To evaluate the effectiveness of a Sepsis Fast Track (SFT) programme initiated at a regional referral hospital in Thailand in January 2015.A retrospective analysis using the data of a prospective observational study (Ubon-sepsis) from March 2013 to January 2017.General medical wards and medical intensive care units (ICUs) of a study hospital.Patients with community-acquired sepsis observed under the Ubon-sepsis cohort. Sepsis was defined as modified Sequential Organ Failure Assessment (SOFA) Score ≥2.The SFT programme was a protocol to identify and initiate sepsis care on hospital admission, implemented at the study hospital in 2015. Patients in the SFT programme were admitted directly to the ICUs when available. The non-exposed group comprised of patients who received standard of care.The primary outcome was 28-day mortality. The secondary outcomes were measured sepsis management interventions.Of 3806 sepsis patients, 903 (24%) were detected and enrolled in the SFT programme of the study hospital (SFT group) and 2903 received standard of care (non-exposed group). Patients in the SFT group had more organ dysfunction, were more likely to receive measured sepsis management and to be admitted directly to the ICU (19% vs 4%). Patients in the SFT group were more likely to survive  adjusted for admission year, gender, age, comorbidities, modified SOFA Score and direct admission to the ICUs.The SFT programme is associated with improved sepsis care and lower risk of death in sepsis patients in rural Thailand, where some critical care resources are limited. The survival benefit is observed even when all patients enrolled in the programme could not be admitted directly into the ICUs.NCT02217592. The study hospital used the published framework, SCAN-TEACH-TREAT programme to develop a context-specific quality of care improvement for sepsis in a tropical resource-limited setting.The study took advantage of a robust prospective observational study design that strengthened causal inference by providing pre-intervention information, having an appropriate control group from both pre-intervention and post-intervention periods and controlling important confounding factors  Score).We found that most measured sepsis interventions increased.The study did not record dosage of dobutamine, dopamine, epinephrine and norepinephrine, arterial blood gases were rarely performed and the modified SOFA Score (maximum 23) may be lower than the SOFA Score (maximum 24).The observational study may have residual confounding factors such as improvement of care and profile of organ failure recognition overtimes.Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection,7–10Following the SSC 2012,15Here, we analysed data from our prospective observational study of community-acquired sepsis patients presenting to a referral hospital in Thailand over 4 years (from March 2013 to January 2017)We conducted a retrospective study to evaluate the effectiveness of the SFT programme by using the data of a prospective observational study (Ubon-sepsis).10.1136/bmjopen-2020-041022.supp1Supplementary dataDetails of the Ubon-sepsis cohort have been published elsewhere.The reporting of this study follows the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Written, informed permission was obtained from participants prior to enrollment in the Ubon-sepsis cohort.2/FiO2 indices were not available for the majority of subjects due to infrequency of arterial blood gas tests, the score was modified as follows: subjects were scored a maximum of 2  if they received advanced respiratory support  and arterial blood gas test was not performed.For this study, we evaluated patients who were included into the Ubon-sepsis cohort and had community-acquired sepsis. Sepsis was defined as an infection with organ dysfunction in accordance with the 2016 international consensus (Sepsis-3) guidelines for sepsis.Main exposure of the study was the SFT programme. All patients included in the Ubon-sepsis cohort from March 2013 to December 2014 who received standard care were considered as the non-exposed group. Patients included in the Ubon-sepsis cohort from January 2015 to January 2017 who received standard care or received care in the SFT programme by attending medical teams using their criteria on admission  were conPatients in the non-exposed group received standard care according to local guidelines. Patients in the SFT group received the standard of care along with a recommended sepsis care protocol of the SFT programme. First, preprinted recommended doctor orders for the SFT programme were used as of January 2015 . The recThe primary outcome measure was 28-day mortality as recorded in the Ubon-sepsis cohort.16 17The sample size of the study was determined by the sample size of Ubon-sepsis cohort. We assumed that about 50% of 3806 sepsis patients in the Ubon-sepsis cohort were enrolled after the implementation of the SFT programme, of which 50% were enrolled in the SFT programme . We assumed that the mortality of the non-exposed group was 21% based on published data.2 test and Mann-Whitney U test to compare the proportions of binary variables and median of continuous variables between groups, respectively. The IQR is presented as 25th and 75th percentiles.All sepsis patients were included in the analysis regardless of whether they were enrolled before or after the implementation of the SFT programme. We used the χIn the primary analysis, we used multivariable Cox proportional hazard models to evaluate the effectiveness of SFT programme on 28-day mortality. The multivariable Cox proportional hazard model was used to adjust the difference between those receiving the SFT programme and the others.Using a conceptual framework, we also consider that admission directly to the ICU could also be a mediator between the SFT and the primary outcome; therefore, we developed another multivariable model not including the variable for direct admission to the ICU. The goodness of fit for the multivariable Cox proportional hazard model was tested with a Hosmer and Lemeshow test. For the Cox proportional hazard model, we assessed whether the HR was constant over time using Schoenfeld residuals.For the secondary endpoints, we used multivariable logistic regression models with similar independent variables as the model for 28-mortality outcome and used each sepsis management process as an outcome. We estimated the total effect of the SFT on each sepsis management by using the multivariable logistic regression models adjusted for difference in characteristics and disease severity of the patients. This was because each sepsis management could be caused by characteristics of the patients, disease severity and the SFT.20We also performed sensitivity analyses by using multivariable logistic regression model, excluding patients enrolled prior to the implementation of the SFT programme, and by replacing direct admission to the ICUs with admission to the ICUs within the first hospital day. All analyses were performed with STATA V.15.1 (StataCorp).No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for recruitment, design or implementation of the study. No patients were asked to advise on interpretation or writing the results. The results will be disseminated to the public through online social media.The observational cohort study (Ubon-sepsis) included 5001 patients presenting with community-acquired infections from March 2013 to January 2017, and 12 patients were excluded due to unknown 28-day mortality outcome. Three thousand eight hundred