Cervical cancer is one of the fourth most common gynecological malignancies and has been identified as the fourth leading cause of cancer death in women worldwide. MicroRNAs (miRNAs) are single-stranded sequences of noncoding RNAs that are approximately 22-24 nucleotides in length. They modulate posttranscriptional mRNA expression and play critical roles in cervical cancer. Single nucleotide polymorphisms (SNPs) in miRNA genes may alter miRNA expression and maturation and have been associated with various cancers. This review mainly focuses on the roles of SNPs in miRNA genes in the development of cervical cancer and summarizes the research progress of miRNA SNPs in cervical cancer and their molecular regulation mechanisms. For example, miRNAs may function as oncogenes or tumor suppressors to regulate the occurrence and development of cervical cancer through special signaling pathways, including the PI3K-AKT pathway Studies have reported that SNPs in pri-miRNA and pre-miRNA genes may interfere with the maturation process or degradation of miRNAs by destroying the secondary structure, reducing the number of mature miRNAs and affecting the expression of mature miRNAs et al. reported that the SNP rs4938723 in the promoter of pri-miR-34b/c was significantly associated with cervical cancer, and the C allele was a risk factor for cervical cancer in a Chinese Han population. In addition, the CT genotype was significantly associated with the clinical staging and poor prognosis of patients MiR-34 is considered to be the first miRNA that is directly regulated by p53, and it has been reported to be dysregulated in many types of cancer et al. found that the SNP rs11134527 in miR-218 was associated with cervical cancer in a Chinese Han population, and the GG genotype can reduce the risk of cervical cancer et al. showed that the SNP rs11134527 was associated with the development of CIN in cervical cancer in a Chinese Han population, and the A allele of rs11134527 was associated with a lower risk of CIN MiR-218 is encoded by the intron of the SLIT2 tumor suppressor gene et al.'s study found that the SNP rs895819 located in the promoter of pre-miR-27a has a significant association with the risk of cervical cancer in a southern Chinese Han population et al. reported that the SNP rs895819 was associated with cervical cancer in a dominant genetic model in a southern Chinese Han population et al. reported that overexpression of miR-27a upregulates the expression of B4GALT3, promotes carcinogenic activity through the β1-integrin pathway, and may be a potential biomarker for cervical cancer Previous study found that miR-27a was highly expressed in cervical cancer tissues and in HeLa and C33A cells et al. reported that the G allele of the SNP rs531564 in the promoter of miR-124-1 was a protective factor in cervical cancer in a Chinese Han population et al. showed that the C allele of rs531564 was the risk allele of cervical cancer in a Chinese Han population, and this SNP was related to the progression from CIN to cervical cancer et al. found that miR-124 can inhibit the mimicry and cell movement of angiogenesis by targeting amotL1 et al. found that miR-124 negatively regulates the target lncRNA NEAT1 and affects the migration and invasion of HeLa cells, EMT and activation of the NF-κB pathway Mature miR-124 is processed by pre-miR-124-1, pre-miR-124-2 and pre-miR-124-3, all of which have reduced expression in a variety of tumor tissue types et al. reported that rs4636297 in miR-126, which was located 12 bp downstream of the pre-miR-126 sequence, was associated with CIN and cervical cancer in a Chinese Han population et al. indicated that the T allele confers a higher risk of developing CIN and cervical cancer Several studies have found that miR-126 is usually underexpressed in human colorectal cancer et al. reported that the SNP rs1625579 in the intron of pre-miR-137 was associated with a significant reduction in the risk of cervical cancer in a Sourthern Chinese population. Compared with the TT genotype, the TG and GG genotypes had a better protective effect on cervical cancer patients MiR-137 is underexpressed in cervical cancer tissues and cell lines and can inhibit the development of tumors et al. detected the expression of miRNAs in six types of cervical cancer cell lines and normal cervical samples, and they found that cancer samples can repeatedly show increased miR-21 expression et al. reported that there were significant differences in the alleles and genotypes of rs1292037, which is located 210 bps from the 3' end of pre-miR-21, in cervical cancer patients in the sensitive and resistant groups. The rs1292037 locus with the G allele in the miR-21 gene may increase the resistance of cervical cancer patients to cisplatin plus paclitaxel l in a Northern Chinese population et al. confirmed that miR-21 was significantly overexpressed in human cervical squamous cell carcinoma tissues and cell lines and found that miR-21 regulates the proliferation, apoptosis and migration of HPV16-positive cervical squamous cells by regulating the expression of the target gene CCL20et al. reported that the overexpression of miR-21 inhibited the expression of the mRNA of the target gene PTEN in cervical cancer cell lines to promote the proliferation, migration and invasion of cervical cancer cells et al. detected the sensitivity of cervical cancer cells to paclitaxel and found that the inhibited expression of miR-21 can inhibit cell proliferation and colony formation by regulating the PTEN/AKT pathway and improve the PTX sensitivity of cervical cancer cells Lui et al. reported that for the polymorphic site rs2292832 of miR-149 in cervical cancer tissues and HeLa and SiHa cells, the TC and CC genotypes increased the risk of cervical cancer compared with the TT genotype The expression of miR-149 is upregulated in cervical cancer tissues and cells The reason behind the association of SNPs with cervical cancer could be because SNPs located in pre-miRNAs may affect the expression of mature miRNAs and be involved in the binding of certain nuclear factors to miRNAs during miRNA processing.et al. found that the expression of miR-146a was upregulated in HeLa cervical cancer cells and C33A cells, and the rs2910164 SNP increased the amount of mature miRNAs in cervical cancer cells. Similarly, Li et al. reported that miR-146a can act as an oncogene, affect the expression of the target gene TRAF6 and regulate the differentiation of Th17 cells through NF-κB signaling to regulate the growth and apoptosis of cervical cancer cells MiR-146a is abnormally expressed in a variety of cancers et al showed that the T allele in the SNP rs11614913 was associated with a reduced risk of cervical cancer development in an Indian population et al. in a Chinese Han population were consistent with those of Nisha et al. Previous studies reported that the expression of miR-196a in human cervical cancer tissues and cell lines was significantly upregulated Therefore, the abnormal expression of miRNAs may directly or indirectly affect the expression of many target genes, and the expression levels of these target genes will also dynamically change under various cell and environmental stimulations. Combining these changes with SNP-related miRNA-level regulation can provide important internal mechanisms for disease development.The occurrence of tumors is the result of the abnormal regulation of signaling pathways related to cell proliferation, differentiation, apoptosis, and the cell cycle. Mutations in the genes that affect different cell signaling pathways could play important roles in the mechanisms of the occurrence and development of cervical cancer. Many studies have found that mutations in miRNA genes may affect the combination of mature miRNAs and downstream target genes by affecting miRNA expression, thereby affecting the regulation of signaling pathways and playing an important role in the occurrence and development of cervical cancer. This review summarizes the SNP sites of miRNAs related to cervical cancer, lays a foundation for in-depth research on the pathogenesis of cervical cancer and identifies new targets for the diagnosis and treatment of cervical cancer.


