), and anti-HER2 ligands in various nanoformulations to target HER2 receptors.Ahmed et al. sheds light on the exploration of MARK4 as a target for the management of hepatocellular carcinoma and establishes the role of phytoconstituents in regulating the expression of proteins and interactions with altered genes.Another interesting advancement is the popularization of network pharmacology as an approach to screening new therapeutic targets and moieties. The research work shared by Upadhyay et al. focuses on the therapeutic potentials of yeast-derived β-1,3-glucan particles as a safe and effective approach to ameliorating cervical cancer. A need to explore alternative therapeutic strategies to improve therapeutic outcomes and the quality of life of patients has been identified. Using instrumental techniques, the authors characterize the particles and establish an effective dosage. The authors also highlight the need for further research in order to develop a deeper understanding of the spectrum of actions and potentials for the clinical use of the agent studied.An intriguing study by Sindhoor et al. investigates the role of alkaloid nanoformulations for lung cancer therapy as an approach to tackling commonly associated problems with the delivery of conventional therapeutic agents for disease management. The review explores the mechanism of different alkaloids with reference to the pathways targeted, discusses the drawbacks associated with conventional treatment strategies, and highlights the need for nanoformulations, moving forward.The review article by Kaur et al. analyze the efficacy of Frankincense oil-loaded nanoemulsion formulation of paclitaxel and erucin, focusing on drug resistance in breast cancer. The study explores the rationale for the selection of the constituents, signaling pathways targeted, and studies that involved evaluation in an animal model to elucidate the synergistic role of the active components in overcoming drug resistance. The study offers an in-depth overview of the formulation considerations and due modulations, effects on various biomarkers, and prospects for further research and development.Singh et al. explore the domain of Ehrlich-ascites carcinoma, proposing the development and use of nanoparticles loaded with erucin, a dietary isothiocyanate isolated from Eruca sativa. The authors discuss the antioxidant property of the phytoconstituent, established using a variety of in vitro assay techniques, and its effects on cellular proliferation. A novel approach to erucin delivery, through the designing of cubosomes, is elucidated, which shall pave the way for further advancements and applications in clinical settings. We sincerely hope you enjoy reading the articles in this Research Topic, which address a subject that is likely to become even more decisive in the coming years.


The facial nerve is the seventh of 12 cranial nerves found in the head and neck region that facilitates several nerve fibers and pathways to perform various functions. Iatrogenic facial nerve injury during surgeries of the head and neck is common, ranging from 4-6%, particularly in procedures that involve mobilization or resection of associated anatomical structures. Any injury to the facial nerve or its branches impacts the quality of life and patient satisfaction as the degree of iatrogenic injury may result in partial or complete facial nerve paralysis. Of the various implementable techniques available to avoid injury, electromyography (EMG) has recently been widely used to monitor facial nerve function intraoperatively to determine the degree of injury and predict postoperative weakness. The purpose of this study was to analyze and review existing scientific literature in determining the role of intraoperative facial nerve monitoring (IFNM) with EMG in decreasing the incidence and degree of intraoperative facial nerve injury among commonly performed surgeries involving the facial nerve.A systematic review was conducted from articles published between September 2006 and December 2022. Suitable articles were identified from the MEDLINE/PubMed databases using relevant terms to meet the inclusion criteria. Articles were subsequently coded based on the inclusion/exclusion criteria as well as the type of surgery performed with concurrent use of EMG and the results from intraoperative monitoring. A total of 47 articles were found in relation to the use of IFNM, including studies to reduce the incidence and determine preventative measures to decrease nerve injury. Eleven articles were used to evaluate the use of EMG during various head and neck surgeries in decreasing the incidence of intraoperative facial nerve injury.Sources found were primarily divided based on the type of surgery performed when determining the use of EMG. Four sources tested the efficacy of EMG during parotidectomy, four sources during vestibular schwannoma resection, two sources during cochlear implant surgeries, and one during a lymphatic malformation surgery. IFNM also decreased the duration of surgery, the severity of facial nerve palsy, and the average time of facial nerve paralysis recovery. IFNM was found to not significantly predict facial nerve injury in the setting of intraoperative nerve injury but tended to preserve potential facial nerve function in vestibular schwannoma cases.The surgical setting determined the efficacy and use of IFNM in decreasing the incidence of facial nerve weakness and paralysis. IFNM had the best preventative and prognostic value when used in vestibular schwannoma resection, and the least in cochlear implants, with mixed evidence seen in the setting of parotidectomy. Overall, IFNM using EMG as an adjunct during surgery may reduce the risk of iatrogenic injury; however, additional studies must be performed to determine the degree of long-term patient satisfaction and quality of life achieved in the setting of IFNM. The facial nerve provides innervation to the facial muscles within the head and neck region. As the seventh cranial nerve, it carries motor, sensory, and parasympathetic nerve fibers with general somatic efferent, general visceral efferent, special visceral afferent, and general somatic afferent functions ,2. The mApart from its function, the facial nerve can further be divided into intracranial, intratemporal, and extratemporal parts Figure . The intInjury to the facial nerve or its branches has the potential to cause decreased quality of life and satisfaction as the degree of iatrogenic injury may result in partial or complete facial nerve paralysis ,14. The MethodologyA systematic review was conducted from articles published between September 2006 to December 2022 from the MEDLINE/PubMed databases. Relevant terms such as “facial nerve injury,” “monitoring,” and “electromyography” were used to refine the initial search for iatrogenic facial nerve injury due to surgical intervention. Six records were excluded as full text could not be obtained, while an additional 27 met other exclusion criteria which were outside of date range, not published in English or having an English translation, or only peripherally related. Articles were subsequently coded based on the type of surgery performed with concurrent use of EMG as well as the results from intraoperative monitoring. Articles found were thoroughly analyzed based on relevance to the aims of this report. A total of 47 articles were found in relation to the use of intraoperative facial nerve monitoring, including studies to reduce the incidence and determine preventative measures to decrease nerve injury. After carefully considering the degree of information provided, a total of 11 articles were used to evaluate the use of EMG during various head and neck surgeries in decreasing the incidence of intraoperative facial nerve injury  tested the efficiency of EMG in parotidectomy, 36% (n = 4) during vestibular schwannoma resection, 18% (n = 2) in cochlear implant surgery, and 9% (n = 1) during lymphatic malformation surgery. Many studies were retrospective , along with two prospective studies, one retrospective and prospective study analysis, one randomized control trial, and one cohort study. In the four studies done during parotidectomy, intraoperative facial nerve monitoring decreased the risk of weakness immediately postoperatively and long-term permanently -23. IntrIntraoperative facial nerve monitoring is a valuable resource in locating and mapping out the facial nerve to avoid intraoperative injury and postoperative paralysis. In identifying the course of the nerve, intraoperative facial nerve monitoring allows for the identification of the nerve course, adequate protection, and the preservation of facial nerve function -34. FaciEMG and its research have been relatively emergent; however, newer technology and techniques have also been shown to reduce intraoperative facial nerve injury and better predict nerve injury during surgical interventions. For example, in a recent retrospective study of parotidectomies, magnetic resonance imaging with three-dimensional double-echo steady-state (DESS protocol) and water excitation sequence was a superior method in localizing the facial nerve intraoperatively -45. WithOverall, intraoperative facial nerve monitoring using EMG as an adjunct during surgery may reduce the risk of iatrogenic injury by locating and protecting the facial nerve, but additional studies must be performed to determine the degree of long-term patient satisfaction and quality of life achieved in the setting of intraoperative facial nerve monitoring. Based on the current evidence, surgical settings may determine the efficacy and use of intraoperative facial nerve monitoring in decreasing the incidence of facial nerve weakness and paralysis. Many new techniques should also be considered in understanding the role of other techniques in decreasing the incidence of intraoperative facial nerve injury. Increasing incidences of facial nerve injury seen with various head and neck surgeries support the importance of determining the role of EMG in intraoperative facial nerve monitoring and the need for a predictive intraoperative tool.


This study is conducted on glass fiber-reinforced composite honeycomb sandwich structures by introducing delamination damage through low-velocity impact tests, establishing a three-dimensional progressive damage analysis model, and evaluating the delamination damage characteristics and laws of honeycomb sandwich structures under different impact energies through experiments. Repair techniques and process parameters for delamination damage are explored. It is found that as the impact energy increases, the damage area of honeycomb sandwich panels also increases, and the delamination damage extends from the impact center to the surrounding areas, accompanied by damage such as fiber fracture and matrix cracking. The strength recovery rates of sandwich panels at impact energies of 5 J, 15 J, and 25 J after repair are 71.90%, 65.89%, and 67.10%, respectively, which has a considerable repair effect. In addition, a progressive damage model for low-velocity impact on the composite honeycomb sandwich structure is established, and its accuracy and reliability are verified. Structural lightweight is the eternal theme in the development of aerospace structures. Composite honeycomb sandwich panels are widely used in the primary and secondary load-bearing structural elements of aircrafts by virtue of their superior properties such as high specific strength, high specific stiffness, and strong instability resistance . HoweverThe emerging repair technology can cost-effectively solve the problem of significant decrease in flexural stiffness and structural strength of damaged composite honeycomb sandwich structures. The damaged composite parts can be well restored to their original performance and service life through an appropriate repair process. However, the composite honeycomb structure is characterized by complex structural form, large dispersion of mechanical properties, and various damage modes, which brings difficulty to strength-checking and repair program design. After the repair of the composite sandwich structure, different types of damage from the original ones may occur in the composite panel, adhesive layer, and honeycomb core layer. The mechanical properties such as the strength restoration effect of the repaired structure are important references to check whether the composite structure of the airplane can meet the airworthiness requirements. Therefore, combining with the engineering practice to reasonably assess the damage of composite sandwich structures before repair, proposing better repair methods, as well as predicting and evaluating the damage and strength of the repaired structure have become urgent issues in composite research, which are of great significance to further promote the application of composites in the field of aerospace .For composite honeycomb sandwich structures, Avery et al.  and HansThis paper focused on the panel damage identification and repair of glass fiber-reinforced composite honeycomb sandwich structures. The initial damage in the composite honeycomb sandwich structure is introduced by a drop hammer impactor to establish a three-dimensional progressive damage analysis model. The finite element numerical simulations and tests for low-velocity impact are performed to evaluate the delamination damage characteristics and laws of honeycomb sandwich structures under different impact energies. The sensitivity of the damage to the impact energy