and six patients (76%) met criteria for sepsis within the first 24 hours of admission with a modified SOFA Score ≥2, and were included for the analysis. The primary outcome, mortality within 28 days, occurred in 205 of 903 (23%) in the SFT group and 574 of 2903 (20%) in the non-exposed group . In the As we considered that direct admission to the ICU could be a mediator between the SFT and the outcome, a sensitivity analysis was performed by excluding the variable direct admission to the ICU . The effWe also performed a sensitivity analysis by excluding the 1636 patients enrolled in the observational study prior to the implementation of SFT programme. Similar differences in baseline characteristics were observed when comparing 903 patients in the SFT group to the 1267 patients in the non-exposed group enrolled after the implementation of the SFT programme . A higheUsing multivariable logistic regression models, we found that patients in the SFT group were more likely to receive most sepsis management interventions than patients in the non-exposed group adjusting for baseline characteristics, severity of sepsis and direct admission to the ICU . Those iIn this study evaluating patients with community-acquired sepsis, enrollment into a programme to identify and initiate sepsis care implemented at the study hospital (SFT programme) was associated with 28% lower risk of mortality. In recent years, there has been an increasing need to understand benefit and cost effectiveness of implementation of sepsis care interventions in LMICs because of concerns that international sepsis guidelinesThe lower odds of receiving mechanical ventilation in the SFT group could be a sign of improved sepsis care. Patients in the SFT group are monitored closely either in or outside the ICUs, and the attending physicians aim to obviate the need for airway intubation when possible.It is not surprising that patients in the SFT group had more organ dysfunction than those in the non-exposed group. This is because the severity of organ dysfunction among patients with septic shock, respiratory failure and alteration of conscious can be assessed clinically on admission, and those patients could be enrolled in the SFT programme when the laboratory test results were not yet available. However, the non-exposed group was defined as having sepsis based on clinical findings and all laboratory test results within 24 hours of admission  may be lower than the SOFA Score (maximum 24). Nonetheless, the modified SOFA Score is strongly associated with mortality in sepsis.Our study successfully demonstrated effectiveness of a sepsis programme implemented in an LMIC. Measuring effectiveness of a sepsis programme is a complex issue, and we used a data of a prospective observational study and carefully controlled for severity of sepsis and temporal trends in our analyses. Care in sepsis patients improved after the implementation of the programme. Additional research is needed to better understand cost of the intervention, long-term benefits and impact of the programme on a national scale. National strategies aimed at saving lives from sepsis in LMICs should be encouraged. Such strategies should include analysis of resources and local circumstances, followed by development, implementation and assessment of customised programmes.


Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder characterized by the impairment of the cognitive function of a child. Studies suggested that the intestinal microbiota has a critical role in the function and regulation of the central nervous system, neuroimmune system and neuroendocrine system. Any adverse changes in the gut–brain axis may cause serious disease. Food preferences and dietary patterns are considered as key in influencing the factors of ASD development. Several recent reviews narrated the importance of dietary composition on controlling or reducing the ASD symptoms. It has been known that the consumption of probiotics confers several health benefits by positive amendment of gut microbiota. The influence of probiotic intervention in children with ASD has also been reported and it has been considered as an alternative and complementary therapeutic supplement for ASD. The present manuscript discusses the role of microbiota and diet in the development of ASD. It also summarizes the recent updates on the influence of dietary supplements and the beneficial effect of probiotics on ASD symptoms. An in-depth literature survey suggested that the maternal diet and lifestyle are greatly associated with the development of ASD and other neurodevelopmental disorders. Mounting evidences have confirmed the alteration in the gut microbial composition in children suffering from ASD. However, the unique profile of microbiome has not yet been fully characterized due to the heterogeneity of patients. The supplementation of probiotics amended the symptoms associated with ASD but the results are inconclusive. The current study recommends further detailed research considering the role of microbiome, diet and probiotics in the development and control of ASD. Autism spectrum disorder (ASD) is one of the serious neurodevelopmental disorders characterized by the impairment of the interactive and social communication ability of a child and the repetitive specific patterns of activities, behaviors (self-injuring activities), abnormal sensitivity and gastrointestinal (GI) difficulties ,2. The iSeveral recent studies revealed that the intestinal microbiota has a critical role in the function and regulation of the central nervous system, neuroimmune system and neuroendocrine system. Any adverse changes in the gut–brain axis may cause serious diseases such as autoimmune disorders ,9. The GFood preferences and dietary patterns are also considered as one of the key influencing factors of ASD development. Several recent reviews narrated the importance of dietary composition on controlling or reducing the ASD symptoms ,12,13. TSeveral studies proved that the probiotics  supplementation confers several health benefits by the positive amendment of gut microbiota ,15,16,17This review preparation was carried out by collecting related scientific information from Scopus, PubMed, Google Scholar and ASD-related databases using the keywords “autism” “autism and probiotics” and “autism and microbiota”. The relevant papers published in English were selected for the preparation of the manuscript without any chronological restrictions. The current manuscript narrates the updated information about the role of microbiome and diet in the development of ASD. This manuscript also explains the beneficial effect of dietary supplements and probiotics in the improvement of ASD symptoms. This review highlights that probiotics can be used as an adjuvant therapeutic agent and with added nutritious support (dietary supplements) but suggests that still more detailed studies are required to develop more efficient therapeutic methods to improve the quality of life of the ASD children.Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disorders characterized by the impairment of the social interaction and communication skills with rigid and repetitive behaviors. Autism affects both children and adults, based on severity and intellectual ability; they may either lead a normal life or suffer a devastating disability requiring institutional care . DistincMounting evidences revealed that de novo mutations, copy number variations, rare and common variants are major genetic factors leading to ASD. Around 50% of ASDs are hereditary caused due to defects in the gene and chromosomal abnormalities leading to disruption in the neuronal connection, brain growth and synaptic morphology ,21,22,23Non-predisposed factors such as exposure to environmental factors and pharmaceutical drugs, autoimmune disorder, microbial infection and diet during the prenatal and postnatal periods cause gut dysbiosis and immune dysregulation together contributing to ASD . Recent Gut–brain cross talk involves a complex communication system involved in the proper maintenance of GI homeostasis, which is termed as the gut–brain axis (GBA). The GBA is a bidirectional communication network between the central nervous system (CNS) and the enteric nervous system linking the emotional and cognitive centers of the brain with peripheral intestinal functions via neuro–immuno–endocrinal mediators . The bidGut microbiota interacts with the brain through endocrine and neurocrine pathways, while the brain influences the microbial composition through the autonomic nervous system with the active involvement of the immune and humoral systems. Gut microbiome modulates the brain by influencing the production of neurotransmitters such as serotonin, gamma amino butyric acid (GABA) and the brain-derived neurotrophic factor (BDNF) via short chain fatty acid, tryptophan metabolites, secondary bile acids and ketones thereby influencing memory and learning processes. These molecules transmit signals by interacting with the farnesoid receptor (FXR) and G protein-coupled bile acid receptor (TGR5) in the enteroendocrine cells (EEC), releasing fibroblast growth factor (FGF19), which readily crosses the blood–brain barrier and regulates the secretion of neuropeptide Y in the hypothalamus, thereby regulating the glucose metabolism via the release of glucagon-like peptide (GLP-1) ,36,37. TIn addition, the secretion of biologically active peptide by enteroendocrine cells, mainly involved in GBA interaction, is controlled by the nutritional level of microbiota. SCFA acts as the major signaling molecule mediating the gut microbiome–brain communication, via EEC and ECC. The brain influences the microbial population through several stresses: by altering the size and quality of the mucus secretion, by slowing the recovery of the migratory motor complex pattern, by the induction a transient delaying of gastric emptying, and by enhancing the frequency of cecocolonic spike burst activity, which affect the GI transit modulating the nutrient supply to enteric microbiota. Different psychological stressors in adults and newborns modulate the composition and biomass of enteric microbiota  Figure .Gut microbiota, which is non-genetic and inheritable, has a great impact on immune, metabolic and neuronal developments. As gut microbiota is a notable contributor for human health, gut microbial dysbiosis leads to negative consequences such as GI-tract-related disorders such as Crohn’s disease and ulcerative colitis, systemic diseases such as metabolomic disorders and CNS-related disorders . NoticeaWakefield and colleagues reported the incidence of a new variant inflammatory bowel disease (autistic enterocolitis), which is characterized by chronic patchy inflammation and lymph nodular hyperplasia in the ileum or colon of individuals with ASD . ScientiBacteriodetes and an increased ratio of Firmicutes to Bacteriodetes. Pyrosequencing of fetal microflora in the fecal stools of autistic children showed a high prevalence of Desulfovibrio species and Bacteroides vulgatus when compared to healthy volunteers [Clostridium and Ruminococcus species, while a real-time PCR analysis showed a rich source of Clostridium cluster groups I and XI and Clostridium bolteae [Clostridium hystolyticum in the ASD children compared to healthy children [Bifidobacterium and Enterococcus and an increased level of Lactobacillus strains, despite being beneficial, which is quite paradoxical. Commensal bacteria such as Bacillus spp. and Klebsiella oxytoca, that are neither harmful nor beneficial, were reported to be present in autistic children [Prevotella, Coprococcus and Veillonellaceae in ASD, substantiating the link between gut microbiome and ASD. Pyrosequencing results showed the altered gut microbial diversity in autistic children with a relatively high abundance of Caloramator, Sarcina and Clostridium genera, Alistipes and Akkermansia species, Sutterellaceae and Enterobacteriaceae and low level of Prevotella, Coprococcus and unclassified Veillonellaceae, concomitantly associated with the altered level of free amino acids and volatile organic compounds in fecal samples compared to the control samples [The metagenomic analysis of ASD-gut-microbiome showed mucosal dysbiosis with a low level of lunteers . The 16S bolteae . Culturechildren . The accchildren . A pilotchildren  reported samples . The aboClostridium, Bacteroides and Desulfovibrio. Experimental studies with rodents treated with propionic acid exhibited ASD-associated symptoms, such as impaired and restricted social behavior and cognition, together with an enhanced neuro-inflammatory response, which might be due to alteration in mitochondrial function or the epigenetic modulation of ASD-associated genes [p-cresol) and its conjugate p-cresylsulfate were observed in the urinary samples of children affected by autism. The increased level of p-cresol, derived either from the environment or gut microbiome, aggravates the ASD severity by inhibiting the neurotransmitters associated with enzymes and cofactors required for sulfonation reaction in the liver [The metabolites produced by gut microbiome affect the neural process based on their level. Metabolomic studies in urine, fecal and serum samples of ASD patients using LC-MS and GC-MS revealed an enhanced level of microbial metabolites, such as increased levels of SCFAs, para-cresol and ammonia, which affect the neural process ,51. SCFAed genes . The elehe liver . Urinary metabolomic research in ASD children revealed the presence of an abnormal level of common microbial metabolites such as dimethylamine, hippuric and phenylacetylglutamine and altered tryptophan, when compared to healthy children ,55. The Bacteroides fragilis colonization, restrict T helper cell response eliciting an autoimmune disorder [Several studies in human and animal models of ASD revealed the presence of an enhanced level of pro-inflammatory cytokines, brain-specific auto-antibodies in the cerebrospinal fluid and serum, illustrating an elevated immune response substantiating the fact that immune dysregulation acts as a key factor contributing to the pathophysiology of ASD ,59. Furtdisorder . AlthougEpidemiological and experimental studies revealed a strong linkage between maternal infection and the development of ASD in the offspring. The gut microbial composition of a newborn infant varies with respect to the mode of delivery primarily colonized by the maternal microbiota. Hence, any imbalance in maternal microbiome with respect to environmental stress or genetic risk will be transferred to the offspring at the time of birth ,65. ScieStudies strongly showed that the maternal diet plays a critical role in the ASD development in their offspring ,71. GeneIndividuals with ASD have a serious problem in their nutrition due to the stringent food selection, defects in food digestion and absorption. Children with ASD show high selectivity towards food containing starch, snacks and processed food, but deny fruits, vegetables and proteins . It is kKetogenic diets (KD) that are rich in fat (65–90%) are the