Homing peptides and cell-penetrating peptides allow for systemic targeting of diseased tissues and/or efficient intracellular delivery of payloads. The translational potential of peptides as targeting ligands is strengthened by their small size, low immunogenicity, and biocompatibility. Whereas early studies on homing and cell-penetrating peptides focused on cancer delivery, a number of other disease indications have been demonstrated to be targetable with the peptides for improved diagnosis and therapy.The original contributions in this Special Issue address the development of internalizing peptides as facilitators of intracellular cargo uptake ,2,3 as wThe field of peptide-guided drug delivery is a vibrant multidisciplinary research area and this Special Issue serves to present a number of important advances in as outlined below.An intriguing study from the laboratory of Dr. Hongbo Pang at University of Minnesota (USA) investigated whether a co-incubation with the cell-penetrating peptide transportan can facilitate cellular uptake of cargo compounds . This moA study by Dr. Rafael Morán-Torres et al. at National Autonomous University of Mexico deals with development of short selective cell-penetrating peptides, referred to as “moonlighting peptides” . The autIn another original report in the current Special Issue , the teaTwo studies in this Special Issue deal with applications of homing peptide called CAR (amino acid sequence: CARSKNKDC), which was originally reported to target neovasculature in injured regenerating tissues. CAR recognizes the unique sulfation pattern of heparan sulfate proteoglycans on the target cells. The first study  coordinaIn the second study on CAR-mediated systemic targeting, Iqbal et al. used the peptide for precision delivery of therapeutic antifibrotic TGF-β modulator Decorin to skeletal muscle to slow progression of a mouse model of muscular dystrophy .Development of contrast agents remains challenging due to lack of sensitivity, low signal to noise ratio, and/or difficulty in tissue penetration in the case of optical imaging agents. The work by the team of Dr. Juliana Hamzah and colleagues from the Harry Perkins Institute of Medical Research and Curtin University  reported development of iron oxide nanoparticles functionalized with CSG peptide to detect tumor stroma, based on the over-expression of laminin-nidogen-1 complex that is recognized specifically by the CSG peptide . The autIn a paper by Hingorani et al., the authors report development of activatable cell-penetrating peptide conjugate for delivery of resiquimod, a TLR 7/8 agonist that has antitumor efficacy [In the study by Saghaeidehkordi et al., the authors targeted breast cancer cells with homing peptide 18-4 that targets cell surface Keratin 1 [The reports in this Special Issue are important advances that illustrate the multifaceted and interdisciplinary efforts on development of peptide-based strategies for precision-guided therapy and diagnosis of disease. We wish to thank all the authors of this Special Issue for contributing their high-quality research and for the critical evaluation of their manuscripts.


Most intervention programs in the dementia domain have exclusively focused on the caregiver (CG) or the patient (CR), despite evidence of a reciprocal interaction between the dyad. This presentation will describe a randomized controlled trial that is evaluating the feasibility and efficacy of an innovative dyadic intervention (DT) that is delivered through an interactive technology that includes an evidenced-based CG component, an evidenced-based cognitive training component for the CR and a dyadic component. The program is designed to: be synergistic and emphasize issues important to CGs in the earlier stages of caregiving. The sample involves 200 informal CGs and CRs with early-stage dementia. Data will be presented regarding factors influencing the feasibility of implementing a dyadic intervention such as recruitment challenges , and mutual engagement of both the CG and CR. Strategies implemented to maintain the trial during the COVID-19 pandemic will also be discussed.


A 9-year-old male child was brought by his father to the emergency department of the hospital with chief complaints of swelling on the left half of the abdomen since birth. The father of the child told that he had swelling of small size at birth which started gradually increasing in size for 18 months and then it was static up to 6 years of age. Later it again started increasing in size and now it has occupied the entire left abdomen. On clinical examination, the swelling was soft in consistency, non-tender with mild reddish-blue discolouration of overlying skin and no local rise of temperature. There was no pus discharge and itching over the swelling. For further investigation child was referred to the department of radiodiagnosis for contrast-enhanced computed tomography and ultrasonography of the abdomen. On computed tomography multiple varied size hypodense areas, most of them communicating with each other seen in the subcutaneous plane of anterior abdominal wall more on left side extending from left hypochondrium to left lumbar region inferiorly and crossing midline reaching right hypochondrium laterally on the posterolateral aspect of the abdominal wall. Few areas showed hyperdense content within with no significant enhancement on all post-contrast phases. On ultrasound, multiple cystic anechoic areas with internal debris independent part and showing no vascularity were noted.


The original version of the article contained inaccuracies in the Ethics declarations.The Ethical approval and the Statement of human rights are replaced by the following disclosure.Ethical approvalAll procedures performed in the case report involving human participant were in accordance with the ethical standards of Soonchunhyang University Cheonan Hospital and with Helsinki Declaration (1964) and its later amendments or comparable ethical standards. This study was approved by the Institutional Reviewer Board (IRB) of Soonchunhyang University Cheonan Hospital (IRB No. 2020-07-043).Also the article reports on findings that were presented at the ISCEV Symposium in Miami in 2017 and published in our journal (


This article has been corrected to remove images of the BREAST-Q scales . Permission to use the BREAST-Q is granted by way of a license agreement, signed by the intended users. The license agreement prohibits the reproduction of the BREAST-Q in publications or any other public documents. The authors of this article violated the license agreement by reproducing the BREAST-Q scales in the Appendix of this article. As a result these images have now been removed.


Al Mandhari, Regional Director, WHO Regional Office for the Eastern MediterraneanWHO defines self-care interventions as a variety of tools which can be accessed and used by individuals with or without the direct supervision of a health worker. Advances in evidence-based health information, medicines, diagnostics, products and technologies have increased the potential for self-care interventions to increase health coverage for promotive, protective, preventive, curative, rehabilitative and palliative needs of individuals, families and communities. The increasing demand for sexual and reproductive health (SRH) services in the Eastern Mediterranean Region (EMR) and the importance of ensuring universal health coverage (UHC) including coverage, quality and financial protection for SRH also highlights the need for engagement of WHO Member States in the EMR.The 2019 WHO consolidated guideline on self-care interventions for health (“Guideline”) contains evidence-based recommendations and good practice statements on Sexual and reproductive health and rights (SRHR) [Successful introduction and uptake of self-care interventions at the country level will depend on an interplay of factors linking these two pathways, but also on elements that lie beyond the control of individuals and the traditional scope of the health sector. Translating these complex, multilevel and critical changes into effective policy measures requires high levels of commitment and engagement from diverse and relevant partners. Experiences from regions and countries are also needed to make clear what public goods are available to policy-makers, programme managers, health workers and laypersons for harnessing the potential contribution of self-care interventions.The work undertaken by the WHO Regional Office for the Eastern Mediterranean (EMRO) is an example of how this process can be approached. In 2019, WHO EMRO held several regional- and national-level discussions to disseminate the Guideline and consultative meetings and workshops on integrating self-care interventions for SRH in national health policies, programmes and practices in the EMR. Access to health is undermined by critical shortages of human and financial resources as well as lack of security of SRH essential medicine and commodities in many countries of the region, in addition to tangible physical and logistical barriers and the disruption and insecurity caused by humanitarian emergencies . FollowiSeveral themes appear across the papers and outline three priority steps for a dynamic approach to national-level policy changes that can ultimately accelerate strengthening and advancing SRHR Fig. . While aFirstly, political will and leadership and multi-stakeholder partnerships are required. One example of how catalyzing the political will to act can lead to effective, positive change is shown in the key role played by parliamentarians  to promote innovative self-care interventions through their legislative, budget allocation, oversight and advocacy roles. Public sector ownership and patronage  in advocating for better national policies has also been shown to be effective in enabling introduction of self-care interventions.A second step towards effectively enabling self-care interventions is protecting people’s human rights irrespective of their socioeconomic background, gender, sexual orientation or age in ensuring quality of care. The work of community pharmacists  in increasing coverage of self-care interventions through counselling and over-the-counter access to essential medicines demonstrates how accessing services in pharmacies and outside of traditional health facilities can expand the reach of health services to even the most vulnerable populations. Moreover, even during the pandemic, rights-based approaches to healthcare delivery can improve health outcomes of men who have sex with men , and point to the need to further support policy changes in task-shifting. From a public health perspective, it is advantageous for licensed products to be available over the counter, and the readiness of national regulatory guidelines could lead to increased access, availability and usage of essential self-care interventions . This in turn contributes to ensuring a rights-based foundation for the introduction of self-care interventions.Thirdly, the papers highlight the importance of evidence-based normative guidance, because they provide trustworthy, reliable sources to inform health decision-making for policy-makers, health workers and laypersons. Results from the regional component  of a global cross-sectional values and preferences survey give a glimpse of the knowledge and priorities of laypersons and health workers around access, use and uptake of self-care interventions for SRH. Policy-makers can consider the participant narratives regarding the need to consider both the heterogeneity of self-care interventions and the needs and lived experiences of diverse populations to ensure that the policies reflect the priorities and needs of people .The papers included in this supplement provide concrete examples of how policy action leading to implementation of self-care interventions in the EMR can lead to tangible, positive shifts in healthcare delivery. This starts with a constructive policy debate to understand how self-care interventions fit in the context of health, community and policy systems . Policy-Evidence on the patterns of use and uptake of health services and on the effectiveness of specific self-care interventions is not enough to develop effective policies. It must come with better evidence on what strategies work to enhance the capacities of individuals and communities to access quality self-care interventions. A structure to support further research that includes stakeholder values and identification of core gender, equity and human rights standards and principles can strengthen the evidence base . Strong Several of the papers in this supplement highlight the importance of training health workers to promote and counsel on the use of self-care interventions . This will involve training and development of competencies that go beyond biomedical approaches or a disease focus to a more empathetic and compassionate mindset which considers the person at the centre of care and leverages and understands the need for demonstrable supportive attitudes, adequate knowledge and skills; and codes of conducts and specific trainings to eliminate the current power dynamics between health workers and clients. People in different settings and circumstances have varying abilities to access health services, and the ability to promote self-care interventions in populations who may be stigmatized or marginalized and/or lack trust in existing health systems, and to support them as needed with quality care, has the potential to improve health and equitable distribution of healthcare.Another area of importance is facilitating the linkages between digital and self-care interventions. Although digital health technologies are growing rapidly, access is likely to be unequal due to the digital divide. Closing this gap will require action from policy-makers to ensure sustainable, safe and ethical use of technology in the health sector. Evidence-based, high-quality self-care interventions can be delivered via digital technologies and can offer effective alternatives to some face-to-face interactions with providers. During the COVID-19 pandemic, for instance, such innovative approaches using digital platforms allow health systems to better maintain the delivery of essential SRH services .The experience provided in the papers from this supplement can help other countries accelerate progress on self-care interventions in SRHR. Rapid introduction and scale-up of self-care interventions can be a game-changer for accelerating positive health impact through sustainable action at the local level that is driven by the health needs of people. The examples highlighted from the EMR show how individuals can be are enabled to play an active role in improving their own health , engage successfully with community action for health , and push governments to meet their responsibilities in addressing health and health equity . For policy-makers, self-care interventions are important for responding to people’s priorities, needs and rights with regard to health. Ensuring availability of quality, regulated self-care interventions is part of the duty of policy-makers to protect their constituencies against harmful or exploitative practices. Despite the diversity of the countries in the EMR, the opportunities and challenges in the regional examples show the need for quality data  to inform how the public health community and policy-makers could not just improve health outcomes, but also transform health systems through self-care interventions. Self-care interventions for SRH is crucial component of health systems and their availability is a pre-requisite to ensure SRH service delivery responds to people’s needs and rights to reach UHC.