is studied. The repair technology and process parameters for the delamination damage to improve the strength of the composite honeycomb sandwich structures after repairing are also researched and discussed.ETT is the elastic modulus in the T-direction of the honeycomb core; GLT and GWT are the shear moduli in the LT and WT directions, respectively; XTT is the tensile and compressive strength in the T direction; SLT and SWT are the shear strengths in the LT and WT directions, respectively; the subscript L represents the length direction of the honeycomb panel, W represents the width direction, and T represents the height direction.The raw materials used to manufacture the specimens are shown in The hand lay-up process was used to manufacture the test specimens. The manufacturing process of specimens is shown in After the panel is fully cured, the core layer will naturally bond to the panel. In addition, all panels were extruded with a rigid smooth board of the same weight before placement of the core layer. Rigid matting with a thickness of 1 mm was laid around the perimeter to ensure that the panels were made with the same fiber content each time and air bubbles were expelled. After there was no resin outflow, the rigid panels were removed. Finally, the other side of the panel was completed in the same manner. The advantage of this preparation method is that it ensures a strong bond between the core layer and the face sheets, and the uncured panel is always in the lower part during the molding process to avoid the resin flowing into the pores of the core layer. After the molding was completed, the specimens were cut according to the standard to 150 mm × 100 mm.The low-velocity impact tests on the honeycomb sandwich structures were carried out using the INSTRON CEAST 9350, CEAST Headquarters, Vicenza, Italy, which consists of a test bench, spare parts box, electrical cabinet, and control instrumentation, as shown in Prior to the low-velocity impact test, all specimens were subjected to an ultrasonic C-scan to ensure that no initial damage existed in specimens. The C-scan results indicated that no significant initial damage existed in any of the specimens and that the test requirements were met. The ultrasonic scanning result is shown in The raw data exported from the testing machine were processed to obtain the load–displacement curves at different impact energies, as shown in Damage to the sandwich panels after low-velocity impact tests is difficult to recognize by the naked eye and thus often observed by other means. Ultrasonic C-scans were performed on the specimens after the impact test to determine the area of delamination damage and the impact damage pattern of the honeycomb sandwich structure. The C-scan results are shown in The low-velocity impact process was numerically simulated using ABAQUS v6.14 . A modelFor the adhesive layer between the interfaces, cohesive units were inserted between the layers to simulate the interfacial delamination damage. The cohesive intrinsic relationship is shown in The fiber bundles constituting the core material can be regarded as unidirectional panels, and in this paper, the panels are regarded as composites with only one layer of fabric layup. Cheng et al.  and YangWeft fiber stretch failure  and (10):The numerical simulation results of ABAQUS are compared with the test data to validate the model, as shown in Sandwich structures under low-velocity impact are often accompanied by typical damage patterns such as fiber breakage, matrix cracking, and delamination. However, it is difficult to observe and identify the damages during the impact test, and thus, numerical simulations are necessary, since identifying the damage patterns is very important for the safe design of the sandwich structures. The simulated damage at different impact energies is shown in In the damage cloud maps at different impact energies shown in Analyzing the damage of the cohesive layer shown in Repair studies of composite honeycomb sandwich structures focus on panel repair and honeycomb core layer repair. Core layer repair generally removes the damaged part of the core layer and replaces it with new honeycomb. Panel repair is mainly categorized into two types: patch-and-glue repair and gouge-and-glue repair. Patch repairs are generally used for thin structure repairs or temporary repairs, while gouge repairs are usually used for thicker structure repairs and permanent repairs. Gouging and gluing repairs are further divided into two types: diagonal gluing-gouging repairs and step gluing-gouging repairs ,24. WithCombined with the molding characteristics of the specimen and the form of damage, the stepped gluing gouge repair process is selected. The repair angle is determined to be 5°. The repair schematic is shown in Compression tests were carried out on the intact parts, parts with damage introduced, and repaired specimens to measure their compressive strength. The compression test was carried out using an MTS static testing machine and the test standard was executed according to ASTM D7137M , and theThe damage load of the repaired specimen was analyzed in comparison with the damage load of the intact and damaged pieces. The damage load of the intact part was 28.50 kN, and the strength recovery rate is shown in The composite honeycomb sandwich structures were fabricated using a hand lay-up molding process. A progressive damage model that can be applied to the low-velocity impact of the composite sandwich panels was established. The consistency between the simulation results and test data was verified, which confirms the accuracy and reliability of the model. The relevant mechanical responses and damage modes under different impact energies were also obtained. It was shown that with an increase in impact energy, the damage area of the specimen increases, accompanied with fiber fracture, matrix cracking, delamination, and other damage modes.Compression tests were conducted on the intact, impact-damaged, and repair specimens. It was found that the compression strength of the repaired specimens was improved to a certain extent compared with that before repair. The strength recovery rates of sandwich panels at impact energies of 5 J, 15 J, and 25 J after repair were 71.90%, 65.89%, and 67.10%, respectively, which had a certain repair effect.The low-velocity impact model established in this paper can effectively simulate the impact response and delamination damage of honeycomb sandwich panels. The failure modes such as honeycomb collapse and instability were not considered. A more accurate prediction model can be improved in the future. In addition, the repaired sandwich panel can also be subjected to multiple impacts to study the residual strength under more complex conditions.