common choice to manage the ASD. Several studies revealed some of the favorable impacts of KD on the behavior and symptoms of ASD in human and animal models ,78,79. HOmega-3 fatty acids (ω-3) are generally used as a food supplement and considered as a potent complementary and alternative therapeutic agent for ASD . Omega-3Oxidative stress is one of the factors associated with the etiology of ASD and the defect in the antioxidant system may affect the brain function and disturb the immune system ,91,92. TSeveral studies have been reported based on the role of the supplementation of minerals and multi-vitamins in improving the symptoms of ASD ,96,97. HOther food supplements such as fermentable saccharides and a polyols diet are also believed to have a protective effect on ASD. However, scientific evidence is lacking to support the aforementioned statement. Due to calcium deficiency, ASD children suffer from defective intestinal permeability, which roots for several GI-associated diseases and discomforts. In addition, the evidence to support the beneficial effects of the Feingold diet  is not sufficient. The results of the previous studies claimed that further extended research is essential before recommending any kind of food-based alternative therapy for ASD .The exclusion of some of the food materials is also significantly considered to improve the ASD and/or to prevent the worsening of the ASD. A gluten-free and casein-free (GFCF) diet is considered as one of the effective food-based alternative treatments for ASD since the peptides derived from gluten and casein can trigger inflammation ,100. AltRecent evidences showed that a high-fat diet  affects the dopamine system  and causes some of the ASD-associated behavioral changes ,110,111.Lactobacillus plantarum WCSF1 on the gut microbiota, gut function and the behavior of the children with ASD. Supplementation of L. plantarum WCSF1 (4.5 × 1010 CFU per day) to the ASD children (4 to 16 years old) significantly altered the fecal microbiota, a notable level of increase was observed in enterococci and lactobacilli group and a reduction was observed in Clostridium cluster XIVa. Bowel function was improved during the probiotic intake compared to the placebo feeding. The GI symptoms, such as intestinal bloating, abdominal pain and flatulence, were found not to be significantly altered, but stool consistency was observed to be improved significantly during the probiotic feeding compared to that of the placebo treatment. The behavioral scores assessed using the Development Behavior Checklist questionnaire were found to be improved during the probiotic feeding compared to baseline. The study suggested that the supplementation of WCSF1 amended the microbiota and behavior of ASD children [Parracho et al.  conductechildren .Lactobacillus strains, two Bifidobacterium strains and a Streptococcus strain  for four months decreased the amount of Bifidobacterium and Desulfovibrio spp. and also normalized the ratio of Bacteroidetes/Firmicutes in the feces of ASD-children. The study showed that the severity of the ASD has a strong positive correlation with the severity of the GI dysfunctions in the subjects. The level of TNFα was decreased after probiotic supplementation. No strong correlations were found between the plasma levels  and fecal microbiota. Overall, probiotic supplementation altered the composition of gut microbiota in ASD children [Tomova et al.  investigchildren .A study by Adams et al.  revealedCandida spp. and the ratio of d-arabinitol/l-arabinitol is one of the biomarkers of candidiasis. The supplementation of the probiotic  for two months to autistic children significantly reduced the level of urine d-arabinitol and d-arabinitol/l-arabinitol ratio and also improved the concentrating power and the ability to respond to an order [d-arabinitol is a metabolite of pathogenic an order . Lactobacillus delbrueckii subsp. Bulgaricus (reclassified as L. helveticus), L. acidophilus, B. breve, B. longum, B. infantis, L. paracasei, L. plantarum, S. thermophilus) for four weeks significantly improved the autistic core symptoms and reduced the severity of the GI symptoms in a boy (12-years-old) with ASD and a severe disability of cognitive function. Moreover, during the follow up treatment period (four months), a VSL#3 intervention reduced the Social Affect domain of Autism Diagnostic Observation Schedule (ADOS) score after two months of treatment and further reduced the score after another two months. There was no fluctuation in the ADOS score up to 10 months (follow up period). This study suggested that the proper use of probiotics may improve the ASD symptoms, but more research is necessary [A case study reported by Grossi et al.  revealedecessary .B. longum, L. rhamnosus, L. acidophilus; 1 × 108 CFU per gram; 5 g per day) for three months significantly altered the fecal microbiota of ASD children, specifically the level of Bifidobacteria and Lactobacilli, which were found to be increased after intervention compared to baseline. The severity of the ASD and the severity of the GI symptoms, were measured by ATEC and a six-item GI Severity Index (6-GSI) questionnaire, respectively, and were found to be reduced after probiotic supplementation in ASD children compared to baseline. The study suggested that probiotic supplementation improves the behavioral pattern and the GI discomforts in ASD children [The supplementation of a mixture of probiotic strains (children  (Table 1L. rhamnosus GG (1010 CFU per day) was supplemented to pregnant women for four weeks before delivery and continued the probiotic supplementation for six months to the mother (if breastfeeding) or to the infant. The clinical evaluation and behavioral assessments were made at three weeks and at 3, 6, 12, 18 and 24 months of age and final attention-deficit hyperactivity disorder (ADHD) and Asperger syndrome (AS) records were made at the age of 13. The results showed that probiotic supplementation reduced the risk of the development of a neuropsychiatric disorder compared to that of the placebo group [bo group .Mounting evidences confirmed the alteration in the gut microbial composition in children suffering from ASD. However, the unique profile of microbiome has not yet been fully characterized due to the heterogeneity of patients. GI disorders such as bowel dysfunction and GI tract inflammation are more frequent in severe cases of ASD. The findings of several recent studies showed that amendments of gut microbiota may improve the ASD symptoms and revealed the beneficial impact of probiotic supplementation on the improvement of symptoms of ASD, which suggest that probiotics can be used as a potent adjuvant therapeutic agent for neurodevelopmental disorders such as ASD. In addition, studies have suggested that the dietary regulations may strengthen the therapeutic advancement in ASD treatment. However, sufficient research evidence is missing to authenticate the potential effects of probiotics and dietary interventions on the symptoms of ASD. More scientific research is needed to address the issues such as the optimum dose and duration of probiotic supplementation for ASD treatment, the fate of microbial metabolites in the human body and the compatibility of dietary supplements and probiotics, which would help us to develop typical and effective treatment strategies to improve ASD symptoms. Overall, the improvement of the life quality of ASD children requires mutual and moral support from parents and society, in addition to therapeutic approaches.