The activity of the left and right central pattern generators (CPGs) is efficiently coordinated during locomotion. To achieve this coordination, the interplay between the CPG controlling one leg and that controlling another must be present. Previous findings in aquatic vertebrates and mammalians suggest that the alternate activation of the left and right CPGs is mediated by the commissural interneurons crossing the midline of the spinal cord. Especially, V0 commissural interneurons mediate crossed inhibition during the alternative activity of the left and right CPGs. Even in humans, phase-dependent modulation of the crossed afferent inhibition during gait has been reported. Based on those previous findings, crossed inhibition of the CPG in one leg side caused by the activation of the contralateral CPG is a possible mechanism underlying the coordination of the anti-phase rhythmic movement of the legs. It has been hypothesized that the activity of the flexor half center in the CPG inhibits the contralateral flexor half center, but crossed inhibition of the extensor half center is not present because of the existence of the double limb support during gait. Nevertheless, previous findings on the phase-dependent crossed inhibition during anti-phase bilateral movement of the legs are not in line with this hypothesis. For example, extensor activity caused crossed inhibition of the flexor half center during bilateral cycling of the legs. In another study, the ankle extensor was inhibited at the period switching from extension to flexion during anti-phase rhythmic movement of the ankles. In this review article, I provide a critical discussion about crossed inhibition mediating the coordination of the anti-phase bilateral rhythmic movement of the legs. Anti-phase bilateral rhythmic movement is produced during locomotion in mammals. The central pattern generators (CPGs) produce the rhythmic movement of the limbs Guertin, . PreviouThe CPGs in the spinal cord produce locomotion in mammals Brown, . Even inIn rats, locomotor activity in each side of the limb was produced even the spinal cord was separated with a midline cut (Kudo and Yamada, Even though the CPG on each side of the spinal cord is possible to produce rhythmic movement in each leg separately, activity of the left and right CPGs must be coordinated during locomotion in humans, according to an observation that humans move the legs coordinately during gait Perry, . PreviouV interneurons, and inhibitory V0D interneurons. The role of the V0 commissural interneurons on the left-right alternation of the motor output is dependent on the frequency of the locomotion cycle (Talpalar et al., V interneurons maintained an alternate activity at low-frequency cycle of locomotion, but switched to a synchronized activity at high-frequency cycle of locomotion (Talpalar et al., V commissural interneurons play a role in the left-right alternation during the high-frequency cycle of the locomotion. In contrast, ablation of the inhibitory V0D interneurons eliminated the left-right alternation at low-frequency cycle of the locomotion, but maintained it at high-frequency cycle of the locomotion (Talpalar et al., D interneurons play a role in the low-left-right coordination of the low-frequency locomotion.V0–V3 commissural interneurons represent the classes of the postmitotic spinal interneurons based on the transcription factor expression (Butt et al., D interneurons receive exaction from the ipsilateral flexor centers and inhibit the contralateral flexor half center (V commissural interneurons are involved in two possible connections. One is that the excitatory V2a interneurons receive excitation from the ipsilateral flexor center and excite V0V interneurons but inhibit contralateral flexor half center through the inhibitory interneurons (V interneurons, and then, V0V interneurons excite the contralateral flexor half center (The pathways mediating the alternate activity of the half centers during locomotion have been proposed by a computational model (Rybak et al., f center . On the rneurons . Anotherf center . Taken tAccording to the discussion above, the alternate activity of the left and right CPGs is likely mediated by crossed inhibition between the CPGs; activity of the half center on one side inhibits the contralateral half center. Crossed inhibition induced by the activity of the CPG in one leg has been examined by observing the effect of the rhythmic movement of one leg on the soleus H-reflex in the contralateral leg at rest in humans. The soleus H-reflex at rest was suppressed by the contralateral leg cycling in the flexion phase and the end of the extension phase (McIllroy et al., However, those previous findings on the unilateral rhythmic movement are not direct evidences indicating the mechanism underlying the coordination of the leg movements during the anti-phase bilateral rhythmic movement during which both left and right half centers are alternately activated. In addition, we have to note supraspinal influence on crossed inhibition during unilateral movement. Unimanual activation of one finger muscle increases interhemispheric inhibition from the active hemisphere to the resting hemisphere (Vercauteren et al., In humans, one important neural event indicating the existence of the inhibitory pathways crossing the midline of the spinal cord is crossed afferent inhibition. The soleus H-reflex in the leg at rest was suppressed by the conditioning stimulation of the tibial nerve in the contralateral leg given 3–33 ms after the test stimulus (Stubbs et al., Soleus H-reflex amplitude is suppressed by the contralateral cutaneous stimulation of the dorsum of the foot in the early stance phase of gait (Suzuki et al., Such crossed afferent inhibition is possible to be induced by passive movement of the contralateral leg. For example, passive rhythmic movement of one leg suppressed the contralateral soleus H-reflex at rest (McIllroy et al., Based on those findings, the activity of one half center is inhibited not only by the active rhythmic movement of the contralateral leg, but also by the passive rhythmic movement of that. The somatosensation is induced, but the CPG is inactive during passive movement. It has been stated that the CPG is capable of reorganizing the sensory input to reconfigure itself to evoke the appropriate pattern Frigon, . AccordiAs discussed above, crossed inhibition of the contralateral CPG is a possible mechanism underlying the anti-phase bilateral rhythmic movement. Crossed inhibition is supposed to be achieved through mutual inhibition between the extensor half centers, between the flexor half centers, or between the extensor half center and contralateral flexor half center (see “Crossed Pathways” section and D commissure interneurons proposed by Rybak et al. and Danner et al. (Rybak et al., This hypothesis by Dietz was supported by a previous finding on the split-treadmill gait (Yang et al., In human experiments, crossed inhibition of the CPG during activity of the contralateral CPG has been examined by comparing the motor output between the unilateral and bilateral rhythmic movements. For example, peak power during unilateral cycling was greater than that during the anti-phase bilateral cycling (Dunstheimer et al., V commissural interneurons (Previous findings on the phase-dependent inhibition of the rhythmically moving one leg induced by the rhythmic movement of the contralateral leg were not in line with the hypothesis proposed by Dietz. For example, during bilateral anti-phase cycling, the activity of the tibialis anterior, biceps femoris, and rectus femoris muscles in the flexion phase was less than that during the unilateral cycling of the tested leg (Ting et al., rneurons . HoweverAnother previous study had tested the soleus H-reflex of the rhythmically moving ankle with and without rhythmic movement of the contralateral ankle (Hiraoka et al., A previous study reported that the soleus H-reflex during bilateral leg cycling was not significantly different from that during the unilateral cycling of the leg contralateral to the tested side (McIllroy et al., An important finding in the previous study by Hiraoka and colleagues is that such phase-dependent inhibition was not present during the in-phase movement of the ankles. This finding suggests that crossed inhibition during the switching period of bilateral rhythmic movement is particularly present during the anti-phase bilateral movement. It has been suggested that the control process of the in-phase bilateral movement of the hands is different from that of the anti-phase movement (Shih et al., Because pre-stimulus background muscle activity level was equivalent between the conditions in this previous study by Hiraoka and colleagues, suppression of the soleus H-reflex during bilateral rhythmic movement observed is likely presynaptic origin. In humans, rhythmic leg activation during gait was greatly controlled by presynaptic inhibition (Stein and Capaday, The conflict between the finding by Hiraoka and colleagues and the finding by Ting and colleagues may be due to the difference in the measurement of the motor status. The