During free flap surgery, the surgeon sometimes encounters problems with anastomosis such as intractable arterial spasms or vessel size discrepancy in venous anastomoses. End-to-side (ETS) anastomosis has the advantages of limited chance of vessel spasm and easy handling by adjusting for vessel size discrepancy. We introduced the arterial and venous end-to-side anastomosis (AV-ETS) strategy, which is based on the ETS anastomosis to the main artery and accompanying veins, to avoid intraoperative anastomotic problems when creating a free flap. The aim of this study was to compare flap outcomes and intraoperative anastomotic problems before and after introduction of the AV-ETS strategy in extremity free flap surgery.We retrospectively examined 72 consecutive extremity free flaps. Before introducing the AV-ETS strategy, we used the conventional strategy in which the recipient artery was selected according to the number of the remaining main artery and the anastomosis technique was flexibly changed, although the end-to-end (ETE) technique was used in most cases.The conventional group had 18 flaps and the AV-ETS group had 54 flaps. The rate of flap survival did not differ between these groups, and there were no cases of flap failure after the introduction of the AV-ETS strategy. The AV-ETS group had significantly fewer flaps that required a change in preoperative planning for the recipient artery or anastomotic site of the artery.The AV-ETS strategy may facilitate reliable preoperative planning and the performance of stable free flap surgery without requiring a flexible response during surgery. Of the 94 free flaps of 76 patients who received free flap surgery in an extremity, for soft tissue defects caused by severe trauma or infection at our centre between April 2015 and March 2022, we retrospectively examined 72 flaps in 59 consecutive patients, after excluding four flaps for toe defects and 18 flaps for finger defects because of no nearby greater vessels in those areas. For each flap, patient and flap demographics, anastomosis details, flap outcomes, and complications were examined. Any intraoperative anastomotic problems related to intraoperative arterial spasm or a vessel size discrepancy ≥1 mm were also examined.All surgeries were performed by four surgeons under the supervision of M.M., an orthopaedic surgeon, after careful preoperative planning, which included the selection of the recipient vessels and methods for performing the anastomoses.From April 2015 to July 2017, free flap surgery was performed based on the conventional strategy;The AV-ETS strategy for free flaps was introduced in August 2017 . Regardl,We always used the microscopic parachute ETS (MPETS) technique as the anastomosis technique. This technique included a wide-slit vesselotomy of the recipient vessel and a parachute technique at the heel of the flap vessel, where anastomosis can be difficult, for both arterial and venous anastomosis.t-test. A p value <0.05 was considered to be significant. All analyses were performed using Bell Curve for Excel .The patient and flap demographics, anastomosis details, intraoperative problems, and flap outcomes were compared between the conventional and AV-ETS groups using Fisher's exact test, chi-square test, or Welch's The patients were 43 men and 16 women, with an average age of 56 years (range 22–87 years). The average follow-up duration for each flap was 23 months (2–84 months). In two patients, the flap surgery was performed twice during the periods before and after introduction of the AV-ETS strategy. Excluding these two, 13 patients were in the conventional group and 44 in the AV-ETS group. Except for sex distribution, the patient background characteristics did not differ significantly between groups . The conDetails of the vascular anastomoses are shown in Intraoperative anastomotic problems such as intractable arterial spasms occurred in three patients in the conventional group but in no patients in the AV-ETS group. Vessel size discrepancy ≥1 mm occurred in 33 flaps for arterial anastomosis and in 20 flaps for venous anastomosis; the vessel size discrepancy did not differ significantly between the two groups. In the conventional group, the recipient artery was changed to a more suitable artery for three flaps, and the anastomotic site was changed to the proximal site using a vein graft for two flaps because of intraoperative arterial spasm. In the AV-ETS group, the recipient artery was changed for only one flap because the route of the flap pedicle vessels was likely to be squeezed. In the AV-ETS group, the anastomotic site was changed to the proximal site for only one flap because the recipient artery was damaged by excessive traction during recipient vessel preparation, and an ETE anastomosis was performed using a vein graft. Significantly fewer flaps required a change in the recipient artery or anastomotic site in the AV-ETS group than in the conventional group .Table 4ISeventy of the 72 flaps survived . In the We introduced the AV-ETS strategy when using free flaps to treat soft tissue defects in the extremities caused by trauma and infection . Unlike ,,,,,,,Because a completely transected artery tends to retract, contract, and stop bleeding,,,,,,,,,Selection of the recipient vein and proper venous anastomosis are also important for avoiding serious complications in free flaps.,,,A stable ETS technique is required when introducing the AV-ETS strategy. ETS is a more complicated procedure than ETE, and no single method has been shown to be superior, although various ETS techniques have been reported.,,,The surgeon's experience is considered to be the most important factor in determining the outcome of the free flap technique.1)As previously described by Godina,2)Because of the large vesselotomy to the recipient vessel, exposure of the recipient vessels in the MPETS technique should be larger than when performing the common ETS with a small vesselotomy.3)The artery and veins of the flap pedicles need to be well separated to avoid becoming kinked because all vessels will be anastomosed to the adjacent vessels.We believe that surgeons should consider the following three items to ensure the safe use of the AV-ETS strategy with the MPETS technique.Although vascular occlusion occurred in three cases in the AV-ETS group, we believe that these complications could have been avoided by considering these precautions. In the unlikely event that the recipient artery is damaged by the intraoperative procedure, it would be better to reconstruct the injured main artery first using a vein graft and then perform the ETS again using the implanted vein as the recipient artery.,In this study, many serious postoperative complications were observed in addition to blood flow disorders in the free flap. Due to the relatively large number of infected cases, many deep infections were observed as postoperative complications. We should have performed an appropriate culture test and confirmed that the bacteria had been removed after debridement before performing the free flap technique.Our study has some limitations. First, this was a retrospective study with a small number of flaps, and the patient and flap backgrounds did not match perfectly in the two groups. Second, due to the different sample sizes between the two groups, statistically significant difference may not have been adequately detected. Although the number of cases in the conventional group cannot be increased because of the introduction of the AV-ETS strategy, studies with larger sample sizes may show significant differences in clinical outcomes between the two groups. Finally, the difference in treatment time between the conventional and AV-ETS groups means that the operator's learning curve may have been an uncontrolled factor in this study. Especially in the early cases of the conventional group, there was a tendency to choose the proximal stump of the damaged vessel and to use the ETE technique rather than the unfamiliar ETS, which is thought to sometimes result in arterial spasm.In this study, we compared the flap outcomes and intraoperative anastomotic problems for extremity free flap surgery before and after introduction of the AV-ETS strategy. Unlike the conventional strategy, in the AV-ETS strategy, the main arteries and accompanying veins closest to the soft tissue defect, which had good blood flow, were selected as the recipient vessels regardless of the number of remaining main arteries, and all anastomoses were performed using the ETS technique. The rate of flap survival did not differ significantly between the groups, but there were no cases of flap failure after introduction of the AV-ETS strategy. In addition, significantly fewer flaps required a change in the preoperative planning for the recipient artery or the anastomotic site of the artery after introduction of the AV-ETS strategy. When operating on soft tissue defects caused by severe trauma or infection, the AV-ETS strategy may facilitate reliable preoperative planning and the performance of stable free flap surgery without requiring a flexible response during surgery.None.None.