It has been demonstrated that PDA can not only form uniform coatings on various organic and inorganic substrates including superhydrophobic surfaces, but also allow for further functionalization and secondary reactions. Due to its excellent biocompatibility and low cytotoxicity, PDA and its composite nanostructures have found many applications in various biomedical fields. This Research Topic collects a diverse range of fundamentals and applications of PDA, including nanomaterial synthesis, enzyme encapsulation, electrochemical sensing and antifungal agents.Polydopamine (PDA) is a brown-black insoluble biopolymer with a melanin structure. Inspired by the powerful adhesion of invertebrate mussels, PDA came to public attention as a new coating material in 2007. One of the advantages of PDA coating is its mild and simple process which is based on the Xiong et al. summarized the application of PDA in photosensitizer. This is an important emerging area particularly for photodynamic therapy field. PDA-based materials are leveraged to overcome many most crucial shortcomings of current photosensitizer such as low light stability, rapid blood clearance and poor water solubility. The second review article wrote by Talon et al. focused on the use of PDA to improve host responses to polytetrafluoroethylene-based implants, specifically for the treatment of the Congenital Diaphragmatic Hernia. The PDA coating on the polytetrafluoroethylene surface showed incredible performance for cell attachment. Based on the in vitro evaluation, in vivo experiments in rats were recommended by authors to further confirm the results.The Research Topic contains two review articles. Tran et al. reports the preparation of PDA hollow capsules by coating silica particles with PDA followed by dissolving silica template simply in water. Biomacromolecules such as catalase could be encapsulated into PDA hollow capsules with remained bio-functionality. This work provides an eco-friendly approach for hollow capsule fabrication which could be utilized as a drug delivery system. In the second work, Alves et al. investigated the antifungal performance of the polydimethylsiloxane after the surface modification of liposomal amphotericin embedded PDA. This work shows the liposomal amphotericin embedded PDA coating has an ability to prevent the attachment of Candida albicans and kill the adherent cells, without having toxic effect toward mammalian cells. The third work conducted by Fu et al. investigated the use of the PDA-functionalized graphene for the extraction of plant essential compounds for the electrochemical medical plant identification. The plant tissue wrapped by PDA-functionalized graphene has a very good film-forming property. Additionally, the PDA-functionalized graphene could adsorb and concentrate bioactive components from plant tissue and subsequently enhance the electrochemical signals.The three original research articles are showcases of three specific applications of DPA. The first work by in vivo study of the use of the PDA is worthy of exploring in the near future.The contributions in this Research Topic of Polydopamine-Based Nanostructures: Synthesis and Biomedical Applications highlight that manipulating PDA for surface modification enables to reach toward utilization. The applications covered in this Research Topic, supported by the state-of-the-art analysis and characterization, provide a dissection of the status of the field of the PDA-based biomedical applications. The 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.