experiment by Ting and colleagues observed the EMG and force. Thus, the finding indicates the direct inhibition of the motoneurons causing the decrease in the motor output. In contrast, the experiment by Hiraoka and colleagues observed the suppression of the H-reflex with equal EMG activity. Thus, the finding in the study by Hiraoka and colleagues indicates the inhibition of the excitatory synaptic transmission to the motoneurons. This process is not direct inhibition of the motoneurons, and thus, does not indicate the change in the motor output. Such difference may be related to the conflicting findings between the studies.In the studies on bilateral coordination in humans, as introduced in the present study, actual locomotion is not performed; pedaling movement (Ting et al., The mesencephalic locomotor region and the lateral hypothalamus project to the reticulospinal neurons, and those neurons project to the spinal cord for activating the CPGs (Jordan et al., In this article, previous studies on the phase-dependent crossed inhibition underlying the anti-phase coordination of the rhythmic movement of the legs were reviewed. V0 commissural interneurons mediating crossed inhibition of the contralateral half center likely contribute to the alternate activity of the left and right CPGs. Crossed inhibition of the contralateral leg motor system has been reported in previous studies in humans. Accordingly, alternate activity between the left and right CPGs may be coordinated by crossed inhibition of the spinal cord in humans. On the one hand, a previous finding suggested that the flexor half center is inhibited during the activity of the contralateral extensor half center. On the other hand, another recent study indicated that the extensor half center is inhibited at the period switching the activity from the extensor to flexor half center while the contralateral limb is at the period switching the activity from the flexor to extensor half center. Future studies are needed for further insight into those findings.KH wrote this article.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Since Nd is the most abundant lanthanide element with a magnetic moment, the Nd-Fe-B magnet was considered as the final solution in the permanent magnet industry. However, this material had a poor high-temperature performance, particularly low coercivity. To deal with this weakness, heavy rare earth elements (HREE) such as Tb and Dy have been used to improve the coercivity, which raised another issue arising from the criticality of HREE. This raised worldwide attention about a decade ago, and the development of advanced permanent magnets with less critical metals have become active all over the world. As a result, new knowledge and technologies concerning the material science of the high-performance rare earth magnets have been acquired in the last decade.Permanent magnet is one of the most important industrial materials in modern society and its function is to generate magnetic flux in a space without any supply of energy. The most powerful and commercially important permanent magnet today is the Nd-Fe-B magnet that appeared in 1983. This material is composed of an iron-based hard magnetic compound, Nd2Fe14B. A blind search with only human experiences over numerous compositional and processing parameters has been proved to be insufficient after decades of research.The science and technology of permanent magnets contain a wide spectrum of disciplines from physics of magnetism, phase equilibria and process sciences. The functionality of a permanent magnet comes from the large hysteresis of magnetization, which is a typical structure-dependent phenomenon. Permanent magnets are normally used in the second quadrant of the hysteresis below the external field called ‘coercivity’ at which magnetization reversal occurs. So, the major issue in the development of permanent magnets has been how to achieve high coercivity by controlling the microstructure of the alloys that contain a hard magnetic compound as a major constituent phase. Another important activity in permanent magnetism is the search for new hard magnetic compounds whose intrinsic hard magnetic properties are comparable or superior to those of NdToday, the science and technology of permanent magnet materials is in a totally different stage as compared to the situation a decade ago. The first-principles calculations of the ground state magnetism of rare earth magnetic compounds are now possible with great precision and finite-temperature magnetic behaviors are now handled considering the contributions of phonons in the electronic calculations on one hand and by using effective atomistic spin models in mesoscopic scales combined with micromagnetic stochastic simulations or thermodynamic Monte Carlo simulations on the other. The fundamental understandings of microstructures and local magnetic properties have been completely renewed in the case of the Nd-Fe-B magnet by the use of advanced analytical technologies for atomic-resolution structural, chemical, and magnetic properties.The selection of authors in this Focus Issue is biased to Japanese institutes. Instead of trying to take an international balance, this Focus Issue attempted to update the activities in two decade-long national projects in Japan, namely, Elements Strategy Initiative Center for Magnetic Materials (ESICMM) under the subsidy of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and the Technology Research Association of Magnetic Materials for High-Efficiency Motors (MagHEM) under the subsidy of the Ministry of Economy, Trade and Industry (METI). The majority of contributions to this Focus Issue are from ESICMM, which has been given the role of laying out the scientific bases of permanent magnets rather than industrial developments.12-type rare earth magnets which are attracting attention due to their intrinsic magnetic properties superior to those of Nd2Fe14B. The paper by Trinh et al. from Kyoto University reviews the synthesis of mesoscopic particles of rare-earth permanent magnet compounds via a chemical route from nano-sized precursors. One area that has shown marked advances in the past decade is the theoretical understandings of coercivity on the basis of atomistic spin models of the rare earth permanent magnets constructed from information obtained by the first-principles calculations. Ghoda from Tokyo Institute of Technology summarizes the recent advances in the large-scale first-principles computation of atomistic structure and magnetic properties of near grain-boundary interfaces in Nd-Fe-B and SmFe12-SmCu systems. The paper by Tsuchiura et al. from Tohoku University reviews finite temperature magnetic properties in equilibrium and the switching field of the magnetization of particles, based on an atomistic spin model. The paper by Miyashita et al. from The University of Tokyo describes advances in the theoretical computation of finite-temperature dynamics of magnetization process and thermodynamics associated with coercivity phenomena in the spin model. The paper by Okamoto from Tohoku University summarizes the advances in experimental approaches for micromagnetic measurements and analysis of the coercivity mechanism. The paper by Miyake et al. from AIST is a review of the high-precision first-principles calculation of the stability and magnetic properties of the rare earth permanent magnet compounds. The paper by Abe et al. is a brief summary of combined studies of equilibria experiments and theoretical calculations for the construction of a prototype database for thermodynamic assessments using the Calphad-type methods to describe important features of production processes of the multi-component Nd-Fe-B-type permanent magnets.The paper by Li et al. from NIMS addresses the most frequently asked questions about the coercivities of Nd-Fe-B permanent magnets by summarizing the advances in the understanding of microstructure–coercivity relationships of Nd-Fe-B based permanent magnets. The paper by Koyama and Tsukada from Nagoya University and Abe from NIMS describe the recent understandings of the thermodynamics of formation of the thin intergranular phase, which is necessary to achieve a high coercivity in Nd-Fe-B magnets. The paper by Takahashi, Sepehri-Amin and Ohkubo from NIMS reviews the development of the Fe-rich ThMn2Fe17N3 and related materials.The invited paper by Hioki from Daido Steel Co. Ltd. provides an account of the development of hot-deformed Nd-Fe-B magnets that pioneered installment of the Dy-free Nd-Fe-B magnet in hybrid electric vehicles in 2016. The paper by Horikawa et al. of Aichi Steel Corporation is a review of recent advancements of anisotropic bonded magnets based on Nd-Fe-B and Sm-Fe-N partly conducted under MagHEM and ESICMM. Another paper by Takagi et al. from AIST reports recent results of their activities on powder materials processing for SmAs guest editors, we are confident that this Focus Issue provides a concise summary of the advancements in the science and technology of permanent magnets in Japan during the past decade and perspectives of the future direction of R&D in this field of research.


