While vaccines traditionally have been designed and used for protection against infection or disease caused by one specific pathogen, there are known off-target effects from vaccines that can impact infection from unrelated pathogens. The best-known non-specific effects from an unrelated or heterologous vaccine are from the use of the Bacillus Calmette-Guérin (BCG) vaccine, mediated partly through trained immunity. Other vaccines have similar heterologous effects. This review covers molecular mechanisms behind the heterologous effects, and the potential use of heterologous vaccination in the current COVID-19 pandemic. We then discuss novel pandemic response strategies based on rapidly deployed, widespread heterologous vaccination to boost population-level immunity for initial, partial protection against infection and/or clinical disease, while specific vaccines are developed. Since the introduction of the smallpox vaccine in 1796, and the Bacillus Calmette-Guérin (BCG) vaccine in 1921, vaccination-related reductions in non-specific morbidity and mortality have been described. Carl Näslund was the first to establish the concept of non-specific immunological vaccine effects, also known as heterologous effects of vaccination (HEV), when BCG vaccination started in Sweden (Aaby and Benn Measles vaccination (MV) can also have non-specific effects. After the introduction of MV in Guinea-Bissau, there was a significant decrease in childhood mortality . Since its introduction in South America, reports revealed an interference with the replication of other enteroviruses, resulting in fewer diarrheal deaths , but the primary data in fact only supports the conclusion of increasing risk with decreasing number of DPT innoculations.Until recently, the lack of studies evaluating the underlying mechanisms of HEV has been a major obstacle in recognizing and taking advantage of these effects during a pandemic. In this mini-review, we review the immunological mechanisms and the development of the idea of Heterologous Vaccine Intervention (HVI), referring to the exploitation of heterologous or non-specific effects of current approved vaccines against one or more unrelated pathogens. This novel pandemic “early response” intervention, that could be rolled out in parallel with non-pharmaceutical interventions (NPIs) could be used for the current COVID-19 pandemic and for future pandemics to come.+ monocytes and imprints a persistent transcriptomic myeloid bias on human hematopoietic stem and progenitor cell compartment in the bone marrow  after a primary exposure, such as an infection or vaccination, that leads to an altered response towards a second exposure after the return to a non-activated immune state, is termed ‘trained immunity’(Netea et al. Other innate immune cells that can contribute to protective HEVs include NK cells by increased cytokine production (Rozot et al. Less well studied mechanisms in BCG and other live vaccines are from viral interference (Seppälä et al. In addition to the effect of a heterologous vaccine on innate immune mechanisms, vaccines can also alter adaptive immune responses to unrelated pathogens and antigens. Two different mechanisms have been described: cross-reactivity and bystander activation. The classical adaptive immune response corresponds to T cells that respond to antigen presentation, but these T cells may cross-react with a different antigen with amino acid similarity (Frankild et al. Toxoplasma gondii in adults are stimulated through bystander activation, upon immunization with tetanus toxoid (Goodridge et al. An illustrative example of cross-reactivity resulting from molecular mimicry is the existence of memory T cells specific to viral antigens in unexposed adults, such as herpes simplex virus, cytomegalovirus and HIV-1, possibly as a consequence of cross-reactivity with antigens in the environment. Furthermore, the seasonal influenza vaccine can stimulate T cells specific for a cross-reactive bacterial homologue (Su et al. The durability of the heterologous effects after vaccination is unknown, although vaccinia and BCG vaccinations are associated with better long-term survival during a 40-year follow up (Rieckmannet al. Several ecological studies have suggested a negative association between different vaccines and the prevalence or mortality of COVID-19. Escobar et al. attempted to mitigate potential confounding factors and reported a strong correlation between their BCG index and COVID-19 mortality in different socially similar European countries, specifying that every 10% increase in the BCG index was associated with a 10.4% reduction in COVID-19 mortality (Escobar et al. An inverse association between influenza vaccination coverage rate in the elderly, at a county or region level in the US (Zanettini et al. Using the quadrivalent inactivated influenza vaccine applied in the Netherlands in the 2019–2020 influenza season, Debisarun et al. demonstrated the induction of trained immunity response in an in vitro model, including improvement of cytokine responses, after stimulation of human immune cells with SARS-CoV-2 (Debisarun et al. The concept of Heterologous Vaccine Intervention is being developed with BCG vaccination, and several randomized trials are underway to study if BCG vaccination reduces the incidence or severity of COVID-19 in different countries (NIH U.S. National Library of Medicine Although specific COVID-19 vaccines have been released and given emergency use approval, they are still in limited supply and the slow pace of COVID-19 vaccination is a global challenge. Public health policies against pandemics may derive benefit from the concept of HVI, authorizing the early use of non-specific vaccines either generally as a boost, second dose after the COVID-19 vaccine prime (Hupert et al.


Focused electron beam (FEB) and focused ion beam (FIB) technologies have opened novel paths for material science research and technology at the micro and nano scales in recent decades. These technologies are highly adaptable, and flexible tools are used successfully in fundamental and applied research projects allowing visualization, elemental and structural analysis, and additive and subtractive manufacturing, as well as efficient modification of materials. All of this can be done on scales ranging from hundreds of μm to one nanometer. The unique flexibility of focused beams enables them to be used for rapid prototyping as well as nanostructure editing and analysis. Today, these technologies play an important role in the development of new integrated circuits based on miniaturized electronic devices.Concerning the additive nanofabrication, the use of gas injection systems with advanced programs  allow to grow in single-step nanostructures in three dimensions by the partial decomposition of a precursor material produced by the effect of the beam scanning. This technique is called focused ion/electron beam-induced deposition (FIBID/FEBID). Nanostructures grown using this additive manufacturing technique can have arbitrary shapes, both in-plane  and out-of-plane , and also can host insulating, metallic, ferromagnetic, or superconducting properties.+ FIBID deposits with in situ heating ,  nan nan+ FIBs [+ FIB ,8.1) Purification of FEBID nanostructures: Markus Rohdenburg et al. [ Purifica2) High-resolution nanostructures using FEBID: Sangeetha Hari et al. [ High-res3) A new approach for the nanofabrication of metallic nanostructures based on FEB: Luisa Berger et al. [ A new ap4) Tuning of diameters in 3D FEBID nanostructures: Lukas Seewald et al. [ Tuning o5) Evolution of the microstructure and resistivity in Pt FIBID deposits with in situ heating: Chaorong Zhong et al. [ Evolutio+ FIB-induced processing for photonic applications: Mariachiara Manoccio et al. [6) Nanofabrication using Ga Nanofabr+ FIB: Alex Belianinov et al. [7) Fabrication of 3D FIBID nanostructures using He Fabricatv et al.  have repI would like to thank all authors who submitted their papers to this Special Issue. I would also like to thank all the reviewers for dedicating their time to provide careful and timely reviews to ensure the quality of this Special Issue.


Tinel et al.; Aschauer et al.; Wu et al.; Okamura et al.) and three comprehensive Review articles  on immunogenomics of SOT and HSCT that include both animal and human studies.Alloreactivity is caused by the extensive difference in polymorphic genes between allogeneic donor and recipient, primarily in the major histocompatibility complex (MHC). As key mediators of alloresponses, alloreactive T cells are educated by self MHC and thus acquire the ability to recognize non-self MHC, leading to graft rejection and graft-versus-host-disease (GVHD), in solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT), respectively . ThroughShi et al. provides an insightful review of genomic-based approaches to the study of transplant rejection, including microarray, RNA sequencing (RNA-seq), and spatial transcriptomic techniques. This review traces the developmental history of these approaches and extends it to the current fast-paced field of emerging technologies, which includes the integration of single cell RNA-seq with T cell receptor (TCR) and B cell receptor (BCR) sequencing to profile immune repertoires, with mass cytometry and featured barcode antibodies to measure protein expression, and with chromatin sequencing to explore gene regulatory networks. The authors discuss the advantages and limitations of each approach. Application of these analysis tools will contribute to a fundamental understanding of the alloresponse and likely promote novel therapeutic options to overcome rejection and GVHD.Tinel et al. performed miRNA and mRNA profiling of kidney allograft biopsies to reveal new pathways involved in microvascular Inflammation (MVI), the main histological injury associated with AMR. This study identifies six differentially-expressed miRNAs that are correlated with the intensity of MVI. mRNAs/miRNAs interplay analysis further elucidates the crosstalk between renal-resident and allograft-infiltrating cell subsets and suggests that epithelial, rather than endothelial, metabolism modifications occur during AMR. This study illustrates the great potential of multi-omics to decipher rejection mechanisms.To investigate the role of microRNAs (miRNAs) in antibody-mediated rejection (AMR) after SOT, Tian et al. reviews recent advances in TCR-seq and computational tools and discusses the potential of using TCR-seq to profile alloreactive T cell repertoires. Defining and tracing donor- and recipient-reactive TCRs may reveal the fingerprint of alloreactive T cells, providing valuable indication of graft rejection, acceptance and treatment response after SOT.TCR repertoire diversity and turnover dynamics are related to rejection and tolerance in SOT . The preAschauer et al. analyzes donor-reactive TCRs in pre-transplant blood and post-transplant kidney biopsies in the presence and absence of TCMR to find little repertoire overlap in these two sites. While circulating donor-reactive repertoire is increased in both groups, donor-reactive T cells in kidney are only enriched during a TCMR episode with substantially diverse TCRs, indicating the capability to respond against a variety of epitopes in the allograft.Frequencies of circulating donor-reactive T cells were elevated in kidney transplant patients receiving conventional immunosuppression , 7. HoweFu et al. further discusses the use of TCR-seq to discern the factors behind human T cell repertoire development and how this approach can be used in combination with human immune system mouse models to understand human repertoire selection. The article explains current understanding of the propensity of alloreactive TCRs as a consequence of thymic selection. It also notes the limitations of techniques historically used to study human TCR repertoires and provides descriptions of innovative tools the authors are utilizing  TCR diversity is narrowed in allogeneic T cells; 2) top dominant T cell clones are highly shared across circulation