The application of computer-aided design and computer-aided manufacturing (CAD/CAM) technology in dentistry has rapidly expanded. This survey aimed to investigate attitudes and current practice of dentists in Riyadh, Saudi Arabia regarding chair-side CAD/CAM technology. An online questionnaire was prepared and sent to a convenience sample of dentists in Riyadh. Questions related to practice aspects of chair-side CAD/CAM system, attitudes and training were presented. A total of 114 questionnaires were completed (77.6% response rate). Study population comprised dentists of a wide range of clinical experience who are working in the various regions of Riyadh city, Saudi Arabia. Of the participants, 27.2% indicated the presence of a chair-side CAD/CAM system at their current workplace and 57% used the chair-side CAD/CAM in the fabrication of dental crowns. The vast majority of participants (81%) believe that the overall quality of chair-side CAD/CAM restorations is at least as good as those fabricated by a lab technician or much better. Most responding dentists considered the chair-side CAD/CAM system as important in terms of time saving, boosting the number of visiting patients and income improvement. The willingness to dedicate the time and effort to learn the chair-side CAD/CAM technology was apparent amid a high proportion of dentists (75.4%). The findings of this pilot survey reflect broad satisfaction and positive attitude among the surveyed dentists towards use and outcome of chair-side CAD/CAM technology in the dental clinical practice. It seems that the CAD/CAM technology has infiltrated into the workflow of Saudi dental practices with speculations of growing implementation among the wider sector of dental practitioners in the future. Over the last two decades, the use and application of computer-aided design and computer-aided manufacturing (CAD/CAM) technology in dentistry has rapidly expanded . The higSo far the CAD/CAM technology has become an essential part of modern dentistry . It can This is a sample survey study. All procedures related to this survey were approved by the research and ethical committee of AlFarabi College of Dentistry and Nursing in Riyadh, Saudi Arabia (IRB: PD01390).The target population of this survey was practicing dentists in Riyadh city, the capital of Saudi Arabia.A self-administered questionnaire was designed and piloted among 10 prosthodontists and 10 general dentists to assess clarity of the contents and feasibility of the study. The recorded remarks/comments were utilized to revise the pilot questionnaire. The revised version of the questionnaire was then used in this survey study. The study questionnaire was divided into four sections and presented in English to attract a wider range of participants, as dentists working in Saudi Arabia come from different cultural and educational backgrounds . The firAn electronic copy of the questionnaire was prepared using Google forms. A short electronic link was then created and distributed through email and platforms of social media to a convenience sample of dentists working in Riyadh. The aim of the study was presented first and dentists were encouraged to provide their consent and participate by clicking on the attached link to complete the survey items. Confidentiality and anonymity of the collected information were emphasized. The survey was available for completion over more than 6 months, and during this period, at least two reminders to fill in the survey items were sent to non-respondents.p-value < 0.05 was considered significant.The SPSS statistical package was used for data analysis . Descriptive statistics presented characteristics of participating dentists, and frequency tables were generated to illustrate the response of dentists to survey questions. The Chi-Square statistic was used to assess the association between questionnaire items and dentists’ clinical experience/type of qualification i.e., general dental practitioner versus specialist. A The questionnaire was sent to 150 dentists. Three of the respondents were working out of Riyadh and omitted, 33 dentists declined completion of the survey items, and 114 questionnaires were completed and included in the final analysis (77.6% response rate). Response to practice-related questions indicated that almost two thirds of the respondents operated a chair-side CAD/CAM at some point in the past. Moreover, the chair-side CAD/CAM is available at the current work place of around a quarter of the participants; and a desire to have one was expressed by a significant proportion of participating dentists who do not have a chair-side CAD/CAM at their current practice. In terms of clinical application, a considerable number of the surveyed dentists used the chair-side CAD/CAM in the fabrication of dental crowns (57%). Also, a large number of the participants used the chair-side CAD/CAM in the fabrication of dental inlays and onlays (42% and 37% respectively). However, only a few of the dentists used this machine for the fabrication of fixed partial dentures or implant abutments (16% and 10% respectively). The former results are illustrated in Questions pertinent to attitudes and satisfaction of dentists with chair-side CAD/CAM technology demonstrated a number of interesting findings. Most participants (81%) indicated that the overall quality of chair-side CAD/CAM restorations is at least as good as those fabricated by a lab technician or much better. Around 73% of the dentists evaluated the initial quality of marginal fit, axial contour, proximal contact, and occlusal contact of restorations produced by chair-side CAD/CAM as very good or excellent. Patients’ satisfaction with chair-side CAD/CAM restorations was rated as satisfactory by a considerable proportion of the surveyed dentists (64%). On the dentists’ side, 66% of the participants were satisfied with chair-side CAD/CAM restoration procedure and only a few expressed dissatisfaction (4.4%). More than half of the participating dentists (56%) would likely recommend a chair-side CAD/CAM system to a friend or colleague. The majority of responding dentists considered the chair-side CAD/CAM system as important in terms of time saving, boosting the number of visiting patients and income improvement. The preference for the use of chair-side CAD/CAM system over the conventional restoration system was apparent among three quarters of the surveyed dentists. The abovementioned results are summarized in p = 0.046). Also, an association was determined between clinical experience of the dentist and rating the importance of training on the use of chair-side CAD/CAM system. It has been found that a significantly greater number of dentists with clinical experience of 10 years or less considered the training as very/extremely important in comparison with dentists who have more than 10 years of clinical experience (p = 0.020). No other associations were determined between questionnaire items and dentist’s clinical experience/qualification i.e., general dental practitioner versus specialist.The Chi-Square statistic indicated that a significantly larger proportion of general dental practitioners compared to specialist dentists considered that the overall quality of chair-side CAD/CAM restorations is superior to that fabricated by a lab technician (Despite the major role of CAD/CAM technology in modern dental practice, little information is available about the current practice and attitudes of dentists regarding this innovative technology. In the UK, a survey of dentists was conducted to investigate the status of CAD/CAM technology in UK dental practices . The resIn Saudi Arabia, in recent years there has been more attention to the value and importance of digital dentistry . Dental A recent survey of the commonly used dental materials for indirect restorations among active members of the Saudi Dental Society illustrated that 29.8% of the respondents use the CAD/CAM system in their clinical practice . In our On the level of satisfaction and attitude, the findings of the current survey reflect broad satisfaction and positive attitude amongst participating dentists towards use and outcome of chair-side CAD/CAM in the clinical practice. It can be noted that most participants prefer the chair-side CAD/CAM method over the conventional methods and they appreciate the different merits of the chair-side CAD/CAM system including time saving, income improvement and boosting the number of patients in the clinic. Based on that, it is not surprising that most dentists in this study are ready to recommend a chair-side CAD/CAM system to a friend or colleague. On the contrary to opinions of dentists in the UK survey , the majIn the UK survey, a considerable proportion of dentists who use the CAD/CAM technology in their clinical practice regarded their training on this service as not sufficient . In the A limitation for this study is the relatively small number of participants. This is despite the repeated invitations/reminders to the target population to take part. It can be stated that this survey proved the difficulty of obtaining adequate sample size for an online survey. The shortcomings of such methods for data collection can be recognized. Tools for better outcome should be developed and discussed to overcome the former problem. It has also to be noted that probably the study population comprised dentists who have some experience/are interested in the chair-side CAD/CAM technology and this may have biased the findings.On the positive side, the collected data came from the various sectors of Riyadh city and presented a random sample of dentists. It comprised both genders, Saudi and non-Saudi dentists, specialists and general dental practitioners, and junior and senior dentists. In addition, conducting the survey in Riyadh adds value to the obtained results. Riyadh is the capital of Saudi Arabia. It has the largest number of dentists and dental centers in Saudi Arabia and hence provides a major bulk of oral/dental health services across the Kingdom .To confirm the findings of this pilot survey, future research should aim and be planned to obtain data on a national level with a representative sample of the dentists in Saudi Arabia.The results of this pilot survey reflect broad satisfaction and positive attitude among the surveyed dentists towards use and outcome of chair-side CAD/CAM technology in the clinical dental practice. It seems that the CAD/CAM technology has infiltrated into the workflow of Saudi dental practices with speculations of growing implementation among the wider sector of dental practitioners in the future.