It has long been speculated whether the presence of a cilioretinal artery (CRA) can influence the development of glaucomatous damage in patients with open-angle glaucoma. Studies involving healthy patients have shown a change in flow density (FD) depending on the presence of a CRA. Similarly, studies that compared the optical coherence tomography angiography (OCTA) results of healthy controls and glaucoma cohorts identified a reduction in FD in certain retinal layers for glaucoma patients. These observations raise the question of whether FD is altered in glaucoma patients depending on the presence of CRA, with possible implications for the progression of glaucomatous damage. In this prospective study, 201 eyes of 134 primary and secondary open-angle glaucoma patients who visited the Department of Ophthalmology at the University of Muenster Medical Center, Germany were included. The patients were allocated to different groups according to the presence of CRAs and the level of glaucoma severity. The FD results obtained using OCTA for the CRA and non-CRA groups were compared. While FD differed noticeably between the CRA and non-CRA cohorts in the deep macular plexus, no differences in FD were observed between the two groups when adjusted for glaucoma severity. In both the CRA and non-CRA eyes, increasing glaucoma severity correlated most strongly with a reduction in peripapillary FD. Our results suggest that the presence of CRAs does not significantly affect retinal perfusion in glaucoma patients. Glaucoma is a leading cause of irreversible visual impairment worldwide. This disease is associated with a loss of retinal ganglion cells and subsequent characteristic peripheral vision loss . IntraocThe central retinal artery is responsible for the arterial blood supply to the inner layers of the retina, while the outer layers of the retina are supplied blood via the choroidal vessels. First described by Müller in 1856, cilioretinal arteries (CRAs) —an anatoOptical coherence tomography angiography (OCTA) is a novel imaging technology that facilitates the quantification of the retinal vasculature by measuring flow density (FD) ,7. OCTA Recent trials assessing the eyes of healthy individuals have described macular and peripapillary FD to be higher in the presence of CRAs compared to control eyes without the vessel ,19.This raises the question of whether CRAs can exert an effect on FD in glaucoma patients, with potential implications for structural and functional vision loss.The primary aim of this study was to investigate possible differences in FD in glaucoma patients with and without CRAs using OCTA scans. The secondary objective was to examine the correlation between the presence of CRA and FD in relation to glaucoma severity.This prospective, monocentric study was performed in accordance with the ethical standards issued by the ethics committee of the Medical Association of Westfalen-Lippe and the University of Münster; it also adhered to the tenets of the Declaration of Helsinki.The study was conducted at the Department of Ophthalmology at the University of Muenster Medical Center, Germany. Patient recruitment occurred from February 2017 to August 2022.Patients diagnosed with primary open-angle glaucoma (POAG), pseudoexfoliation (PEX) glaucoma, pigment-dispersion glaucoma, and normal-tension glaucoma were included in the study. The exclusion criteria included reasons other than glaucoma that might cause abnormalities of the optic nerve head . If ophthalmic examination was insufficient to establish such a connection, further testing including neurologic examinations and MRI imaging was performed. Patients showing central retinal pathologies that might influence macular OCTA measurement results were also excluded.The participants of the study underwent a standardized ophthalmic examination including a refractive eye exam, the examination of the anterior segment, funduscopy, Goldmann applanation tonometry, gonioscopy, perimetry using the automated Humphrey visual field analyzer  with the standard program of the 30–2 Swedish interactive threshold algorithm (SITA fast), fundus imaging of the optic disc , and OCTA measurements using the RTVue XR Avanti system . Angiographic imaging of the macula used 3 × 3 mm scans, while measurements of the optic disc used 4.5 × 4.5 mm scans. FD, reflecting the ratio (%) of bright to dark pixels  was automatically calculated using the AngioVue algorithm for different retinal layers and sublocations. Twelve parameters, each related to the macular superficial capillary plexus (SCP) and the macular deep capillary plexus (DCP), and 18 parameters related to the radial peripapillary capillaries (RPC) of the optic nerve head were extracted and analyzed. OCTA measurements were performed in a darkened windowless room under the same mesopic lightning conditions by a qualified examiner. Scans with a quality index (QI) <7 were excluded.The Zeiss VISUCAM photographs and OCTA scans of all individuals included in the study were used to identify CRAs; this was performed by two expert examiners independently. CRAs were characterized as hooked retinal arteries at the rim of the optic nerve head without a connection with the central retinal artery. The eyes were subsequently classified into two cohorts: one cohort included the eyes of glaucoma patients without a CRA, while the other consisted of eyes with at least one CRA. For the severity-adjusted analysis, the CRA and non-CRA patients were further divided into three severity groups according to the perimetry-based level of glaucoma, as suggested by Hodapp et al. . Group 1The statistical analysis was performed using R, Version 4.1.2. Variables related to the basic characteristics of the patients and eyes included in the study were presented as the absolute and relative frequencies for the categorial variables and as the mean ± standard deviation for continuous variables. The patients with one or more CRAs were grouped together and not analyzed with regard to their exact number of CRAs.clusrank, and have reported the resulting p-values [As the normal distribution assumption does not apply to FD variables, we reported the medians of these values; furthermore, we applied non-parametric statistical