Assisted living is generally understood to offer a greater degree of privacy and independence than a nursing home; most residents pay privately, with some receiving support from state subsidies and Medicaid; regulation and oversight are the purview of state agencies. Within these broad parameters, however, one assisted living community may look quite different from another across the country, or down the street, in its resident population and the regulations that govern its operating license. The purpose of this symposium is to explore that variation. The papers leverage an in-depth review of changes in assisted-living regulation from 2007 to 2019 and a methodology to identify Medicare beneficiaries in assisted living using ZIP codes. To set the stage, the first paper examines variation across assisted living licenses to identify six regulatory types and compare their populations’ characteristics and health-care use. The second paper analyzes trends over time in the clinical acuity of assisted living residents associated with changes in nursing home populations. The third paper investigates racial disparities in assisted living associated with memory-care designations and proportions of Medicaid recipients. The fourth investigates how regulation of hospice providers in assisted living affect end-of-life care and place of death. The final paper describes requirements related to care for the residents with mental illness in seven states. The symposium concludes with an expert in long-term care disparities and quality discussing the implications for policymakers, providers, and the population needing long-term care in assisted living.


The objective of the Symposium is to expand familiarity of the application of advanced methods of modern statistical modeling and data management, to administrative health data by combining methodological innovations with practical hands-on demonstrations. Topics will cover a range of methodological and substantive topics including: i) decomposition and partitioning approaches in analysis of disparities and time trends in AD/ADRD; ii) new artificial intelligence technologies that allow us to enrich electronic health record datasets with self-report scores in geriatrics; iii) using administrative data to model adherence to disease management and health-related behavior; iv) the use of longitudinal extension of the average attributable fraction to study health disparities and multimorbidity; and v) the geographic and racial disparities in total and remaining life expectancies after diagnoses of AD/ADRD and other chronic conditions. The increasing availability of large-scale datasets based on electronic health records and administrative claims records provide an unprecedented opportunity for obtaining nationally representative results based on individual-level measures that reflect the real care-related and epidemiological processes. This makes the reduction of barriers to entry to the use of such data of vital importance to the community of geriatrics and health researchers.


Psychosis disorder is a debilitating disorder characterized by multiple admissions to psychiatric care facilities, higher unemployment rates, and decreased life expectancy. All of which create a high burden on the patient, their family, and the healthcare system. Understanding the basic mechanisms of psychotic disorder is essential for early discovery and facilitating better care for those suffering from it .The dopamine hypothesis of schizophrenia  suggestseNeuro paper by A recent eNeuro paper by Increased functional connectivity of VTA with the hippocampus and decreased functional connectivity of the same brain structure with the striatum were also found in individuals at high risk for psychosis in a task-based paradigm . In the Studies in individuals at later stages of psychotic disorders show some differences in the pattern of results. A recent study by This recent paper presents a promising and interesting direction in understanding the mechanisms associated with psychosis, by evaluating resting-state functional connectivity in first-episode psychosis. The alignment of these resting-state findings with task-based results could point toward a possible direction for further investigation. Future studies may focus on longitudinal data, using the previous findings as a model to predict the onset, risk, and course of psychosis based on both task-based and resting-state connectivity. Such a model will enable us to promote better care for individuals suffering from psychosis and their families.


ABSTRACT IMPACT: This work reveals the influence of a season of American football-related head impact exposure on two functional outcome measures in a cohort of adolescent boys, shedding light on the chronic effects of 'subconcussive head impacts.' OBJECTIVES/GOALS: To examine the influence of a season of exposure to head impacts in American football on changes in neurocognitive and oculomotor function in adolescent male athletes. METHODS/STUDY POPULATION: Participants were recruited from a local high school: the football group  was instrumented with sensor-installed mouthguards to track impact exposure during games and practices, and members of the men’s cross-country team were recruited to the control group . All participants were administered Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) and were assessed for near point of convergence (NPC) at pre- and post-season. Linear models will be fit for changes in the five ImPACT composite scores and NPC values, with group and one of the head impact variables as predictors for each model. In a secondary within-group analysis, correlation coefficients will be calculated for the relationships between the head impact variables and the functional change scores for the FB group. RESULTS/ANTICIPATED RESULTS: The two groups did not differ significantly on age or number of previous concussions; the CON group had significantly lower BMI. Group assignment was significantly associated with change in NPC ; no significant associations were observed for any of the head impact variables with change in NPC. Group and each of the head impact variables  were not significantly associated with change in any of the five ImPACT composite scores. Change in visual memory composite score was negatively correlated with total impacts  and sum of PRA . DISCUSSION/SIGNIFICANCE OF FINDINGS: Significant, albeit relatively weak, correlations between change in visual memory composite score and two head impact kinematic variables, coupled with significant increases in NPC in the FB group compared to the CON group, suggest that a season of exposure to football-related head impacts has the potential to elicit minor functional impairments.


The COVID-19 pandemic has generated awareness of the value of the direct care workforce to provide care in settings serving those most at risk from the disease. However, few studies have gauged the impact of COVID-19 on this workforce and their pandemic-related challenges. The purpose of this study was to examine the challenges and stress experienced by direct care workers  and their perceptions of preparation and quality of employer communication during this health crisis. Nursing home (NH) workers reported separation from family members and understaffing as the top external and work-related challenges. They felt adequately prepared and gave their employers high marks for communicating with them during the pandemic. NH direct care workers were more likely to report increased workload and understaffing as a challenge compared to workers in home and community-based settings. They also experienced a significantly higher number of work-related challenges compared to workers in assisted living.