During early embryogenesis, the hemogenic endothelium of the developing dorsal aorta is the main source of definitive hematopoietic stem cells (HSCs), which will generate all blood cell lineages of the adult organism. The hemogenic endothelial cells (HECs) of the dorsal aorta are known to arise from the splanchnic lateral plate mesoderm. However, the specific cell lineages and developmental paths that give rise to aortic HECs are still unclear. Over the past half a century, the scientific debate on the origin of aortic HECs and HSCs has largely focused on two potential and apparently alternative birthplaces, the extraembryonic yolk sac blood islands and the intraembryonic splanchnic mesoderm. However, as we argue, both yolk sac blood islands and aortic HECs may have a common hemangioblastic origin. Further insight into aortic HEC development is being gained from fate-mapping studies that address the identity of progenitor cell lineages, rather than their physical location within the developing embryo. In this perspective article, we discuss the current knowledge on the origin of aortic HECs with a particular focus on the evidence provided by studies in the avian embryo, a model that pioneered the field of developmental hematopoiesis. Hemogenic endothelial cells (HECs) are specialized vascular endothelial cells with the potential to give rise to hematopoietic stem/progenitor cells (HSPC) during vertebrate embryogenesis . During in vitro culture and transplantation assays was used to verify the presence of HSC precursor cells in different embryonic tissues. Data from these studies mostly support an intraembryonic origin for aortic HECs  and the prospective ventral dorsal aorta (intraembryonic), it is important to understand when and how these tissues develop. Both the yolk sac blood islands and the ventral endothelium of the dorsal aorta derive from the splanchnic lateral plate mesoderm, which, together with the endoderm, forms the splanchnopleure . During The yolk sac blood islands give rise to the extraembryonic vascular network and to the first hematopoietic cells of the developing embryo . These sThe dorsal aorta is not only the first and largest intraembryonic blood vessel, but also an important site of secondary hematopoiesis   or develop  origin) . Both hyEarly experimental studies addressed the origin of definitive HSCs before the identification of aortic HECs as their progenitor cells . The colin vivo lineage-tracing and time-lapse imaging methods, which first require the identification of a lineage-specific marker capable of labeling a particular cell population and its progeny  and the conditional reporter plasmid pCAGG-LoxP-mCherry-LoxP-GFP are co-electroporated into chick embryos (stage HH3), as previously reported for neuronal lineages . In thisIn summary, recent evidence suggests that hemangioblasts colonize the presumptive dorsal aorta region (stages HH7–8), contribute to the developing aortic endothelium (stages HH9–10) and give rise to aortic HECs  and European Guidelines (Directive 2010/63/EU).PS performed the experiments and contributed to the manuscript writing. GM helped with the research design, image acquisition, and data analysis. AJ contributed to the data interpretation and scientific discussion. AT designed and performed the experiments, analyzed and interpreted the data, and wrote the manuscript. All authors contributed to manuscript revision and approved the final version.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.


In the present Research Topic we collected papers devoted to the different aspects of the non-invasive photonic techniques capable monitoring real-time microvascular hemodynamics in health and pathology. Compact laser instruments for near-infrared spectroscopy (NIRS), Laser Doppler Flowmetry (LDF), diffuse correlation spectroscopy (DCS), NIRS flow oximetry, and others are routinely and widely used for concurrent non-invasive measurement of different parameters of hemocirculation such as blood perfusion, mean arterial pressure, oxy- and deoxyhemoglobin concentrations, and others. Further development and introduction of these approaches and systems to clinical practice will lead to enrichment and step-by-step substitution of laboratory tests with enabling bed-side diagnostics and wireless distantly controlled patient condition monitoring.The biophotonic approaches became a powerful tool to study dynamic processes such as vascular tone autoregulation and functional hyperaemia which are controlled by vessel vasculature rhythms derived from different regulatory systems: nervous sympathetic and parasympathetic, hormonal and mechanical muscle regulation. A promising area for research is establishing an autoregulatory link between blood flow and level of the metabolic activity where combined LDF and fluorescent approaches can bring significant advantages in the diagnostics. Spectral analysis of different optical data arrays can provide valuable information on neuronal-vasculature and muscular-vasculature coupling autoregulation mechanism under intense stress and/or physical activity in health and at various pathologies. Due to the morphological and physiological differences in the microcirculation bed of the human skin, a non-invasive detailed research of blood microcirculation can be organized using a new class of wearable wireless laser flowmeters adopted to the range of the research areas.This Research Topic brings together the cutting-edge applications of non-invasive biophotonic approaches and techniques allowing to translate personalized data array analysis to distinguished diagnosis.Goltsov et al. applied spectral analysis of the LDF signals for the investigation of cerebrovascular hemodynamics in patients with post-acute ischemic stroke. The observed asymmetry in LDF signals measured on the stroke-affected and unaffected hemispheres of the patients was analyzed by computational modeling of vasomotion of arteriole diameter.In the research paper, Zherebtsova et al. discussed the development and application of the optical non-invasive diagnostic approach for the detection and evaluation of the microcirculatory severity and metabolic disorders in patients with rheumatic diseases and diabetes mellitus. The proposed methods include the joint use of LDF, absorption spectroscopy and fluorescence spectroscopy in combination with functional tests in the field of rheumatology and endocrinology.Semyachkina-Glushkovskaya et al. investigated brain hemorrhages in newborn rats using an integrative