methods. For comparisons between different groups, we used tests for clustered data as proposed by Rosner et al. as well as their implementation of the R package p-values ,22. As tp-values ,22,23. Ip-values below 0.05 and 95% confidence intervals that did not contain 0 were considered noticeable.All analyses were explorative and should be interpreted accordingly. Furthermore, n = 145). Among the eyes with CRA (n = 56), 44 had one CRA (78.6%), 11 had two CRAs (19.6%), and one had four CRAs (1.8%). Further cohort-specific characteristics are summarized in In this study, 201 eyes of 134 primary and secondary open-angle glaucoma patients were included. The patient population characteristics are summarized in Neither age nor the gender ratio differed significantly between the CRA and non-CRA cohorts. Furthermore, neither the imaging-related parameters (such as the mean QI for macular and optic disc images) nor the ocular parameters  were statistically different between the two groups .Statistical testing revealed noticeably higher FD in the CRA eyes compared to the non-CRA eyes at the level of the DCP. No significant difference was found between the two groups at the level of the SCP or the RPC .As mentioned previously, the CRA and non-CRA eyes were further subdivided according to the Hodapp–Parrish–Anderson classification. These allocations were performed to adjust for glaucoma severity, as this was considered as a possible confounder. The results for the FD comparison between the CRA and non-CRA patients, adjusted for disease severity, are summarized in The correlation between the FD reduction and the severity of glaucoma across the CRA and non-CRA eyes was strongest for the RPC sectors, followed by the SCP sectors, while the DCP sectors correlated poorly with the glaucoma severity . This wan = 26) showed noticeably higher FD in the non-CRA eyes (n = 17) compared to the CRA eyes (n = 9) at the level of the SCP in the total cohort comparison and when adjusted for disease severity (p ≤ 0.02). Due to the composition of the NTG cohort, a further disease severity-dependent subanalysis could only reasonably be conducted for early glaucoma patients.The isolated analysis of the eyes of the NTG-patients (The role of CRAs in glaucoma has always been of considerable interest to researchers. Different authors have evaluated whether CRAs have a protective function with regard to glaucomatous damage. In recent years, this issue has received greater attention, as recent publications have described a negative correlation between FD and the severity of glaucoma. This raises the question of whether an additional vessel could improve FD and, consequently, potentially delay glaucomatous damage. This was the first study to investigate the relationship between FD measured using OCTA and the presence of CRAs in primary and secondary open-angle glaucoma patients.In a systematic review, the prevalence of CRAs was found to be 6.9–49.5%. ,25. In oBoth the central retinal artery and the posterior ciliary arteries originate from the ophthalmic artery. The CRAs, in turn, arise from the short posterior ciliary arteries or, in rare instances, directly from the choroidal circulation. As true end arteries, CRAs supply a distinct region of the retina and, in fewer cases, the prelaminar region .Diener et al., analyzed the OCTA-derived FD in healthy patients with and without CRAs. The study group revealed increased FD in the RPC network and in the SCP in patients with CRAs . NotablyAlterations in capillary perfusion related to glaucoma have been extensively described in the literature ,11,12. PEven if this result does not allow for any far-reaching conclusions on the possible influence of the presence of a CRA on glaucoma, it can at least be speculated that the presence of an additional blood vessel influences the FD in NTG patients to a higher extent than in the other presented types of glaucoma for the reasons above-mentioned.Studies investigating POAG patients using OCTA have shown reduced FD around the optic nerve head compared to healthy controls. Furthermore, a correlation was identified between an increase in glaucomatous damage and a decrease in FD ,34.This is in line with our results. In our study, FD was negatively correlated with disease severity defined by MD. However, the degree of correlation differed between the macular and papillary regions. The RPC sectors were affected most severely by glaucomatous damage, followed by the SCP sectors and the DCP sectors. Consistent with our findings, Rao et al. reported that the FD of the RPC region could be used more reliably than macular FD to distinguish between healthy eyes and glaucomatous eyes . Taking Nevertheless, the effect of a CRA on the cup–disc ratio, IOP, and visual field defects has been investigated. The groups investigating this issue have found different results: no effect, a protective influence, or a harmful influence on glaucomatous damage have all been attributed to the presence of a CRA in glaucoma patients.In 2003, Budde et al. examined the influence of the presence and location of CRAs on rim loss and the progression of parapapillary atrophy in glaucoma patients after previous studies had suggested a correlation between the position of the central retinal vessel trunk and glaucomatous damage of the neuroretinal rim; no significant differences were found in the neuroretinal rim area between the CRA and non-CRA groups . FurtherIn addition to the hypothesis that a blood vessel may reduce optic nerve damage via mechanical stabilization, another approach concerns the possible alteration of the blood supply to the optic nerve by a CRA.In their 1988 study, Lindenmuth et al. investigated the relationship between CRAs and glaucomatous optic nerve changes. The study involved 122 individuals with POAG. No significant differences were found between the groups with and without a CRA regarding IOP, the cup–disc ratio, or visual field defects .In their analysis of 20 patients with POAG and unilateral CRAs, Shihab et al. showed a larger cup–disc ratio and more extensive visual field damage in patients with CRAs than in the group without CRAs. The authors assumed the reason for these observations to be the CRA’s ability to shunt blood away