and GVHD target organs in allogeneic recipients; 3) clonal expansion of rare rearrangements from pre-transplant donor T cells may account for the sharing of a few clones among allogeneic recipients. Their findings illustrate immune repertoire sequencing-based methods as a novel personalized strategy to guide diagnosis and therapy in GVHD.T cells are considered as not only the main culprit behind TCMR after SOT, but also the driving force of GVHD after allogeneic HSCT . RecoverOkamura et al. reports that high levels of complement factor Ba a week after HSCT predict the occurrence of TA-TMA and related non-relapse mortality. This finding, once confirmed in a broader cohort, will lay the groundwork for highly-tailored and complement-targeted therapeutics. C5 blockade—which already revolutionized outcomes of atypical hemolytic uremic syndrome  is also a life-threatening medical condition. Although pathogenic variants in complement regulatory genes have been reported as genetic susceptibility to TA-TMA in only a minority of patients , 20, grosyndrome , anothersyndrome .This Research Topic of articles provides an in-depth review of current understanding of alloresponses after transplantation in preclinical and clinical settings from the immunogenomics perspective and encourages future investigations in this field.YW, JZ, and JF collected articles and wrote the editorial review. All authors contributed to the review and approved the submitted version.YW was supported by R01 CA258440 from NIH/NCI (PI: Xue-Zhong Yu). JZ was supported by the Fondation Emmanuel Boussard, IMAGINE Institute, DIM-Thérapie Génique/Région Ile-de-France, Agence de la Biomédecine, and Agence Nationale de la Recherche . JF was supported by a Congressionally Directed Medical Research Program (CDMRP) Discovery Award W81XWH-20-1-0159 funded by the Department of Defense (DoD), a R21 grant AI166069 supported by NIH/NIAID and Nelson Faculty Development Awards UR011630-01 and UR011630-02 from the Nelson Family Transplantation Innovation Award Program at Columbia University Irving Medical Center.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Bipolar disorder is associated with premature mortality, but evidence is mostly derived from Western countries. There has been no research evaluating shortened lifespan in bipolar disorder using life-years lost (LYLs), which is a recently developed mortality metric taking into account illness onset for life expectancy estimation. The current study aimed to examine the extent of premature mortality in bipolar disorder patients relative to the general population in Hong Kong (HK) in terms of standardised mortality ratio (SMR) and excess LYLs, and changes of mortality rate over time.This population-based cohort study investigated excess mortality in 12 556 bipolar disorder patients between 2008 and 2018, by estimating all-cause and cause-specific SMRs, and LYLs. Trends in annual SMRs over the 11-year study period were assessed. Study data were retrieved from a territory-wide medical-record database of HK public healthcare services.Patients had higher all-cause [SMR: 2.60 (95% CI: 2.45–2.76)], natural-cause [SMR: 1.90 (95% CI: 1.76–2.05)] and unnatural-cause [SMR: 8.63 (95% CI: 7.34–10.03)] mortality rates than the general population. Respiratory diseases, cardiovascular diseases and cancers accounted for the majority of deaths. Men and women with bipolar disorder had 6.78 (95% CI: 6.00–7.84) years and 7.35 (95% CI: 6.75–8.06) years of excess LYLs, respectively. The overall mortality gap remained similar over time, albeit slightly improved in men with bipolar disorder.Bipolar disorder is associated with increased premature mortality and substantially reduced lifespan in a predominantly Chinese population, with excess deaths mainly attributed to natural causes. Persistent mortality gap underscores an urgent need for targeted interventions to improve physical health of patients with bipolar disorder. Specifically, we adopted two mortality metrics, namely SMR  and LYLs to quantify the magnitude of excess mortality among patients with bipolar disorder compared with the general population. Changes in SMRs across the study period were also assessed to clarify whether the mortality gap improved or worsened over time.et al., et al., et al., et al., Population statistics and information on all registered deaths in HK between 2008 and 2018  were obtained from the Census and Statistics Department. Data of the patient cohort were extracted from the Clinical Data Analysis and Reporting System , and aged ⩾15 years during the study period as the study population. Diagnosis of bipolar disorder was recorded and verified by the International Classification of Diseases, 10th revision (ICD10 codes: F30 and F31). Final diagnostic ascertainment took into consideration the longitudinal illness course (Chang Causes of death were classified according to ICD10 codes (online Supplementary Table S1), and were divided into natural and unnatural causes. Natural causes were categorised into infectious and parasitic diseases (A00–B99), neoplasms (C00–D48), cardiovascular diseases (I00–I99), respiratory diseases (J00–J99), digestive diseases (K00–K93) and genitourinary diseases (N00–N99). An array of specific natural causes was also identified for analyses. As data on specific unnatural causes (V01–Y98) were not available, we treated unnatural deaths as a single category for analyses.P exact tests. To assess trends in all-cause, natural-cause and unnatural-cause SMRs over time, joinpoint regression analysis was performed which estimated the optimal number of linear slopes and joinpoints with modified Bayesian information criteria  for all-cause and cause-specific deaths were calculated as the primary mortality measures to quantify the relative mortality rate between patients with bipolar disorder and the general population. First, number of observed deaths and person-years of follow-up were computed for each calendar year (2008–2018), sex and age category  for the patient group. The number of person-years for each stratum was multiplied by the corresponding mortality rate in the general population to produce expected number of deaths, indirectly standardising overall mortality ratio by age, sex and calendar year. SMRs were estimated by dividing the observed number of deaths by the expected number of deaths. Crude mortality rates (CMRs) per 100 000 person-years as well as SMRs for all-cause and cause-specific deaths of the patient group over the whole study period, stratified by sex and four broader age groups , were then calculated, with 95% confidence intervals (CIs) of SMRs being derived by mid-et al., et al., et al., et al., et al., et al., lillies  for all-cause mortality were also calculated as a complementary mortality measure. Following the method adopted in previous research for LYL estimation  with 106 147 persons-years of follow-up , and a total of 1042 deaths, of which 821 (78.8%) had a known cause. The numbers of person-years and cause-specific death counts for each demographic subgroup of patients are listed in online Supplementary Table S2.All-cause SMR for bipolar disorder was significantly increased in the total sample  and in each demographic subgroup relative to the general population  and 2. ASMRs for natural and unnatural causes were significantly increased in the total sample  and in each demographic subgroup of patients with bipolar disorder, except the youngest age-group who showed no significant increase in natural-cause SMR  and 2. BNatural causes accounted for most of the known-cause deaths in patients. Approximately two-thirds of all known-cause deaths were attributed to respiratory diseases, cancers and cardiovascular diseases (online Supplementary Table S2). Respiratory diseases represented the leading cause of death and accounted for around one-thirds of all known-cause deaths. Cancers and cardiovascular diseases contributed to about 1 in 5 and 1 in 7 known-cause deaths, respectively. Unnatural causes accounted for approximately one-fifths of known-cause deaths. Men had generally higher CMRs for most listed causes of death than women . MortaliAs shown in Joinpoint regression fitted a linear model of all-cause, natural-cause and unnatural-cause SMRs with no joinpoints over time for the total sample, men and women subgroups. As shown in To our knowledge, this is the first study using LYLs complementary with relative mortality risk measure (SMR) to evaluate the excess mortality associated with bipolar disorder. Our results showed that patients with bipolar disorder had 2.6-fold increased mortality risk compared with the general population. Both men and women with bipolar disorder exhibited a substantially shorter lifespan than the general population, with approximately 7 years of excess LYLs. Natural causes, specifically respiratory diseases, cardiovascular diseases and cancers, accounted for the majority of known-cause deaths, while unnatural cause had markedly elevated SMR, particularly among patients aged <35 years. Generally, the mortality gap persisted over 11 years, albeit slightly improved in men with bipolar disorder.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Our finding on all-cause SMR for bipolar disorder is broadly consistent with the literature which reported 2–3 times greater overall mortality risk than the general population (Chang et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Until now, very few studies have comprehensively examined cause-specific SMRs for natural deaths in bipolar disorder. Consistent with the literature (Crump et al., et al., et al., et al., Patients with bipolar disorder had approximately 8 times greater risk of dying from unnatural causes than the general population. This finding is concordant with the unnatural-cause summary SMR of 7.42 reported by a recent meta-analysis (Hayes et al., et al., et al., et al., et al., Although our analysis suggested small, albeit statistically significant, reduction in annual all-cause mortality rate over time in men with bipolar disorder, the overall mortality gap remained largely unchanged over 11 years. Both natural-cause and unnatural-cause mortality differences also showed no significant improvement across the study period in either sex or in the overall sample. Our results thus agree with most previous studies (Medici et al., et al., et al., Several study limitations should be noted. First, several demographic variables including educational level, socioeconomic or employment status and a number of premature mortality risk factors such as unhealthy lifestyles and obesity were not adequately recorded in medical database and thus were not included in the analysis. Second, missing data on patients’ death causes may compromise the accuracy in evaluating cause-specific SMRs. Third, as information on specific unnatural causes was not available, we were not able to investigate mortality risk for individual categories of unnatural deaths including suicide and accidents. Fourth, the study data did not contain information denoting the disorder subtypes, precluding us from examining potential differences between bipolar I and II disorders in mortality rate and life expectancy. Fifth, patients’ age of illness onset was defined by age of first-recorded diagnosis of bipolar disorder. However, previous studies showed that there could be significant delays between illness onset and ascertainment of bipolar disorder diagnosis (Dagani In conclusion, this large population-based study indicates that bipolar disorder patients have increased mortality risk and markedly reduced life expectancy in a predominantly Chinese population, with excess mortality being primarily attributable to natural causes. Our findings of persistent mortality gap across the study period highlights an urgent need for further research to identify its underlying causes and to implement multi-level, targeted interventions to promote physical health of bipolar disorder patients so as to significantly reduce their risk of preventable physical morbidity and premature mortality.