Increasing requirements of medical aid given to children with infectious-inflammatory diseases of the urinary system stipulate the necessity to improve its quality using evidence-based therapeutic-diagnostic and organization technologies. The aim of the work – to substantiate, develop the improved model of the specialized nephrology care for children with infectious inflammatory diseases of the urinary system at the regional level. The official statistical data have been studied (2006 to 2017); information-analytical and statistical methods have been used. A bacteriological study (2009–2016) of urine samples was carried out for 3089 children (0–17 years old) in the Chernivtsi region. They formed the foundation for substantiation and development of an improved functional-organizational model of the system. In addition to the existing and functionally changed elements contains new elements: regional/inter-regional center of specialized medical aid to children with infectious-inflammatory diseases of the urinary system. Implementation of the elements of the suggested improved model in a part of a rational approach in distribution of functions concerning medical observation of patients at the stages of giving medical aid enabled to make the period of hospitalization of nephrological patients 11,40% shorter and an average period of treatment of patients with infectious-inflammatory diseases of the urinary system 2,93% shorter. Infectious-inflammatory diseases of the urinary system organs are considered an urgent issue in pediatrics due to a high rate of occurrence among the children population and a considerable variation rate of the pathology in the structure of the total sickness of children from various regions of Ukraine –3.Increasing requirements of medical aid given to children with infectious-inflammatory diseases of the urinary system stipulate the necessity to improve its quality using evidence-based therapeutic, diagnostic and organization technologies, an appropriate supply of resources including highly technological interventions in particular –7.The aim of this study was to substantiate, develop the improved model of specialized nephrology care for children with infectious inflammatory diseases of the urinary system at the regional level. The official statistical data have been studied , information-analytical and statistical methods have been used. The modern etiological structure of uropathogens – urinary tract infection (UTI) pathogens among the children of the Chernivtsi region (2009–2016) was studied. A bacteriological study of urine samples was carried out for 3089 children (0–17 years old) in the Chernivtsi region; the regional spectrum of sensitivity to antibacterial drugs was determined among the main groups of UTI pathogens; age, gender, and administrative-territorial differences among the children’s population of the region were analyzed. This work is a fragment of the scientific and research paper entitled “Scientific support, monitoring and evaluation of models of health care development in Ukraine at the regional level” (due date 2015–2017), state registration no. 0115U002852.The approval for this study was obtained from the Ethics Committee of the HSEEU “Bukovinian State Medical University” and Chernivtsi Regional Endocrinology Center, Ukraine .Imperfect normative-legal regulation of the organization of medical aid given to children with urinary tract infection (UTI); lack of clear mechanisms of interaction between health care institutions including the primary, secondary and tertiary aid, out-patient and in-patient stages in giving specialized medical aid to children with infectious-inflammatory diseases of the urinary system in the region -11; inadConceptual areas to improve the standard of giving specialized medical aid to children with infectious-inflammatory diseases of the urinary system at the regional level have been substantiated by the results of the study .On the basis of the existing normative-legal documents regulating standardization of medical aid, clinical recommendations of the European Association of Urology , and the data of our study, a clinical route of a patient aged from 0 to 17 years with infectious-inflammatory diseases of the urinary system is developed and implemented at the regional level into the work of health care institutions in Chernivtsi region which determine stages of giving medical aid .A central element of the system and, in fact, an innovation element of the improved model is a regional/inter-regional center of specialized and highly specialized medical aid given to children with infectious-inflammatory diseases of the urinary system. Its medical staff provides the implementation of information, methodical, therapeutic, medical-organizational work with monitoring of indicators to complete the regional program and other functions through comprehensive therapeutic-preventive, social-economical, hygienic, medical-social, information-educational measures. Thus, they provide completely organizational work depending on the determined area of the region.The center’s medical structure has several units to provide children with infectious-inflammatory diseases of the urinary system with available and effective evidence-based medical aid corresponding to the best world patterns, keeping to the stages of giving medical aid according to the improved clinical route. Functional distribution of the center is the following: out-patient consulting rooms of doctors ; in-patient nephrological department with the priority of day-time in-patient departments with intensive care units and dialysis; specialized microbiological laboratory; department of information-methodical supply and monitoring.The following main tasks of the regional/inter-regional center of specialized medical aid given to children with infectious-inflammatory diseases of the urinary system are determined:•achievement of final diagnosis, choosing the tactics of treatment, its correction, if necessary, rehabilitation and further out-patient care of children with UTI; •organizational-methodical, clinical dynamic control over the results of the therapeutic and rehabilitation technologies used while giving medical aid to children with UTI in the region; hemodialysis of newly organized beds, referring to the Institute of Nephrology, National Academy of Medical Sciences of Ukraine, (a state institution) if highly specialized in-patient medical aid is necessary;•to monitor changes of the regional spectrum peculiarities of bacterial causative agents in the urine of patients with UTI in various groups of children considering their gender and age; to organize the continuous treatment of children in case of relapses and exacerbations, to refer patients to be examined by medical-social experts if necessary, sanitary-resort treatment; to obtain epidemiological remarks by sickness rates of children suffering from UTI, their occurrence, and efficiency of medical aid they got ;•achievement of organizational-methodical, informative, communicative functions of the center in work with medical professionals in the region, public organizations, mass media concerning prevention and early finding of children with UTI.The functions of the center include its organizational interaction with regional health care institutions giving medical aid to children and teenagers. The stages of this interaction are presented in Therefore, the improved functional-organizational model of giving medical aid to children with infectious-inflammatory diseases of the urinary system at the regional level is based on a reformed medical aid system for the population. It consists of the following elements:1.Already existing elements of the health care system giving medical aid to children with infectious-inflammatory urinary system diseases;2.Existing but partially changed elements at the expense of their functional optimization such as pediatric service of the secondary health care institutions, microbiological laboratories of the health care institutions (HCI); interaction of HCI in giving various medical aid according to the improved clinical route; clinical and scientific base for the system of continuous postgraduate education of medical professionals giving medical aid to children with infectious-inflammatory diseases of the urinary system; first of all – general practitioners or family doctors, pediatricians, pediatric nephrologists and urologists;3.The elements of new quality – the foundation of a regional/inter-regional center of specialized medical aid given to children with infectious-inflammatory diseases of the urinary system, introduction, and provision of work of the electronic register of patients, the electronic-information system as elements of the regional target comprehensive program for saving health of children in the Chernivtsi region. Results of the expert evaluation of the suggested innovations made by qualified independent experts were indicative of their importance in order to improve medical aid given to children with infectious-inflammatory diseases of the urinary system at the regional level by the major directions: systematic, comprehensive, stage-by-stage, successive approaches, and rational use of resources. On the whole, the suggested model was evaluated by the independent experts in the total sum of 9.26±0.08 points out of 10.0 possible, and coordinated agreement of the experts in making their decision (CV (%) = 2.50–5.07).Therefore, under conditions of the current and prognosticated threats  , 26, disImplementation of the elements of the suggested improved model in a part of a rational approach in distribution of functions concerning the medical observation of patients at the stages of giving medical aid allowed making the period of hospitalization of nephrological patients and the average period of treatment of patients with infectious-inflammatory diseases of the urinary system shorter by 11.40% and 2.93%, respectively.The efficiency of implementation of certain elements of the suggested model with its positive evaluation by independent experts and its compliance with the strategy of branch reforms enables to recommend the improved functional-organization model of giving medical aid to children with infectious-inflammatory diseases of the urinary system at the regional level to be introduced into the health care system of Ukraine.The approval for this study was obtained from the Ethics Committee of the Bukovinian State Medical University and Chernivtsi Regional Endocrinology Center, Ukraine .The authors declare that there is no conflict of interest.