from the optic disc, leading to reduced perfusion. They speculated that while CRAs have no negative effect on the eyes of healthy patients, they could cause an increase in glaucomatous damage on the predamaged optic discs .In contrast, when Lee and Schwarzt compared two groups comprising a total of 34 glaucoma patients with and without CRAs, they found that patients with a CRA retained visual field and visual acuity more often. According to the authors, the role of a CRA may be to provide greater circulation to the temporal rim of the optic disc .Due to the small number of eyes included in these studies, Type I and Type II errors must be taken into account when evaluating the respective results. Thus, effects that actually exist may be overlooked or falsely assumed ,37.In our study, there were no noticeable differences in the FD between the CRA and non-CRA groups across all glaucoma types when adjusted for glaucoma severity. Subgroup analysis of the NTG patients showed evidence of a noticeable difference in FD at the SCP level between the two groups. We therefore suggest that the influence of CRAs on retinal perfusion in glaucoma patients in general is rather limited, but may be more important in NTG patients.In our study, the age, the gender ratio, IOP, MD and disease severity, distribution of glaucoma types, mean spherical equivalent, and QI did not differ noticeably between the CRA and non-CRA groups, making it improbable that these factors could have exerted a noticeable confounding effect on the OCTA imaging results. However, as OCTA represents a rather novel imaging technology, our study design might not have accounted for other as-yet-unidentified influencing factors. Furthermore, the spectral-domain technology used in this trial limited the possibility of the high-resolution angiography imaging of retinal layers other than the ones elaborated on. An investigation of choroidal FD using swept-source devices is of interest as both CRAs and choroidal arteries originate from the posterior ciliary arteries. Further longitudinal studies are needed in this regard.In conclusion, this investigation showed no noticeable difference in the FD between the CRA and non-CRA glaucomatous eyes when adjusted for glaucoma severity, suggesting that the presence of CRAs does not significantly affect retinal perfusion in glaucoma patients. In both the CRA and non-CRA eyes, increasing glaucoma severity correlated most strongly with a reduction in peripapillary FD. The results support the theory of a disturbed vascular regulatory mechanism in glaucoma patients with regard to the severity of glaucoma. OCTA may help in developing a better understanding of how blood supply might affect glaucomatous damage.


In this sense, most public policies and pragmatic activities targeting mothers and child nutrition relied upon the results of the 2006 Brazilian National Survey on Demography and Health of Women and Children (PNDS 2006) In Brazil, a large country with the largest economy in Latin America, a lack of evidence on maternal-child nutrition indicators remained for 13 years until the completion of the 2019 ,Over decades, Brazil had been classified as a country where anemia and vitamin A deficiency were moderate public health problems, especially affecting the most disadvantaged in the poorest areas. The ENANI-2019 showed that important progress in the reduction of both micronutrient deficiencies was accomplished since they are now classified as mild public health problems with striking reductions in the inequalities by region, maternal education, and race/skin color ,Regarding breastfeeding indicators, despite the non-significant increase in the prevalence over time, it still lags behind international targets for the promotion of optimal breastfeeding practices, such as the World Health Assembly target of at least 70% of children under 6 months of age being exclusively breastfed by 2030. However, advances were reported in the reduction of inequalities, such as the gap between regions, education levels, and race/skin color. Brazil shows a unique and incredible trajectory regarding breastfeeding promotion, including the successful experience with human milk banks and proper work leave to women after childbirth The findings for child anthropometric indicators are intriguing. Over the last decade, no progress has been documented regarding the reduction of malnutrition among children under 5 years old in Brazil Previous Brazilian household surveys have not collected the necessary information to generate internationally relevant child feeding practices indicators. The ENANI-2019, brought attention to the topic on the newly recommended World Health Organization/United Nations Children’s Fund (WHO/UNICEF) feeding indicators by reporting the high prevalence of children who consumed ultra-processed foods, along with the fact that a quarter of children did not consume any fruits and vegetables in the day previous to the survey ENANI-2019 also shows remarkable improvements in demographic characteristics that are directly associated with the indicators studied in the analysis. The changes over time reported by Castro et al. In conclusion, while old public health and nutrition problems must be closely tracked, including the prevalence of stunting and micronutrient deficiencies, new challenges emerge as society progresses, such as the increasing prevalence of overweight and the high consumption of ultra-processed foods among Brazilian children. This epidemiological scenario highlights the importance of health policies based on solid findings. The ENANI-2019 filled the 13 years gap in the evidence on maternal-child nutrition in Brazil and allowed cross-country comparisons of children’s nutritional status as part of international efforts to promote health and well-being of societies, such as the SDG. Monitoring novel public health problems that threaten past achievements , including the COVID-19 pandemic, is imperative and urges the necessity of standardized data periodically produced. A new edition of the ENANI is planned for 2024 and will help monitor the advances made in Brazil for reducing the burden of malnutrition and promoting optimal feeding practices among children under 5 years old.