The increase in number of people suffering from neurodegenerative dementia (ND), such as Alzheimer's disease (AD) and Parkinson's disease (PD), has placed a huge burden on society. Precise detection of ND in an early phase is still challenging in daily clinical practice , 4-[(E)-2-(6-{2-[2-(2-(18F)fluoroethoxy)ethoxy]ethoxy}pyridin-3-yl)ethen-1-yl]-N-methylaniline (18F-AV45), and 7-(6-(18F)fluoropyridin-3-yl)-5H-pyridoindole (18F-AV1451) have been widely used in research and diagnostic imaging of ND. Development of bioinformatics analysis and artificial intelligence methods has significantly facilitated advances in research of ND. Nowadays, researchers are facing difficulties in choosing the best method in order to conduct research in a comprehensible fashion with estimates of accuracy and reproducibility.In addition to metabolic changes such as altered glucose metabolism, alterations of amyloid-beta and tau protein are biomarkers associated with pathology of AD, whereas alpha-synuclein is proven to be related to PD and other NDs  e4 allele might affect the relationship between serum lipid levels and cognitive impairment. In addition, Hu, Li, Zhao, et al. provided evidence that the combination of telmisartan and rosuvastatin might be an effective prevention and/or treatment strategy for cognitive impairment and dementia, especially in hypertensive patients with the APOE e4 allele. Kuang et al. demonstrated that the e4 genotype leads to distinct default mode network (DMN) functional alterations in early phases of AD using persistent homology approach. Lin investigated whether CDGSH iron-sulfur domain 2 (CISD2) gene attenuation had an influence on anti-inflammatory effects and M1-M2 polarization in microglia. This study promised a potential therapeutic target for ND.Based on univariate and multivariate analyses, Jiao et al. focused on plasma biomarkers which are less expensive and invasive than those necessitating a spinal fluid sample. The results of their study showed that the multifactor model of plasma amyloid-beta 42 and total-tau in combination with Montreal Cognitive Assessment (MoCA) could be a viable model separate health and AD subjects in clinical practice. Gao et al. characterized the relationship between plasma amyloid-beta levels and cognitive decline in 1,240 cognitively normal participants. The relationship between plasma amyloid-beta 40 and cognitive decline was an inverted-U shape in a cognitively normal population. None of relationship between plasma amyloid-beta 42, amyloid-beta 42/40, and cognitive decline was found during a 2-year follow-up. Lin et al. enrolled cognitively normal amyloid-beta-positive participants from 2 cohort studies, all types of resilience to cerebrospinal fluid (CSF) amyloid-beta could predict longitudinal cognitive decline.For clinical diagnosis of AD, Yu et al. identified 16 hub genes correlated to the neuropathological stage and 35 potential biomarkers for the diagnosis of AD. Yuen et al. demonstrated a systematic workflow for evidence synthesis of transcriptomic studies using both meta-analysis and bioinformatics methods to identify potential pathogenic factors. The results showed that reduced amyloid-beta clearance in AD pathogenesis was associated with genes encoding Fyn and EGFR, which were key receptors in amyloid-beta downstream signaling. Robin et al. comprehensively profiled phenotypic features over time in one commercially-available induced Pluripotent Stem Cell (iPSC)-derived human neuron cell line. This study provided a tool to investigate neurodegenerative and other central nervous system (CNS) diseases. Deng et al. applied multivariate model to estimate the association between leukocyte telomere length (LTL) and cognitive performance. Their results suggested that LTL might be a biomarker of cognitive aging.Identification of novel molecular biomarkers for diagnosis and treatment of AD is urgently demanded. Based on bioinformatics analysis, Kong et al. explored the links between diabetes and AD by studying the advanced glycation end products (AGEs) and the receptors for AGEs (RAGE). The results of their study suggested that patients with diabetes were at a higher risk of developing AD. They further reviewed the interaction between RAGE and amyloid-beta as well as tau, which highlighted the potential of RAGE to be used as an effective target for AD diagnosis and treatment. Ho et al. explored type 2 diabetes mellitus (T2DM) pathogenesis in the amyloidogenic evolvability. A better understanding of the role of T2DM in amyloidogenic evolvability might reveal new targets for therapeutic intervention in AD patients who are comorbid with T2DM.Li et al. found that T2DM could give rise to the white matter atrophy of several brain regions, including left posterior cingulate, precuneus, insula, and right rostral middle frontal gyrus. In addition, they investigated the white matter structural network disruption in T2DM patients with MCI. Chen et al. developed MR glucose chemical exchange saturation transfer (glucoCEST) imaging in a rat model of AD. The findings from their study showed that this method could explore the occurrence and progress of diabetes-related AD or dementia.Using magnetic resonance (MR) imaging, Feng et al. explored the role and underlying mechanism of calcium-sensing receptor (CaSR) in cognitive deficits in AD mice. Their study might provide novel insights on the potential of CaSR as a therapeutic target for AD. Wu et al. examined whether steroid receptor coactivator 1 (SRC-1) is involved in pathogenesis of AD. Tyagi et al. reviewed the role of cyclooxygenases (COX) and mammalian/mechanistic target of rapamycin (mTOR) and potential therapeutic approaches targeting COX-2 and mTOR in AD and cancer.Based on live-cell imaging combined with behavioral tests, Bjorkli et al. reviewed the preclinical and clinical investigations of commonly used biomarkers in animal models of AD and AD patients respectively. They also provided recommendations for standardization of procedures in sample collection to enhance the translational validity of preclinical study using AD animal models.Zhang, Chen, et al. reviewed the researches about TDP-43 and its relationship with limbic-predominant age-related TDP-43 encephalopathy (LATE).TDP-43 is a protein related to amyotrophic lateral sclerosis (ALS) and many cases of tau-negative frontotemporal lobar degeneration. Zhang, Xie, et al. reported prospects of 2 kinds of reprogramming technologies for neurodegenerative diseases: (1) convert adult somatic cells to iPSCs and (2) directly reprogramming adult somatic cells to induced Neurons (iN).In an effort to develop neurodegenerative disease model at cellular level, Jang et al. provided updates on current progress in stem cell-derived dopaminergic neuron transplantation as a therapeutic alternative for PD. Yang, Zhang, et al. aimed to uncover the metabolic pathways across anatomical regions in the brain of PD and levodopa-induced dyskinesia (LID). Based on principal component analysis (PCA) and multivariate general linear model, the midbrain and right cortex were identified as the primary regions of metabolic abnormalities in PD and LID rats. In addition, PD and LID rats exhibited lower levels of synaptophysin (SYP). All results provided key insights for developing targeted therapies in PD. Harsanyiova et al. discussed the relationship between gastrointestinal tract and the pathology or treatment of PD symptoms.Bao et al. surveyed the various positron emission tomography (PET) radiotracers available for AD imaging and discussed their clinical applications especially in terms of early detection and cognitive relevance. Based on [18F]-APN-1607 PET tracer, Lu et al. detected tau deposition in AD and reported that individual tauopathy is correlated with impaired cerebral glucose metabolism and cognitive function. Using combined PET and MR imaging, Kim et al. investigated the effect of conductive hearing loss in an AD mouse model. The findings from their study indicated that even partial hearing loss could aggravate memory impairment in AD.11C-PE2I is a PET radiotracer targeting neuronal dopamine transporters (DaT). Ivanidze et al. investigated neurovascular unit (NVU) integrity by using arterial spin labeling (ASL) MR imaging and correlated the findings of NVU integrity with striatal DaT density from 11C-PE2I PET imaging. This exploratory research could serve as a foundation for further development of combined NVU and striatal DaT density as early disease biomarkers and potential new therapeutic targets. Based on 11C-CFT and 18F-FDG PET imaging data, Fei et al. studied the relevancy between UPDRS motor scores and PDQ39 mobility sub-scores.31P MR spectroscopy of parieto-occipital lobes with 7-Tesla MR imaging, Das et al. accurately quantified high-energy phosphate and membrane phospholipid metabolites in amnestic MCI (aMCI). Furthermore, they have also found that brain energy metabolism and membrane phospholipid indexes were related to cognitive performance in domains of executive function (EF), memory, attention, and visuospatial skills using aMCI.Based on partial volume-coil Liu, Jiang, et al. explored functional and structural properties of abnormal brain networks associated with PD. The authors showed that both the expressions of metabolic and structural patterns in PD patients were significantly higher than healthy controls, and verified their results in connectome analysis, which provided new information for elucidating the neuropathological mechanisms of PD. Shu et al. developed an integrative nomogram based on white matter radiomics biomarkers and nonmotor symptoms for the identification of early-stage PD.Tsai et al. explored the skull score (SS) distribution of tremor patients, and correlated the SS with image feature from customized skull density ratio (cSDR). This study provided useful information for clinical study of MR-guided focused ultrasound thalamotomy. Chiu, Tzeng, et al. found that the patients with tremor and vascular cognitive impairment (VCI) had high possibility of mixed pathology of PD and Lewy body disease (LBD).Ye et al. investigated the volumetric changes in thalamus and hypothalamus in ALS. The results from their study revealed no significant difference of the volume in thalamus and hypothalamus between ALS patients of normal frontotemporal function and healthy controls.Yu et al. identified the brain function activity differences between MCI patients with depression and MCI patients without depression using resting state MR imaging measurements. This study provided useful information for a better understanding of the relationship between depressive symptoms and memory deficits. Xing et al. explored the alterations in intra- and inter-network functional connectivity of multiple networks in presbycusis patients, suggesting that functional network connectivity can be used to predict potential cognitive impairment in their early stage.Wan et al. compared the changes in subcortical nuclei in older adults with cognitive frailty (CF) and studied their relationship with cognitive decline and physical frailty. Their results showed significant volume reductions in five subcortical nuclei, including the bilateral thalami, left caudate, right pallidum, and accumbens area in older adults with CF. Lee et al. used surface-based analysis to evaluate subcortical structural characteristics