Although the magnitude and rate of aging in Japan and the United States differ, the drastic change in population structure has resulted in common challenges in both countries. One challenge is assisting older people in staying in the community. Enhancement of home- and community-based care allows older people to remain in their homes or spaces of their choice without moving into an institution to receive necessary care. This symposium includes four presentations (two from Japan and two from the U.S.) examining various efforts surrounding home- and community-based care designed to strengthen older people’s abilities to stay in the community. The presenters will cover a wide range of strategies that have been implemented in both countries. The first presenter will describe the development and delivery of a project to expand Arizona’s dementia capable system. The second presenter will describe initiatives of a professional association of geriatrics to promote the concept of aging in place. The third presenter will discuss the Home Hazard Removal Program (HARP), a new home hazard removal and fall risk self-management program delivered in the home by occupational therapists. The fourth presenter will discuss Japan’s national policy priority of promoting the use of home health care within the community-based integrated care system. The symposium will conclude with a review of similarities and differences of various efforts, summarize common goals and challenges, and identify best practices.


In the original article, there was an error in the Funding statement as published. Some of the funders were missing from the original statement.The corrected Funding statement is shown below.This work was supported by the Spanish Ministry of Economy and Competitiveness (grant AGL2013-45339R), the Spanish Ministry of Science, Innovation and Universities (MCIU), State Bureau of Investigation (AIE), and European Regional Development Fund (FEDER) (grant PGC2018-096958- B-I00), and the Catalonian Government (grant 2017SGR499). YE was recipient of an APIF fellowship from the University of Barcelona.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


This paper focuses on whether stronger relationships with parents early in the family lifecycle results in adult children providing more support to them 45 years later, and whether this association is contingent on parents’ remaining years of life. We test time-to-death of parents as an indicator of vulnerability, an easy to ascertain and potentially powerful predictor of support. Data derived from the Longitudinal Study of Generations, a panel of three-generation families, originally fielded in 1971 and continuing to 2016. Focusing on the youngest generation (mean age = 19 in 1971), the analytic sample consists of 356 child-father relationships 473 child-mother relationships. We examined trajectories of instrumental support provided to parents over four waves between 1997 and 2016 as a function of each parent’s remaining years of life . We also examined variation in those trajectories based on frequency of shared activities and intensity of emotional closeness in 1971. Ordinal multi-level growth curve analysis revealed that proximity to death was a significant predictor of instrumental support provided over time. Only in child-father relationships did greater emotional closeness, as expressed in 1971, produce stronger associations between remaining years of life and provision of instrumental support. Findings are discussed in terms of understanding intergenerational dynamics that unfold over many decades and the utility of time-to-death as an alternative metric for assessing vulnerability. This research is timely in light of growing uncertainty about the family as a reliable source of care in later life, particularly for older men.


Communicable diseases including COVID-19 pose a major threat to public health worldwide. To curb the spread of communicable diseases effectively, timely surveillance and prediction of the risk of pandemics are essential. The aim of this study is to analyze free and publicly available data to construct useful travel data records for network statistics other than common descriptive statistics. This study describes analytical findings of time-series plots and spatial-temporal maps to illustrate or visualize pandemic connectedness. We analyzed data retrieved from the web-based Collaborative Arrangement for the Prevention and Management of Public Health Events in Civil Aviation dashboard, which contains up-to-date and comprehensive meta-information on civil flights from 193 national governments in accordance with the airport, country, city, latitude, and the longitude of flight origin and the destination. We used the database to visualize pandemic connectedness through the workflow of travel data collection, network construction, data aggregation, travel statistics calculation, and visualization with time-series plots and spatial-temporal maps. We observed similar patterns in the time-series plots of worldwide daily flights from January to early-March of 2019 and 2020. A sharp reduction in the number of daily flights recorded in mid-March 2020 was likely related to large-scale air travel restrictions owing to the COVID-19 pandemic. The levels of connectedness between places are strong indicators of the risk of a pandemic. Since the initial reports of COVID-19 cases worldwide, a high network density and reciprocity in early-March 2020 served as early signals of the COVID-19 pandemic and were associated with the rapid increase in COVID-19 cases in mid-March 2020. The spatial-temporal map of connectedness in Europe on March 13, 2020, shows the highest level of connectedness among European countries, which reflected severe outbreaks of COVID-19 in late March and early April of 2020. As a quality control measure, we used the aggregated numbers of international flights from April to October 2020 to compare the number of international flights officially reported by the International Civil Aviation Organization with the data collected from the Collaborative Arrangement for the Prevention and Management of Public Health Events in Civil Aviation dashboard, and we observed high consistency between the 2 data sets. The flexible design of the database provides users access to network connectedness at different periods, places, and spatial levels through various network statistics calculation methods in accordance with their needs. The analysis can facilitate early recognition of the risk of a current communicable disease pandemic and newly emerging communicable diseases in the future. Communicable diseases remain a major public health threat worldwide. The COVID-19 pandemic is a stark reminder of the ongoing challenge posed by communicable diseases on human health . The conThe risk of in-flight communicable disease transmission has been a global health concern well before the emergence of COVID-19 . A numbeWe previously analyzed travel data retrieved from the web-based Collaborative Arrangement for the Prevention and Management of Public Health Events in Civil Aviation (CAPSCA) dashboard , which cFlexible analysis of travel data can be performed through in-database processing. Specifically, users can analyze travel data through various network statistics calculations, including network analysis , networkThe CAPSCA dashboard allows us to create a spatial-temporal database by integrating the travel data from different airports to illustrate connectedness at the city, country, or regional levels in accordance with the users' preference. The database can facilitate research and policymaking at local and global levels and provide a spatial outlook of the evolution of the pandemic network for predicting and assessing the risk of a communicable disease pandemic.The database enables the visualization of pandemic connectedness through the workflow of travel data collection, network construction, data aggregation, travel statistics calculation, and visualization with time-series plots and spatial-temporal maps. The workflow of data collection and analysis is summarized in Travel data and meta-information were retrieved from the CAPSCA dashboard through two separate procedures:Extracting the airport meta-information from the rendered JavaScript object “airportData” through a HyperText Transfer Protocol request.Downloading and extracting the flight numbers of civil flights, including both passenger and cargo flights, from the JavaScript Object Notation responses through multiple Asynchronous JavaScript and Extensible Markup Language requests.The collected travel data were filtered for valid International Civil Aviation Organization (ICAO)–formatted airport codes. Raw JavaScript Object Notation responses contain formatted airport codes from various data sources such as the ICAO, IATA, and FAA. Each type of formatted airport code has its specific format. Valid ICAO codes start only with a letter and have 4 letters or digits, valid IATA codes consist of 3 letters, while valid FAA codes are 3-5–character alphanumeric codes. Each format type helps develop a filtering system to extract travel data with specific codes.A live version of the data record, which is maintained up-to-date with the latest data, can be downloaded from our travel database project repository . The datThe aggregated raw inputs are location metadata that contain data at multiple levels—country, city, airport, and geolocation (latitude and longitude)—and travel data, which contain daily information regarding flight origin and the destination, starting from January 2019. These data encompass >200 countries and regions worldwide.The data records (details) are structured into the following 3 comma-separated value (CSV) files:[ICAO_airport_meta.csv] Table of the location metadata (ICAO-CAPSCA airport meta). The fields of the table are as follows:countryName is the name of the countrycountryCode is the International Organization for Standardization (ISO)-3166 alpha-3 code of the countryairportName is the name of the airportairportCode is the ICAO code of the airportcityName is the name of the citylatitude is the geolocation (latitude) of the airportlongitude is the geolocation (longitude) of the airport[flight_2019-01-01_2020-12-03.csv] Table of travel data (daily flight numbers from origin to destination). The fields of the table are as follows:date is the record datenum_flight is the number of flights from the origin airport to the destination airportorig_airportCode is the ICAO code of the origin airportorig_airportName is the name of the origin airportorig_countryCode is the ISO-3166 alpha-3 country code of the origin airportorig_countryName is the country name of the origin airportorig_cityName is the city name of the origin airportorig_latitude is the geolocation (latitude) of the destination airportorig_longitude is the geolocation (longitude) of the destination airportdest_airportCode is the ICAO code of the destination airportdest_airportName is the name of the destination airportdest_countryCode is the ISO-3166 alpha-3 country code of the destination airportdest_countryName is the name of the country where the destination airport is locateddest_cityName is the name of the city were the destination airport is locateddest_latitude is the geolocation (latitude) of the destination airportdest_longitude is the geolocation (longitude) of the destination airport[network_statistics.csv] Table of the calculated network statistics. The fields of the table are as follows:date is the reference date of the network statistics at time ttV is the number of vertices (Vt) at time ttE is the number of edges (Et) at time ttD is the edge density (Dt) at time ttR is the reciprocity (Rt) at time tThe travel data can be used to construct the travel network structure . The basFor example, if we focus on global analysis, we aggregate the airport data at the country level and input the country data as a new set of nodes to form travel subnetworks, which are represented by the country-country–origin-destination matrix with entries being the flight frequencies between 2 countries.We can further aggregate the travel data to obtain overall worldwide flight information. t is the number of vertices of the dynamic network at time t, and Et is the number of edges of the dynamic network at time t, network statistics such as Dt  and Rt  density ) can be t.which refers to the ratio of the number of connections with respect to the maximum possible connections among countries. This equation illustrates how dense the connections in the dynamic network are at time t is based on a directed network structure and is defined as follows:Reciprocity Rt is the ratio of the number of links pointing in both directions, Et<-> , to the total number of links, Lt. In other words, the value of Rt represents the average possibility that a link is reciprocated.where RNetwork statistics data were visualized using time-series plots. In addition, data records of the origin-destination and degree matrices can be visualized using spatial-temporal maps.The time-series plots of network density and reciprocity shown in For example, to analyze the connectedness in Europe during the first wave of the COVID-19 pandemic in early 2020, spatial-temporal maps of Europe at 14-day intervals between March and April 2020 were generated A. Maps dt  or software facilitating network visualization, such as Gephi (The Gephi Consortium).CAPSCA is a voluntary cross-sectorial and multi-organizational collaborative program managed by the ICAO with support from the WHO. The quality of the data on the dashboard should be guaranteed. As a quality control measure, we used the aggregated number of international flights from April to October 2020 to compare the number of COVID-19 cases at hub airports officially reported by the ICAO  with theOngoing systematic surveillance is important to help detect early outbreaks and to evaluate the effectiveness of public health measures and programs ,28. In tOur study provides a clear workflow for data collection and analysis and the suggested software for analysis. Because air transportation is highly relevant to the dissemination of communicable diseases, the database and the analysis can also be applied to investigate the risk of other communicable disease pandemics occurring currently or emerging in the future. In addition, researchers may replicate our workflow for assessing pandemic connectedness by using the same database or other databases.For data quality assurance, we conducted correlation analysis and validated the database. We compared the number of aggregated international flights officially reported by the ICAO for 7 regions from April to October 2020 with corresponding data we collected from the CAPSCA dashboard. We found only minor differences probably owing to data synchronization performed by the ICAO after collecting the daily raw counts of COVID-19 cases. We expect that our findings may help researchers explore and validate freely available health-related databases to conduct ongoing and systematic analysis and interpretation to identify early warning signals, such that necessary action can be taken to prevent and control the spread of communicable diseases.In this study, we demonstrated a workflow to analyze freely available travel data retrieved from the CAPSCA dashboard, together with data on confirmed COVID-19 cases reported by the WHO, for systematic surveillance. Flexible analysis of the travel data can be performed through in-database processing, which allows us to visualize and analyze the risk of a pandemic and pandemic connectedness by using different tools such as time-series plots and spatial-temporal maps. This analysis facilitates early recognition of the risk of pandemics of current communicable diseases and newly emerged communicable diseases in the future.