The stomach is extensively innervated by the vagus nerve and the enteric nervous system. The mechanisms through which this innervation affects gastric motility are being unraveled, motivating the first concerted steps towards the incorporation autonomic regulation into computational models of gastric motility. Computational modeling has been valuable in advancing clinical treatment of other organs, such as the heart. However, to date, computational models of gastric motility have made simplifying assumptions about the link between gastric electrophysiology and motility. Advances in experimental neuroscience mean that these assumptions can be reviewed, and detailed models of autonomic regulation can be incorporated into computational models. This review covers these advances, as well as a vision for the utility of computational models of gastric motility. Diseases of the nervous system, such as Parkinson’s disease, can originate from the brain-gut axis and result in pathological gastric motility. Computational models are a valuable tool for understanding the mechanisms of disease and how treatment may affect gastric motility. This review also covers recent advances in experimental neuroscience that are fundamental to the development of physiology-driven computational models. A vision for the future of computational modeling of gastric motility is proposed and modeling approaches employed for existing mathematical models of autonomic regulation of other gastrointestinal organs and other organ systems are discussed. In silico investigations of gastric motility have been used to bridge the understanding of the interactions between the neural and myogenic components of gastric motility and their implications in pathological developments. In particular, using simulations based on sound biophysical principles and specific experimental data, it is possible to simulate normal and pathological gastric electrophysiology and estimate biomarkers which match these scenarios. However, in these models the role of regulatory mechanisms, like the autonomic nervous system, has been omitted. Simplifying assumptions about the link between gastric motility and electrophysiology have been made in these models, however, with a burgeoning corpus of physiological research it is now possible to revise these assumptions and explore the impacts of autonomic regulation within a mathematical modeling framework  motility is driven by complex interactions between nerves and myogenic electrophysiological mechanisms. Investigations have uncovered the physiological mechanisms of interaction between enteric nerves and interstitial cells of Cajal (ICC) as gastrointestinal pacemaker cells , 2022. Iramework .The core of the ICC network exists in the myenteric (ICC-MY) and submucosal plexus (ICC-SM), with further intramuscular ICCs (ICC-IM) situated within the circular (ICC-CM) and longitudinal muscle layers (ICC-LM). ICC-IM are aligned with the muscle direction in their respective layers. ICC also exist in other GI organs, but their distribution varies. In general, one of the key physiological functions of ICC is to generate the major component of the gastric slow wave which controls rhythmic contractions of GI smooth muscle cells (SMCs) . As a reBioelectrical depolarization of SMC causes an influx of calcium ions and initiates a cascade of actions that lead to the contraction of muscle filaments . It is gThe brain-gut axis is used to label the plethora of interactions between GI organs and the brain. These interactions are mediated through the autonomic nervous system, of which the ENS is a part, and through the endocrine system . The effin vivo stimulation, Extrinsic innervation of the stomach is chiefly provided by the vagus nerve though some sympathetic neurons originating in the T6-T9 level (thoracic) of the spinal cord innervate densely innervate gastrointestinal sphincters adjacent to the stomach . DetaileThe central nervous system influence on the upper gastrointestinal tract, including the stomach and esophagus, is complemented by reflexive control mediated at the level of the brainstem, termed vago-vagal reflexes. Afferent vagus nerve signaling to the nucleus tractus solitarius is integrated by neurocircuitry in the brainstem, and reflexes are relayed via efferent vagus neurons which originate at the dorsal motor nucleus of the vagus nerve. The gastric accommodation reflex results in a relaxation in gastric smooth muscle to accommodate food intake upon the distension of the proximal stomach. Another reflex, the esophagogastric reflex, results in gastric distension in response to stretch of the distal esophagus . The natin silico simulations. A previous review has covered aspects related to neuromodulation modeling of the gut  modeling and network modeling are the two main approaches for simulating multi-cellular level events. The bidomain model has widely been used to model the propagation of electrical activity across the heart, where investigations have focused on the detailed relationship between tissue structure and function . Recent An early example a whole stomach model  used an t). Mathematically this is expressed byThe bidomain model models the flow of current between an intracellular and extracellular domain. The bidomain model was initially extensively used to model the propagation of bioelectrical events across the heart . As noteion) and current due to membrane capacitance, we can form two equations for the bidomain model,where ∇⋅ is the divergence operator and ∇ is the vector gradient operator. Since total membrane current is composed of ionic current  . There iSecondary clinical applications can include generating hypothetical gastric signatures for far-field body-surface mapping investigations . The whoOne clinical application of computational physiology models is in closed loop control of neurostimulation devices . Closed-In conclusion, gastric functions are highly dependent on activity from the vagus nerve and enteric nervous system, yet the exact interactions between the gut and brain remain under-investigated. Advances in experimental and computational techniques will lead the development of predictive multi-scale models that can be used to explore the impacts of various pathological conditions related to the brain-gut axis and generate potential treatment targets for the next generation of neuromodulation devices.OA, RA, LC, and PD were involved in all aspects of manuscript preparation. All authors contributed to the article and approved the submitted version.