and its relationship with early onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD). The results from their study demonstrated that EOAD and LOAD might have different courses of pathomechanism.Qiao et al. examined the neural substrates and mechanisms that generate memory deficits, seizures, and neuropsychiatric abnormalities in encephalitis with leucine-rich, glioma-inactivated 1 (LGI1) antibodies. The results showed that neural disorder and behavioral deficits of anti-LGI1 encephalitis might be associated with extensive changes in brain connectivity and microstructure.Bruchhage et al. performed machine learning to assess the contribution of volume fraction myelin and gray matter volume. They proposed a refined model of cerebellar contribution to early AD development. The results from their study showed higher anterior cerebellar contribution to MCI and higher posterior cerebellar contribution to mild/moderate stages of AD for each tissue property. Ma et al. proposed a generative adversarial network (GAN) framework to distinguish brain images of human subjects of normal brain aging from those of human subjects with AD and frontotemporal dementia (FTD). The results from their study showed an accuracy of 88.28% in distinguishing human subjects of normal brain aging from those of human subjects with AD and FTD based on GAN framework derived from brain image.Hu, Li, Zhang, et al. found that periodontitis was associated with learning and memory impairment, probably induced by neuroinflammation via activating the toll-like receptor 4/Nuclear factor kappa B signaling pathway. Ding et al. aimed to evaluate the value of odors in olfactory identification (OI) test and other known risk factors for predicting incident dementia. The results from their study suggested that peppermint smell capability might be one of the useful indicators for predicting dementia. Nie et al. assessed the differences of eye movement parameters between healthy elderly individuals and patients with MCI. They found that cognitive deficits and eye movement indexes were correlated, which could be further explored as early markers for MCI.Yang, Huang, et al. proposed a neuroimaging approach to identify MCI using a deep learning method and functional near-infrared spectroscopy (fNIRS). Their results indicated that fNIRS imaging approach based on temporal feature maps as a promising diagnostic method for early detection of MCI and clinicians might use it as a tool for evaluation of MCI.The paper by Tseng et al. used multivariate time-series electrocardiogram (ECG) analysis to diagnose cardiovascular diseases. They investigated various ECG features and found some associations between features of ECG and medical records .Chiu, Hung, et al. studied the relationship between freezing of speech (FOS) and dementia with Lewy bodies (DLB). They designed a freezing of speech single questionnaire (FOSSQ) and compared the association factors of FOS in non-demented participants, patients with AD, vascular dementia (VaD), and DLB. The results of their study supported validity of the FOSSQ for discriminating DLB from individuals with non-demented or other forms of dementia. Similarly, Wang, Hung, et al. designed a novel questionnaire for visuospatial dysfunction (VSD) in DLB.Gupta et al. proposed different neuroimaging modalities combined with APOE genotype to form a multimodal system for discrimination of AD to increase the classification accuracy.To distinguish stable MCI (MCIs) from converting MCI (MCIc), Lin et al. developed an extreme learning machine (ELM)-based grading method to predict MCI-to-AD conversion. The method was validated by Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, with an accuracy of 84.7% in prediction of MCI progression to AD within 3 years.In order to determine whether a MCI patient is at high risk of progressing to AD, Wang, Wei, et al. conducted a systematic review and meta-analysis to assess the available preclinical evidence and possible mechanisms of baicalein for animal models of PD. Li et al. investigated the efficacy and safety of 3 Erinacine A-enriched Hericium erinaceus mycelia (EAHE) capsules for the treatment of patients with mild AD. The study lasted for 49 weeks and the results showed that EAHE was well-tolerated without significant side effects. Flavonoid containing natural products, Myricetin (MYR) and Dihydromyricetin (DMY) are abundant in fruits and vegetables. Liu, Guo, et al. reviewed the benefits of MYR and DMY in AD patients at molecular level, including effects on amyloid-beta protein imbalance, neuroinflammation, dyshomeostasis of metal ions, autophagy disorder, and oxidative stress.Lai et al. compared and ranked 9 treatment methods for MCI in AD based on meta-analysis. They pointed out that music therapy might be the best treatment for MCI followed by acupuncture, among the nine treatment methods included for their meta-analysis. Similar to those non-pharmacological interventions, Pei et al. proposed a neurofeedback training based on mismatch negativity to regulate sensory ability and memory.The early intervention for MCI could decrease the rate of conversion from MCI to AD. Stuckenschneider et al. investigated the effects of a 12-month structured exercise program on the progression of 183 amnestic MCI patients. No significant improvement of cognitive performance was found based on the results from their study. In another study based on event-related measurement of auditory memory, Laptinskaya et al. found no improvements of cognitive performance in a 10-week unimodal cognitive or physical training and an active lifestyle for older adults at risk for dementia. In the narrative review by Meng et al., patients with AD who presented with long-term exercise interventions appeared to have improved blood flow, increased hippocampal volume, and improved neurogenesis. These results indicated that exercise intervention might be an important moderator to prevent long term disease progression.Kumar et al. reviewed and discussed nano-enabled drug delivery systems and their current and potential applications for the treatment of various NDs, including AD and PD, in studies to overcome the limits of blood-brain barrier (BBB). Huang et al. developed a medical red light treatment (RLT) device to treat older adults with mild to moderate AD. They planned a study protocol to verify the safety and efficacy for a 24 weeks period. On the other hand, Zhu et al. found that there was more efficacy via tele-health interventions in lowering depression for careers of dementia patients based on meta-analysis.Luo et al. reviewed the therapeutic effect of DBS in AD, and analyzed its stimulation parameters and potential mechanism of action. Tan et al. used a convolutional neural network (CNN) to classify handwritten digits and letters and applied dropout at different stages to simulate DBS effects on engrams. The results of their study showed that dropout of engram nodes might be a possible mechanism by which neuromodulation techniques could disrupt or enhance memory. Hwang et al. pointed out the applications of phase amplitude coupling-based phase-dependent DBS technique in PD, which aimed to deliver timed stimulation pulses to a specific phase precisely to modulate pathological network activities and behavior in real time.Deep brain stimulation (DBS) is widely used in the field of mental and neurological diseases. Tang et al. investigated the effect of electroacupuncture (EA) on cognitive impairment and the role of c-Jun N-terminal kinase (JNK) signaling pathway in AD model mice. The results of their study showed that EA could reverse cognitive deficits and substantially lower the burden of amyloid precursor protein. In another study, Hongna et al. demonstrated the improvements of locomotor function by promoting autophagy flux and inhibiting necroptosis in rats with spinal cord injury treated with Jia-Ji electro-acupuncture.In summary, large number of articles collected in this Research Topic reflected recent advances in mechanistic study of pathophysiology of AD and PD, development of biomarkers and molecular imaging techniques for diagnosis and treatment of AD and PD. We hope that publications of this Research Topic will not only report recent advances in ND research, but also facilitate translation of new discovery to development of new diagnostic tests and therapeutic agents for early diagnosis and treatment of ND, including AD and PD.JJ and KS wrote the draft. FP copyedited for the language. C-YH and W-MK reviewed and revised the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), are typically characterized by progressive neuronal loss and neurological dysfunctions in the nervous system, affecting both memory and motor functions. Neuregulins (NRGs) belong to the epidermal growth factor (EGF)-like family of extracellular ligands and they play an important role in the development, maintenance, and repair of both the central nervous system (CNS) and peripheral nervous system (PNS) through the ErbB signaling pathway. They also regulate multiple intercellular signal transduction and participate in a wide range of biological processes, such as differentiation, migration, and myelination. In this review article, we summarized research on the changes and roles of NRGs in neurodegenerative diseases, especially in AD. We elaborated on the structural features of each NRG subtype and roles of NRG/ErbB signaling networks in neurodegenerative diseases. We also discussed the therapeutic potential of NRGs in the symptom remission of neurodegenerative diseases, which may offer hope for advancing related treatment. Neurodegeneration is characterized by the progressive loss of neuronal structure and function, including the death of neurons, which deteriorates over time and eventually leads to dysfunction of the nervous system. Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic Ilateral sclerosis (ALS) and spinocerebellar ataxia  belong to the epidermal growth factor family of extracellular ligands, participating in the regulation of normal cells and tumor cell growth and survival through the ErbB family receptor tyrosine kinases  is a family of growth factors that plays multiple roles in many neurological disorders, including ALS  has been differently named as neu differentiation factor , heregulin , acetylcholine receptor-inducing activity , glial growth factor , and sensory and motor neuron-derived factor  was originally found in DNA sequence databases and DNA libraries when screening for genes with sequence similarities to members of the NRG1 family  was originally detected in adult pancreas and muscle and was initially identified as a necessary factor for tissue growth  is a neurodegenerative disease with insidious and progressive onset, mainly in the elderly, and its incidence increases with age  is a continuously progressive disease clinically characterized by changes in cognition or behavior  is pathologically characterized mainly by: (1) senile plaque formed by abnormal deposition of β-amyloid protein outside neurons; and (2) NFTs formed by abnormal phosphorylation of tau protein   such as the C-terminal fragments of APP (APP-CTs) have been reported to exert cytotoxic effects in neuronal cells  represents a potential treatment for AD, and lots of BACE inhibitors are progressing through clinical trials at present  increase the levels of pErbB4 receptor and pAkt, and increase the level of Bcl-2 both in in vitro studies and APP/PS1 transgenic mice  family, NRG2 can bind directly to ErbB3 and ErbB4, thus transactivating ErbB2 , a specific ligand for ErbB4 and a neuronal-enriched neurotrophin, has been identified as a protein structurally related to the NRG1. It is involved in the genetic predisposition to a broad spectrum of neurodevelopmental, neurocognitive and neuropsychiatric disorders, including AD, autism and schizophrenia  and the risk of AD development  and in the family sample (p = 0.0166), indicating that genetic variants in the NRG3 gene play a role in AD and SNPs in the NRG3 genes and were more strongly associated with AAO of AD  follows AD as the second severe neurodegenerative disease  toxin-based mouse model of PD, researchers also found that systematic administration of NRG1β1-ECD can rescue nigral dopaminergic neurons via the ErbB4 receptor tyrosine kinase , also known as motor neuron disease (MND) or Lou Gehrig’s disease, is a disease that causes the death of neurons controlling voluntary muscles  of spinal motor neurons (Lasiene et al., In a recent study on the relationship between ErbB4 and ALS/FTD, ErbB4 mutation was found for the first time in ALS/FTD and that its mutation reduced auto-phosphorylation of upon NRG1 stimulation (Sun et al., Schizophrenia is one of the serious psychiatric diseases whose etiology is not fully elucidated. The main clinical characteristics of schizophrenia are perception, thinking, emotion and behavioral disorientations (Owen et al., NRG1 (Harrison and Weinberger, NRGs and the increased risk of schizophrenia development may be determined by the wide-ranging effects of NRGs on brain functions (Wang et al., Studies suggest that NRG1/ErbB4 interactions play a vital role in the pathological mechanism of schizophrenia (Li et al., NRG1 or ErbB4 gene in some schizophrenia patients (Walss-Bass et al., NRG1 or ErbB4 may only account for a small part of schizophrenia cases (Harrison and Weinberger, The direct and chronic disturbance of NRG1/ErbB4 signal transmission, such as the mutation of NRG3 are associated with cognitive and psychotic symptom severity, which is accompanied by increased expression of prefrontal cortical NRG3 (Meier et al., In order to reveal the role of NRG2 in the modulation of behaviors with relevance to psychiatric disorders, Vullhorst et al.  found a Although scientists are looking forward to finding cures for neurodegenerative diseases with complex and unclear pathogenesis, no comprehensive and effective treatments and drugs have been developed. The results of a growing number of studies suggest that NRG1 regulates cell maintenance, differentiation, proliferation, migration, and survival or apoptosis in both neuronal and nonneuronal cell types (Mei and Xiong, Current evidence has indicated that NRGs play important roles in neurological disorders such as brain trauma (Fricker et al., In order to strengthen the understanding of NRGs in neurodegenerative disease prevention and treatment, further relevant mechanisms need to be clarified in the future. More in-depth future research on NRGs is necessary to improve diagnostic solutions for neurodegenerative diseases, thereby reducing the burden on both patients and families.W-jZ: conceptualization. W-jZ, G-yO, and W-wL: writing—original draft preparation. W-jZ and G-yO: writing—review and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Sci., 2021, 12, 14432–14440, DOI: 10.1039/d1sc04138j.Correction for ‘Plasticizer and catalyst co-functionalized PEDOT:PSS enables stretchable electrochemical sensing of living cells’ by Jing Yan  The authors regret that there was an error in the equation of the calibration curve of PPL/PDMS in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


Helicobacter pylori) has been classified by the International Agency for Cancer Research as carcinogenic in humans but many other are the subject of intense research. Most studies on the role of microbiota in GI tract oncogenesis focus on pancreatic and colorectal cancers with the following three species: Helicobacter pylori, Escherichia coli, and Porphyromonas gingivalis as likely causative factors. This review summarizes the role of bacteria in GI tract oncogenesis.Disturbances in gastrointestinal (GI) microbiota could play a significant role in the development of GI cancers, but the underlying mechanisms remain largely unclear. While some bacteria seem to facilitate carcinogenesis, others appear to be protective. So far only one bacterium ( Cancer is currently a major world-wide health problem: it is estimated that approximately 18.1 million new cancer cases and 9.6 million cancer-related deaths occurred in 2018 alone, and there is a 20% risk of developing cancer before turning 75 years old, and 10% risk of dying from it   correlated positively with tumor development, while members of the Clostridiales, especially Clostridium Group XIVa, were associated with decreased cancer risk, probably due to the production of butyrate, which has anti-inflammatory and anti-tumorigenic properties  mouse model in which gut microbiota changes, which occurred during tumorigenesis, supported increased tumorigenic process in the later stages , which develop spontaneous colitis due to microbial-induced activation of effector T cells , Firmicutes (mainly Streptococcus), and Actinobacteria (mainly Rothia) , while Firmicutes predominated in saliva and mouthwash (predominant taxa Streptococcus and Prevotella). Interestingly, Acinetobacter and Fusobacterium, which were enriched in the neoplastic tissue, remained increased in the late stage of OSCC facilitating cancer progression by their ability to cause local inflammation. Zhang et al. (F. nucleatum infections may cause cancer through their effect on MMP9 pathways and upregulation of cytokines such as tumor necrosis factor (TNF)-α, IL-1β, and IL-6 (Whitmore and Lamont 2014).Zhang et al.  examinedg et al.  performeg et al. . These ag et al. . It was Streptococcus  has become the focus of extensive microbiota analysis , but infection alone is not sufficient   dying within 5 years of initial diagnosis 2. Furthermore, the authors found that hypoxia, a dominant feature of the PDAC microenvironment, greatly enhances P. gingivalis intracellular survival , complement activity and TLR4 activation. These effects facilitate local inflammatory responses that contribute to progression of periodontitis  is currently the third leading cause of cancer-related death worldwide . Although HCC is closely related to chronic infection with hepatitis B virus and hepatitis C virus as well as to chronic liver damage   increased intestinal permeability caused by alterations in the tight junctions between enterocytes allowing for the inflow of such harmful substances as LPS into portal blood. (2) Modification of specific receptor activity which consequently allows for passage of microbial metabolites into circulation. (3) Increased secretion of biochemically active factors  was proposed by Ni et al  and 13 potentially harmful bacteria, which are often increased in these patients   is the second leading cause of cancer death in the USA  showed that B. fragilis was proposed as a likely carcinogen because of its ability to produce metalloprotease in CRC patients  are also likely to be important for colonic tumorigenesis  through TLR4 expression on CRC cells F. nucleaKanazawa et al.  studied Bacteroides fragilis toxin which decreases E-cadherin on the surfaces of epithelial cells loosening intercellular junctions and thus allowing for an increased inflow of harmful substances and antigens from the gut (Sears et al. Several mechanisms have been proposed to explain the effect of bacteria on CRC development. The “alpha-bug” hypothesis assumes that bacteria induce CRC by a specific action such as the one described for E. coli and B. fragilis already at an early noncancerous stage (Dejea et al. Interestingly, the colonic mucosa biofilm in patients with familial adenomatous polyposis was reported to be composed mainly of F. nucleatum has been confirmed in studies involving global cohorts. However, this biomarker is not sufficiently specific and sensitive to allow for non-invasive CRC diagnosis (Chang et al. Streptococcus bovis, which has been associated with colon cancer (Tjalsma et al. S. bovis antigen profiles could distinguish 11 out of 12 colon cancer patients from 8 control subjects, whereas E. coli antigen profiles were not useful (Tjalsma et al. S. bovis antigen profiles were also detected in patients with polyps, suggesting that this infection occurs in the early stage of carcinogenesis. This could be a promising diagnostic tool for the early detection of human colon cancer (Tjalsma et al. Based on metagenomic analyses a number of microbes have been proposed as biomarkers of CRC, but only Probiotics show promise as agents of host–microbiome modulation therapies for several diseases, including CRC (Torres-Maravilla et al. Although the overwhelming majority of studies support the role of the microbiome in cancer, some authors did not find significant associations. For example, in the study by Olson et al.  there weA large number of studies have been devoted in recent years to the analysis of the role of microbiota in GI oncogenesis. New treatments such as fecal transplantation, phage-based therapy, antibiotics, and probiotics therapies are currently tested in clinical settings to detect, prevent or improve the clinical course of various cancers. There is also a concerted effort to develop a fast, non-invasive, sensitive, and specific cancer detection test. However, these novel treatment interventions and diagnostic tests require validation in rigorous clinical trials before they could enter clinical practice.


Dauncey et al., Chem. Sci., 2019, 10, 7728–7733.Correction for ‘A dual photoredox-nickel strategy for remote functionalization  The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


Obesity is the result of an energy imbalance caused by an increased ratio of caloric intake to energy expenditure. In conjunction with obesity, related metabolic disorders, such as type 2 diabetes mellitus, dyslipidemia and hypertension, have become global health problems . ReducinGanoderma lucidum inhibits differentiation and lipid accumulation of 3T3-L1 adipocytes via reducing the expression of genes responsible for lipogenesis and the phosphorylation of mitogen-activated protein involved in cell proliferation and differentiation and is, thus, a promising natural agent for obesity and related metabolic diseases. Lee et al. [Schisandra chinensis ameliorates lipid accumulation and induces a brown fat-like phenotype through AMP-activated protein kinase in 3T3-L1 adipocytes. The authors also described that gomisin N inhibits adipogenesis and lipogenesis by enhancing fatty acid oxidation and thermogenesis and may have a potential preventive and therapeutic agent to combat obesity. Lee et al. [In studies using cell and animal models, Jeong and Park  providede et al.  showed te et al.  demonstrIn a human study, Auguet et al.  reportedIn a recent review, Kuryłowicz and Puzianowska-Kuźnicka  summarizThis Special Issue offers interesting findings from cell, animal and human studies on medicines for the treatment of obesity and suggests strategies for the development of future antiobesity therapies.