Agricultural systems all over the world are key for supplying vital goods such as food, fibre and energy from biomass. These agricultural systems form the foundation of human material well-being. However, increasing intensification, monocultures and overexploitation have often led to the serious degradation of the ecosystems upon which agricultural systems are embedded. Therefore, the functioning of these systems and their constituent biodiversity are at risk  what kind of land use trade-offs and synergies among agricultural production, ecosystem services and biodiversity can be identified at the landscape scale; and (b) how can the influence of agricultural land use on ecosystem services and biodiversity be monitored and evaluated at the landscape scale? The idea for this Special Issue emerged at the Landscape 2018 - Frontiers of agricultural landscape research Conference in Berlin, from where the individual contributions were drawn. The aim of the Conference was to present recent advances in landscape research to promote the development of sustainable agricultural land use and landscape strategies in an interdisciplinary and application-oriented manner.In this Special IssueThe research in this Special Issue addresses these landscape-related issues: (a) a general approach to enhance the indication of the supply of provisioning ecosystem services in agricultural landscapes is introduced by Bethwell et al. ; (b) asp


There were errors in the Funding statement. The corrected funding statement is below:This research was funded by the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia. The project number is PNU-DRI- Targeted-20-019.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


In the original article, we inaccurately cited the report of Sun et al. . The autGenome Editing for CNS Disorders, Alzheimer's Disease, Paragraph 1. The corrected paragraph is shown below.A correction has been made to in vivo studies in adult mice, the CRISPR-APP system was split into two AAV9 vectors and delivered to the dentate gyrus of WT mouse brains. The injection of CRISPR-APP reduces the level of the processed C-terminal fragments (CTFs) by half while having no or minimal impact on the total APP protein. No additional in vivo tests were performed to evaluate treatment efficacy in the context of AD  is the main cause of dementia, affecting millions of people worldwide (Winblad et al., The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


Objective: This project report outlines the development and implementation of digital tutorials  by peer tutors (TUTs) based on previously established in-person tutorials, as well as the subsequent combination of both approaches. The TUTs' objective, in spite of corona-related restrictions and strict hygiene requirements during the pandemic, was to provide fellow students with the opportunity to learn, practice and reflect on clinical-practical skills.Methodology: In a collaborative undertaking, the TUTs first analyzed the learning objectives of the in-person tutorials in order to be able to design content-matched digital tutorials without entirely abandoning the practical aspect. The Moodle learning management platform was selected as the appropriate tool for delivery of the relevant theoretical knowledge. Practical exercises are embedded in the digital tutorials during online meetings. The participants (PTs) create their own models in the sense of a home skills station based on instructions provided via Moodle. Acceptance was systematically documented via questionnaires.Results: The digital tutorials were well accepted by the PTs (n=64). Evaluation (response rate: 37.5%) outcomes were consistently positive. Both course implementation and the PTs' own progress were rated “good” to “very good”. Nevertheless, the PTs do not yet feel well-prepared to carry out the various activities practiced independently.In the winter semester of 2020/21, the in-person tutorials were also reintroduced in a combined format. The marked demand for the tutorials may indicate the PT preference for practice on the simulation center models.Conclusion: The systematic combination of digital and in-person tutorials using the flipped classroom approach would appear to make sense in the long run. The effectiveness and sustainability of this approach in comparison with in-person tutorials only should be further investigated. The long-term plan, even once the pandemic has passed, is to combine them with the digital tutorials. For example, the Moodle course could be serve as the flipped classroom by providing information materials and forums as theoretical preparation for practical application during in-person tutorials [Starting from the winter semester 2020/21, in-person tutorials can again take place in compliance with the hygiene regulations of the Faculty of Medicine at the Klinikum rechts der Isar, see [utorials . In addiThe hybrid form of the course now envisaged should be assessed in terms of effectiveness and sustainability as part of accompanying research with the initial presence-only event. It is already clear that the still fledgling student tutorial program “How to... train your skills!” has undergone significant and promising further development. This is the result not only of the combination of digital and in-person tutorials, but also of the situational change of perspective and being constrained to apply practical skills at a distance and with the simplest improvised means.The authors declare that they have no competing interests.