Chinese university students are at high risk for depressive symptoms and the ongoing coronavirus disease 2019 (COVID-19) pandemic may have exacerbated the mental health of university students. However, existing studies on depressive symptoms in Chinese university students during the COVID-19 pandemic reported a wide range of prevalence estimates, making mental health planning for this population difficult. The objective of this study was to conduct a systematic review and meta-analysis of surveys that assessed the prevalence of depressive symptoms in Chinese university students amid the COVID-19 pandemic.Major Chinese  and English  databases and preprint platforms were searched to identify cross-sectional studies containing data on the prevalence of depressive symptoms in Chinese university students during the pandemic. Two authors independently retrieved the literature, evaluated the eligibility of potential studies, assessed the risk of bias (RoB) of included studies, and extracted data. RoB was assessed with the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data.I2 = 99.9%, p < 0.001). The pooled prevalence of depressive symptoms was 26.0% (95%CI: 23.3–28.9%), which was significantly higher in female than in male students , in postgraduates than in undergraduates , in students living inside than in those living outside the COVID-19 epicentre , in students from universities at the epicentre than in those from universities outside the epicentre , in students who had close contact with COVID-19 than in those who did not , and in students who had acquaintances or relatives infected with COVID-19  than in those who did not. Five sources of heterogeneity were identified from the subgroup analysis: survey period, % of males among the survey sample, scale of depressive symptoms, cutoff score of the scale and level of RoB.In total, 1177 records were retrieved, and 84 studies involving 1 292 811 Chinese university students during the pandemic were included. None of the included studies were rated as completely low RoB. Statistically significant heterogeneity in the prevalence estimates of included studies was detected (Over one-fourth of Chinese university students experienced depressive symptoms during the COVID-19 pandemic. Mental health services for this population should include periodic evaluation of depressive symptoms, expanded social support and psychiatric assessment and treatment when necessary. It is also necessary to design depression prevention programmes that target higher-risk cohorts of university students. The transition is challenging because of the high level of academic and employment stress and the prevalent interpersonal, romantic and emotional problems in this particular stage for university students  pandemic has caused a global mental health crisis. Lessons learned from the 2003 severe acute respiratory syndrome (SARS) epidemic in China suggest that depressive symptoms are one of the most common mental health problems among university students; for example, during the SARS epidemic, 25.4–29.6% of the Chinese university students had depressive symptoms  guidelines, and the protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD 42020206666.The inclusion criteria for eligible studies were (a) cross-sectional surveys or baseline surveys of cohort studies with meta-analysable data ; (b) study subjects were Chinese university students, including overseas students and postgraduates; (c) the presence of depressive symptoms was assessed with standardised instruments and (d) the study was conducted during the COVID-19 pandemic (since 1 January 2020). We excluded studies with mixed samples that did not present results separately for university students and studies that assessed depressive symptoms with unstandardised instruments .We searched potential studies published between 1 January 2020 and 10 February 2021 in both Chinese and English bibliographic databases: China National Knowledge Infrastructure, Wanfang data, VIP Information, PubMed, Embase and PsycInfo. Key terms used were: (adolescen* OR teenager* OR youth* OR student* OR young adult* OR undergraduate* OR universit* OR college*), (coronavirus disease 2019 or severe acute respiratory syndrome coronavirus 2 or COVID-19 or COVID) and (depress*). To avoid missing relevant studies, reference lists of the retrieved reviews and included studies were also hand-searched. Preprint servers were also searched to retrieve grey literature: medRxiv, bioRxiv, PsyArXiv, ChinaXiv and Research Square. The literature search was ended on 12 February 2021. Detailed search strategies are provided in online Supplementary Table 1.By using a predesigned electronic form, the following variables were extracted from included studies: first author, study site, study period, characteristics of the study sample, sampling method, sample size, survey method, assessment of depressive symptoms and rates of depressive symptoms. According to the State Council Information Office of the People's Republic of China  Critical Appraisal Checklist for Studies Reporting Prevalence Data (abbreviated as ‘JBI checklist’ hereafter) to assess the RoB of included studies , a fixed-effect model was used to generate the pooled estimates; otherwise, the random-effect model was used. The pooled rates of various cohorts were compared by using the Z test. We used subgroup analysis to explore the source of heterogeneity in the prevalence estimate of depressive symptoms. The Q-value test was used to test the significance of differences in prevalence rates between subgroups. Publication bias was assessed with funnel plots and Begg's test, since Begg's test is fairly powerful for large meta-analyses that include 75 or more original studies  for the prevalence of depressive symptoms in the whole sample and in various cohorts of the sample. Forest plots were adopted to display the prevalence rates and pooled estimates. We used the et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., n = 37), followed by Zung's Self-rating Depression Scale (SDS) (n = 22), the depression subscale of the Symptom Checklist-90-Revised (SCL-90-R) (n = 8), the depression subscale of the Depression, Anxiety and Stress Scale – 21 Items (DASS-21) (n = 7) and the Center for Epidemiologic Studies – Depression Scale (CES-D) (n = 7). The average and median reported prevalence rates of depressive symptoms were 27.3% and 25.8%, respectively. Other detailed characteristics of the included studies are shown in The process of study inclusion is shown in n = 62) and problematic sampling method (n = 58) (online Supplementary Table 2).In total, 31 studies had a RoB score of ‘0–3’, 42 had a RoB score of ‘4–6’ and 11 had a RoB score of ‘7–8’. No study was scored nine. The two most common methodological issues were inappropriate sample frame  . Pooled v. 28.6%, p < 0.001), in students with siblings than in only child students , in overseas than in domestic students , in postgraduates than in undergraduates , in students living in Hubei than in those living in provinces other than Hubei , in students from universities of Hubei than in those from universities of other provinces , in students who were in close contact with COVID-19 than in those who had no history of COVID-19 contact , and in students who had friends, classmates or relatives infected with COVID-19 than in those who did not   .Table 2p value of the Begg's test was 0.169. No statistically significant publication bias was detected across the 84 included studies.As shown in v. 21.8%, p = 0.015), in studies with a percentage of males <50% than in those with a percentage of males ⩾50% , in studies assessing depressive symptoms with CES-D than in those using SCL-90-R , in studies defining the presence of depressive symptoms as ‘PHQ-9 ⩾ 5’ than in those defining it as ‘PHQ-9 ⩾ 10’ , and in studies with a high RoB than in those with a low RoB .Five factors were identified as sources of heterogeneity across included studies : survey v. males), in students with siblings (v. only children), in overseas students (v. domestic), in postgraduates (v. undergraduates), in students living within the COVID-19 epicentre (v. those living outside), in students from universities at the epicentre (v. those from universities of provinces other than Hubei), in close contacts of COVID-19-infected persons (v. those without a history of COVID-19 contact) and in students who had COVID-19-infected friends, classmates or relatives (v. those who did not). In addition, 1.69% of Chinese university students had severe depressive symptoms.This systematic review and meta-analysis summarised studies estimating the prevalence of depressive symptoms among Chinese university students amid the COVID-19 pandemic. We found an overall prevalence rate of 26.0% of depressive symptoms in Chinese university students and significantly higher rates in female students   .et al., et al., et al., One possible explanation for the higher risk of depressive symptoms in overseas than in domestic students is the status of ethnic minority groups in foreign countries , the sample representativeness of overseas students may be limited in our study. Finally, patterns of utilisation of mental health services among depressed students are very important for mental health planning and policy-making in the context of the COVID-19 pandemic, but the included studies provided little information on service use.This study has some limitations. First, none of the included studies were rated as completely low RoB. Subgroup analysis according to RoB level found a significantly higher prevalence of depressive symptoms in studies with a high level of RoB, so it is possible that the reported overall pooled estimate overestimates the true prevalence. Second, because several included studies used strict criteria to define the presence of depressive symptoms (i.e. PHQ-9 ⩾ 10), we may have underestimated the prevalence of depressive symptoms. Given the above two limitations, it is difficult to assess the magnitude and direction of bias in the prevalence estimate. Cautions are needed when generalising our findings. Third, even after stratifying the studies, high levels of heterogeneity were still kept within each strata of study in the subgroup analysis, so there remained other factors associated with the risk of depressive symptoms that were not identified. The heterogeneity of the results suggests that further rigorously designed studies using widely accepted assessments of depressive symptoms and representative samples of Chinese university students amid the COVID-19 pandemic are warranted to arrive at accurate estimates. Fourth, because of the small number of studies during the postoutbreak period, longitudinal data are needed to examine the trajectory of depressive symptoms in Chinese university students in the postpandemic era. Fifth, since the sample size of overseas students was relatively small  indicate that cohort-specific prevention programmes, which are probably cost-effective, need to be designed.China is a mental health services resource-poor country, so university managers and staff, including campus psychological counselors, should have a critical role in depression prevention; for example, they could provide expanded social support to students at risk, engage in follow-up care, mental health education and periodic screening of depressed students and promote social connectedness between students. Although the pandemic increases physical distances between staff and students, support services can be easily provided to students via smartphones.In addition, the 28.9% prevalence of depressive symptoms during the postoutbreak era in this study  and some


There is growing evidence that damage to spermatozoa by reactive oxygen species (ROS) play a key role in male infertility. The aim of the present study was to assess seminal plasma levels of total antioxidant capacity (TAC), free 8-Isoprostane and activities of catalase and superoxide dismutase (SOD) in men with asthenozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospermia compared with normozoospermic males.The patients consisted of 46 men with seminal parameters abnormalities. The patients were grouped into asthenozoospermic (n = 15), asthenoteratozoospermic (n = 16) and oligoasthenoteratozoospermic (n = 15). The control group consisted of 16 healthy males with normozoospermia. Catalase activity was measured by Aebi spectrophotometeric method. Levels of TAC and SOD were measured by commercially available colorimetric assays. Level of free 8-Isoprostane was assessed by commercially available enzyme immunoassay (EIA) method. Differences between groups were assessed using Mann-Whitney U test and Kruskal-Wallis test. Coefficients of correlation were calculated using Spearman's correlation analysis. All hypothesis tests were two-tailed with statistical significance assessed at the p value < 0.05 level with 95% confidence intervalsLevels of catalase and TAC were significantly lower in patients than the control group. No significant changes were seen in SOD activities. Levels of free 8-Isoprostane were significantly higher in patients than the control group. Furthermore, asthenozoospermic, asthenoteratozoospermic and oligoasthenoteratozoospermic groups had significantly lower values of catalase activity and TAC when compared to normozoospermic males. Levels of free 8-Isoprostane were significantly higher in all patients subgroups than the control group. Levels of catalase and TAC were positively correlated with sperm motility and morphology. Free 8-Isoprostane levels showed an inverse correlation with sperm motility and morphology.Decreasing seminal plasma antioxidants levels, especially catalase and TAC, could have significant role in etiology of impaired sperm function. Measurement of 8-Isoprostane may be used as a specific biomarker for assessing oxidative stress on sperm. In the etiology of male infertility, there is growing evidence that damage to spermatozoa by reactive oxygen species (ROS) play a key role ,2. Spermet al study showed statistically significant change in activity of SOD in infertile men compared to normozoospermic samples. They also observed that the SOD activity exceeds values obtained for normozoospermic samples only in oligozoospermic males [et al investigated activities of SOD and catalase in men with asthenozoospermia, teratozoospermia and oligozoospermia compared to normozoospermic males. Their study showed a significant elevation in intracellular activity of SOD and decreasing in catalase activity in infertile samples [et al study showed that seminal plasma activity of SOD in infertile men is significantly grater than in fertile men while catalase activity is not different between these groups [et al showed seminal plasma enzymatic  and nonenzymatic (TAC) antioxidant capacities do not alter in the asthenozoospermic specimens, whereas SOD activity is lower in oligoasthenozoospermic samples than normozoospermic males [et al investigation showed that there is not a significant difference in seminal plasma or sperm SOD activity between normozoospermic and oligo- or asthenozoospermic males [et al observed that whole semen SOD activity is higher in men with oligoszoospermia than those with normozoospermia [et al study showed that seminal plasma TAC in infertile asthenozoospermic and asthenoteratozoospermic males is lower than fertile men [The findings on the seminal plasma catalase and SOD activities and total antioxidant capacity (TAC) are controversial. Sanocka ic males . In anot samples . Zini ete groups . The stuic males . Hsieh eic males . This grospermia . Koca ettile men . They alAvailable data on the impact of oxidative stress on sperm are based on the measurement of seminal plasma and sperm levels of malondialdehyde (MDA) by the thiobarbituric acid-reacting substance (TBARS) assay -25. ReceThe aim of the present study was to assess seminal plasma levels of TAC and free 8-Isoprostane and activities of catalase and SOD in men with asthenozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospermia compared to normozoospermic males.6/ml of ejaculate and specimens with hyperviscosity were excluded from this study. The criteria for sperm normality were as follows: sperm concentration ≥ 20 × 106/ml of ejaculate, sperm motility ≥ 50% and normal sperm morphology ≥ 30% [A case-control study was designed. Following Institutional Review Board approval, the semen samples were collected from the case and the control groups. All specimens were collected into sterile plastic containers by masturbation after an abstinence period of 3–5 days, and were analyzed within 1 h of collection. After allowing at least 30 min for liquefaction to occur, semen analysis was performed to measure sperm concentration, sperm motility and sperm morphology using Sperm Quality Analyzer IIC  ,30. Sampgy ≥ 30% ,29,30. Tgy ≥ 30% ,31. The 2O2 (250 μmol/L) was then added to all tubes, and absorbance (A2) was read exactly after 3 minutes. The difference between A2 and A1 (ΔA) was calculated. The TAC of the sample was then calculated by the following formula: TAC = Concentration of the Standard × (ΔA Blank - ΔA Sample)/(ΔA Blank - ΔA Standard). The results were expressed as mM.TAC was measured by colorimetric assay ,33. We u10 of standards and SOD activity was expressed as U/ml.SOD activity was measured by colorimetric assay ,31. We uCatalase activity was estimated by the method of Aebi . CatalasWe assessed free form of 8-Isoprostane and only the fraction shedded to seminal plasma from cell membranes.Free 8-Isoprostane was purified by affinity chromatography method . We usedAt first, the elution solution was evaporated to dryness using a vacuum centrifugation. Then, the concentration of free 8-Isoprostane was measured by enzyme immunoassay (EIA) method . We usedDifferences between groups were assessed using Mann-Whitney U test and Kruskal-Wallis test. Coefficients of correlation were calculated using Spearman's correlation analysis. All hypothesis tests were two-tailed with statistical significance assessed at the p value < 0.05 level with 95% confidence intervals. The data were expressed as the mean ± SEM. Statistical computations were calculated using SPSS 11.5 for windows software .Seminal parameters of the subjects are reported in Table Then, we examined the correlation between seminal parameters and seminal plasma levels of 8-Isoprostane, TAC, SOD and catalase in total case group. Levels of TAC showed a positive correlation with sperm motility  and morphology . We also observed a direct correlation between catalase activity and sperm concentration , sperm motility , and sperm morphology . Seminal plasma levels of free 8-Isoprostane showed an inverse correlation with sperm motility  and sperm morphology . Levels of SOD did not show any correlation with seminal parameters.The most relevant findings of this study were (i) significant elevation of seminal plasma levels of free 8-Isoprostane and decreasing of catalase and TAC levels in asthenozoospermic, asthenoteratozoospermic, oligoasthenoteratozoospermic samples compared with normozoospermic men (ii) both catalase and TAC showed a positive correlation with sperm motility and morphology while an inverse correlation was seen with free 8-Isoprostane levels.et al [et al results about catalase activity in infertile men [et al. evaluated antioxidant capacity of seminal plasma in asthenozoospermic and oligoasthenozoospermic specimens with normal viscosity and hyperviscosity [et al., we observed a significant decrease in catalase activity and TAC in men with asthenozoospermia compared to normozoospermic men. Our finding about SOD activity in asthenozoospermic men was similar to Siciliano et al study. In another study, Hsieh et al evaluated SOD activities in seminal plasma and spermatozoa in infertile men with normozoospermia and oligoasthenozoospermia [et al also observed that SOD activities of seminal plasma and sperm are positively but nonsignificantly correlated with sperm motility and concentration. Our results about the SOD activity of the seminal plasma in oligoasthenozoospermic men were similar to Hsieh et al study. Koca et al evaluated TAC in infertile asthenozoospermic and asthenoteratozoospermic men compared to normozoosperic fertile men [et al study also showed that TAC correlates positively to sperm motility. We also observed these findings. Tkaczuk-Wlach et al evaluated activity of SOD in the whole semen of patients with oligozoospermia compared to patients with normozoospermia [et al study was limited by the fact that they used whole semen sample, because the membrane-bound oxidases or antioxidants associated with cellular debris and/or organelles can influence activities of antioxidant enzymes such as SOD and catalase [Our findings about activities of SOD were contradicted the results of Sanocka et al ,11. Our iscosity . Their sospermia . They obtile men . Their sospermia . Their scatalase .et al study [et al also observed that there is an inverse significant correlation between seminal plasma TAC and ROS levels. They suggested that the inverse correlation between TAC and ROS might be associated with an increase in the consumption of soluble, non-enzymatic antioxidants in seminal plasma which is resulted from over production of ROS. In our study the correlation between TAC and sperm morphology was positive. According to Gil-Guzman et al study, this finding could be interpreted that in semen with high rate of abnormal forms, because of high levels of ROS production, consumption of non-enzymatic antioxidants will be higher.Immature spermatozoa with abnormal morphology and cytoplasmic retention are the most sources of ROS production in semen. This has been confirmed by Gil-Guzman al study . Their set al [et al and our study might suggest that the higher level of antioxidant status prevents lipid peroxidation in spermatozoa and therefore results in higher sperm motility. Hsieh et al observed a slightly positive correlation between seminal plasma SOD activity and sperm concentration [et al. Immature spermatozoa generate primary superoxide anion. This anion is dismuted to hydrogen peroxide by SOD activity. Detoxification of hydrogen peroxide is carried out by catalase activity. Hydrogen peroxide is the primary toxic ROS for human spermatozoa that its high concentration induces lipid peroxidation and results in cell death. Therefore, the balance of the SOD and catalase activities in semen is important for maintaining sperm motility [The inverse correlation between lipid peroxidation and sperm motility has been shown by Keskes-Ammar et al . In our ntration . Their imotility .Our results are agreed with some previous studies that show increasing of lipid peroxidation by measuring MDA in sperm and seminal plasma in males with asthenozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospemia ,23. SimiMDA is widely used index of lipid peroxidation due to its simplicity. The TBARS test application to body fluids and tissue samples is unreliable. Application of a gas chromatography/mass spectrometry (GC/MS) assay for MDA has indicated that the commonly used TBARS assay overestimates the actual MDA levels by more than 10-fold, possibly resulting from cross reactivity with other aldehydes and the harsh conditions used in sample preparation .sn-2 position of phospholipids by phospholipase A2, isoprostanes are formed initially in situ, where they may contribute to the effects of oxidative stress on membrane biophysics. Measurement of 8-Isoprostane may provide a reliable marker of lipid peroxidation in vivo, because, it is a stable compound. In addition, 8-Isoprostane is specific product of free radical-induced lipid peroxidation. 8-Isoprostane has also been found to be present in detectable quantities in all normal biological tissues and in free form in all normal biological fluids. This is important because it allows the definition of a normal range such that small increases in its formation can be detected in situations of mild oxidant stress. Finally, the levels of 8-Isoprostane is unaffected by lipid content of the diet [Recent studies have focused on 8-Isoprostane, as an index of lipid peroxidation. Isoprostanes are formed in situ in cell membranes; following free radical attack on the arachidonic acid. Unlike prostaglandins, which are formed from arachidonic acid following its release from the the diet ,28.Evidence is beginning to emerge suggesting that isoprostanes are not only markers of oxidative injury, but active participants in the pathophysiology of some disorders. The capacity of isoprostanes to readily esterify to cell lipid membranes, and the resulting marked distortion of membrane structure and function, undoubtedly contribute to their pathophysiologic potential. As well, the existence of specific receptor for isoprostanes has been proven . So, becIt is concluded that decreasing seminal plasma antioxidant status, especially catalase activity and TAC, may have significant role in the etiology of impaired sperm function. Measurement of 8-Isoprostane may be used as a specific biomarker for assessing oxidative stress on sperm. However, further studies with a larger sample size are required to confirm these findings.The author(s) declare that they have no competing interests.Ali Khosrowbeygi carried out all of the experiment and participated in data analyzing and writing the manuscript.Nosratollah Zarghami designed the study and participated in data analyzing and writing the manuscript.The pre-publication history for this paper can be accessed here:


Several authors advocate spleen preserving distal pancreatectomy, because of the increased complication rate after splenectomy.Postoperative complications and survival after distal and total pancreatectomy, were recorded and retrospectively analyzed according to spleen preservation. Patients, who underwent distal and total pancreatectomy without histologically proven adenocarcinoma, or extrapancreatic disease, were included in the cohort which was divided into splenectomy and no splenectomy groups. Statistical analysis was performed using Fisher's test.The study group consisted of 62 patients who underwent distal and total pancreatectomy between 26/11/1987 to 6/1/2006. Splenectomy was performed in 35 out of 62 patients (56.5%), distal pancreatectomy was performed in 49 out of 62 patients (79%). Morbidity rate was 28.6% in splenectomy group and 14.8% in the no splenectomy group (p = 0.235), while 30 days mortality rate was 2.9%; one patient died in the splenectomy group (p = 1).Spleen-preservation did not influence the outcomes after distal and total pancreatectomy in our series. Pancreatectomy may be accompanied with splenectomy in distal and total pancreatic resections. Elective peripheral pancreatectomy is safer than pancreaticoduodenectomy, but carries a high morbidity rate -4; intraIn our study, postoperative complications after distal and total pancreatectomy, were recorded and analyzed according to spleen preservation, in patients with pancreatitis (chronic and acute), benign neoplasms and other benign diseases.th of November 1987 and 6th of January 2006. Patients with histologically proven adenocarcinoma, patients with cystadenocarcinoma, patients who underwent completion pancreatectomy after postoperative complication of pancreaticoduodenectomy, patients who underwent pancreatectomy because of abdominal trauma, patients who had hepatic metastases in laparotomy, patients who had cancer in the pancreatic head or lower common bile duct and patients who had additional procedures such as gastrectomy and colectomy were excluded from the study. The patients were divided into splenectomy and no splenectomy group. The following parameters were recorded and analyzed for each of the above mentioned groups: sepsis (SIRS and MODS), acute renal failure, pulmonary complications , ARDS , cardiac complications , central nervous system complications , intra abdominal abscess (defined as an infected fluid collection identified by CT or ultrasound scan-guided needle aspiration and microbiologic culture), postoperative primary intra abdominal hemorrhage , postoperative primary gastrointestinal hemorrhage (1ry GI), delayed gastric emptying, wound infection, wound dehiscence, first 30 postoperative days mortality.Prospective collected data were retrospectively analyzed for patients who underwent distal or total pancreatectomy with or without splenectomy between 28®, Chicago, IL, USA). A p value less than 0.05 was considered significant.Statistical analysis was performed using Fisher's two-tailed test, in the "Statistical Package for the Social Sciences" version 12 for Windows . After fulfilling the exclusion criteria, our study group consisted of the rest 62 patients who underwent total and distal pancreatectomy with or without splenectomy. The demography, types of operations and final diagnoses are shown in Tables Hospital data included 160 patients who underwent distal and total pancreatectomy between 28Using the Fisher's test no studied factor was correlated with splenectomy vs no splenectomy groups Table . InteresThe two cases of intra abdominal access were treated by the radiologist with a CT guided drainage. The only case of primary postoperative hemorrhage needed a reintervention after a failed embolization.The 30 days mortality rate in the study group of patients was 2.9%. One patient died (stroke) in the splenectomy group (p = 1). There was not recorded any postoperative death due to postsplenectomy sepsis.et al., [et al., [et al., [et al., [et al., [Spleen preserving distal pancreatectomy has been advocated by many authors, because of splenectomy associated immunologic alterations and septic postoperative complications ,16,24,25et al.,  and Beno[et al.,  studied [et al.,  studied [et al., ,27. Aldr[et al.,  in a gro[et al.,  demonstr[et al.,  studied [et al., , in a co[et al., ,4,28 aftThe authors conclude that spleen preservation does not influence the outcome after distal or total pancreatectomy, in benign diseases and selected benign neoplasms.The author(s) declare that they have no competing interests.IK: Designed the study, performed bibliographic research, drafted and revised the manuscript.AT: Carried out the data and participated in the writing process.RB: Participated in the design of the study, helped to draft the manuscriptand and performed the statistical analysis.SB, JB, DM: Participated in manuscript revision process.All authors read and approved the final manuscript.


The importance of prophylactic aspirin use in both developed and developing countries can hardly be overemphasized. I am troubled, however, by Stafford and colleagues' failure to cite and discuss United States studies that show much higher rates of antithrombotic use than they report . Using aTwo factors probably account for these differences. First, Stafford et al.'s federal surveys of ambulatory care encounters miss a significant proportion of aspirin use. Studies in a variety of populations that used direct patient surveys and other methods, some of which are cited in Brown et al. , have foThe experience of the nonprofit-integrated systems is also important because it calls into question Stafford et al.'s suggestion, emphasized in PLoS's accompanying synopsis, that direct-to-consumer advertising of statins explains the 1997–2000 dip in aspirin use in their data. Kaiser Permanente and HealthPartners members were equally exposed to direct advertising, but maintained high aspirin use during this period—despite probably also using statins (and angiotensin converting enzyme [ACE] inhibitors) at higher rates than individuals in other US care-delivery settings.The US nonprofit HMO experience nevertheless reinforces the authors' main conclusion that “aggressive and targeted interventions are needed to enhance provider and patient adherence to consensus guidelines for CVD risk reduction” . Aggress


The condition appears to be inherited in an autosomal dominant mode, although sporadic cases have been reported. It is a rare disease, a few families have been described in the literature. In the British family, the locus for oculo-oto-dental syndrome was mapped to 20q13.1 within a 12-cM critical chromosomal region. Dental management is complex, interdisciplinary and will include regular follow up, scheduled teeth extraction and orthodontic treatment. Hearing checks and, if necessary, hearing aids are mandatory, as well as eye examination and ad hoc treatment if necessary.The otodental syndrome also named otodental dysplasia, is characterised by a striking dental phenotype known as globodontia, associated with sensorineural high frequency hearing loss and eye coloboma. Globodontia occurs in both primary and permanent dentition, affecting canine and molar teeth ( The Otodental syndrome has been described under various names:• Otodental dysplasia ,2;• Familial otodentodysplasia ;• Globodontia; the term globodontia refers to the enlarged bulbous fused malformed posterior teeth with almost no discernable cusps or grooves -6;• In some families, an associated ocular phenotype was recognized  and it wThe condition has been described in at least 9 families. The first case of otodental syndrome was described in Hungary in a mother and her son by Denes and Csiba, 1969 ,8, a girThe otodental syndrome, also named otodental dysplasia, is characterised by a striking dental phenotype known as globodontia, associated with sensorineural high frequency hearing loss and eye coloboma.per se diagnostic. It consists mainly of enlarged canine and molar fused teeth  both in the primary and in the permanent dentition. The incisors are not affected. In a few cases described in the literature the condition was discovered in young children (around 3 years of age) [The dental phenotype is  of age) ,11 consuSensorineural high frequency hearing loss and coloboma was reported in the British family only ,8.et al., 1976 [et al., 2002 [et al., 1975 [Some authors have reported dysmorphic facial features. Witkop l., 2002  had alsol., 1975  had symmet al., 1975 [Constitutional short stature was diagnosed in a patient followed by Levin l., 1975 . HoweverThe association of sensorineural hearing loss and dental anomalies can be found in other syndromes:• autosomal recessive sensorineural hearing impairment, dizziness and hypodontia ;• bilateral sensorineural hearing loss and multiple anterior dens invaginatus ;• Kantaputra and Gorlin, 1992 [et al., 2002 [OOD was mapped to 20q13.1 within a 12-cM critical chromosomal region.The condition appears to be inherited on an autosomal dominant basis. In the British family described by Vieira l., 2002 , the locet al., 2002 [Sensorineural hearing loss of about 65 dB is found at all frequencies but is more pronounced at about 1000 Hz. It usually plateaus by the fourth decade . The agel., 2002 . Speech Frequent ear abscesses were noted in one patient .Differential diagnostic audiometric test suggested a cochlear site of lesion .et al., 2002 [Eye phenotype was described by Vieira l., 2002 . AbnormaThe gingiva was described as inflamed and enlarged in a patient . GingivaThe oral/dental anomalies affect both the primary and the permanent dentition and could be classified as anomalies of eruption, number, size, shape and structure.There was a significant delay in eruption of the primary and permanent dentition ,16, espeet al., 1988 [Missing teeth, especially premolars, were reported . The prel., 1988 .Large bulbous canines and molars crowns can summarize the clinical intraoral findings.globodontia [et al., 1981 [et al., 1975 [Permanent molars are malformed with fusion of cusps. The crowns of the canines and posterior teeth are enlarged, bulbous and malformed with multiple prominent lobules. The deciduous dentition is more severely involved. The relation between cusps and the major groove is eliminated hence the use of the term bodontia . Cook etl., 1981  describel., 1975  noted laThe canines have been described as large with a marked bulbous cingulum . Based oet al., 1971 [et al., 2001 [The average size premolars had convex occlusal surfaces with no developmental grooves or fossae . In the l., 1971  premolarAn enamel defect (hypoplasia) was frequently found on the buccal surface of canines .et al., 2002 insisted that the incisors were not normal, demonstrating also the yellowing and pitting enamel defects [The teeth might be prone to decay . The ena defects .The molars displayed taurodontism (an inverted crown-body/root ratio). The roots were short and tapered and some were taurodont in configuration . The decet al., 2002 described also the enlarged pulp chambers, the pulp stones and the abnormal root defects [Vieira  defects .et al. [Various malocclusions were described in the family members examined by Vieira et al. . Case 1 et al., 1988 [The boy presented by Chen et al., 1984 [Odontomas, the most common type of odontogenic tumors, were reported by Beck-Mannagetta l., 1984  in the pet al., 1984 and Toledo et al., 1971 [The histological findings described by Beck-Mannagetta l., 1971 ,20 showeIn the area of hypoplastic enamel, slightly reduced enamel thickness and alterations existed with prominent enamel rods, irregular incremental lines and rod sheath area containing voids, defects very similar to those observed in hypomaturation enamel defects. The amelodentinal junction in these areas was displaced towards the surface of the tooth and the subjacent underlying dentin had scanty irregular tubules .Genetic counselling is important. Inheritance is clearly autosomal dominant with complete  to variaad hoc treatment if necessary.Dental management is complex, interdisciplinary and will include regular follow up, scheduled tooth extraction and eventually orthodontic treatment. Hearing check and, if necessary, hearing aids are mandatory; as well as eye examination and The identification of the gene involved in this disease is of importance in our understanding of the development of various tissues and organs .