approach including magnetic resonance imaging, monitoring of cerebral blood flow using Doppler coherent tomography, oximetry, coherent-domain optical technologies for visualization of the cerebral blood flow, investigations of the deformability of red blood cells, and morphological analysis of brain tissues. Combination of these techniques in the monitoring of the pre- and post-hemorrhage periods allowed authors to investigate a time-dependent stress inducing changes in neonatal brain areas which are involved in higher cognitive functions in progress of the pathology.Caicedo et al. developed a new computational method for the decomposition of NIRS signals into the partial linear contributions of different physiological signals. Authors combined Oblique Subspace Projections in order to define adequate signal subspaces and the linear regression model of NIRS signals to calculate regression parameters and estimate the contribution of various input variables. Authors evaluate the performance of the developed methods by case studies in the field of cerebral hemodynamics monitoring using NIRS and concomitant measurements of MABP, EtCO2, HR, SaO2, and ECMO signals.In the method article, Esenaliev reviewed optoacoustic technique which is a novel medical diagnostic platform for non-invasive measurement of physiologic variables, functional imaging, and hemodynamics monitoring. Authors discussed the application of optoacoustic methods to the measurement of important physiologic parameters including temperature, thermal coagulation, freezing, concentration of molecular dyes and nanoparticles in organs, oxygenation, and hemoglobin concentration with high temporal and spatial resolution.In mini-survey, Guo et al. analyse the daily rhythm of dynamic cerebral autoregulation by simultaneous measurement of the arterial blood pressure at the brachial artery and cerebral blood flow velocity over the course of a day in healthy adults.Obata et al. used simultaneously recorded the ECG and plethysmograph in the investigation of the effect of body position and exercise on pulse arrival time taken for the pulse wave to reach the vasculature of various peripheral tissue beds. Authors analyzed vascular autoregulation mechanisms that maintain the optimal arrival time irrespective of its distance from the heart.Revin et al. presented results of the detailed biophysical investigation on the hyperglycaemia effect on morphological changes in erythrocytes. Authors combined Raman spectroscopy in the observation of conformational changes in hemoglobin with laser interference microscopy to determine structural transition and a composition change in the erythrocyte membranes at graduated hyperglycaemia. Ivanov et al. investigated the possibility of the application of microwave radiometry method to non-invasive monitoring of the physicochemical properties of circulating proteins. In brief research report article, authors provided results on the application of commercially available microwave radiometry equipment to the investigation of denaturation kinetics of albumin in solution. Plekhanova et al. investigated the potential role of plasminogen activators (PA) in the promotion of outward arterial remodeling after injury in rat common carotids. Authors studied a gene expression profile change after injury and local treatment with the recombinant PA in the vessel wall related to vascular tone. Li et al. discussed the prospective researches of the plasma matrix metalloproteinase-9 (MMP-9) contents that can serve as a predictive indicator for cardiovascular disease mortality in the Chinese Han population.Several papers in the Research Topic are devoted to the biophysical investigation of vascular regulation at the molecular, cellular, and tissue levels. The results presented in this Research Topic by different research groups show a wide spectrum of the current directions for the development and application of biphotonic techniques in medicine. As seen, the mainstream research in biophotonics focuses on the monitoring and processing of concurrently collected biomedical signals in patients to enhance current clinical diagnosis and develop novel diagnostic techniques and equipment.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.AG is employed by company M&S Decisions LLD. VS is employed by the company SPE “LAZMA” Ltd. The remaining 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.


Populus pruinosa Schrenk plays an important role on ecological services in desert areas. The complete chloroplast genome was reported in this study using the PacBio Sequel II Platform. The chloroplast genome with a total size of 157,856 bp consists of two inverted repeats  separated by a large single-copy region  and a small single-copy region . Further annotation revealed the chloroplast genome contains 111 genes, including 78 protein-coding genes, 29 tRNA genes, and 4 rRNA genes. A total of 151 simple sequence repeats (SSRs) were identified in the chloroplast genome. This information will be useful for study on the evolution and genetic diversity of P. pruinosa in the future. P. pruinose, one of the few national protected plants, was mainly distributed along the bank of Tarim river, Yarkand river and Hotan rivers in Xinjiang, northwest of China. It usually formed a pure forest or a mixed forest with P. euphratica to maintain the balance of ecosystem, curb desertification and protect biodiversity in the extremely arid desert areas of Xinjiang . The voucher specimens of different ecotype  are stored in the herbarium of Tarim University, and the data related to the specimens are included in the database of wild plant germplasm resources of the Tarim basin . The chloroplast DNA was extracted using a high-salt method and sequenced using the PacBio Sequel II platform. The whole chloroplast genome was assembled using Canu-1.7  using BLASTN, and found that the newly assembled genome got from PacBio platform was more accurate especially in the repeats. After designing the primer  for inconsistent positions between the genomes with two platforms, we verified the real existence of the insertion assembled by PacBio through Sanger sequencing. The result showed that the PacBio has the advantage of getting more complete chloroplast genome, which is also reported in other plants  and Bayesian inference (BI)  . The ML nce (BI)  based on


Resident-led councils represent an important initiative to involve trainees in patient safety, but little is known about how to create and sustain one of these councils. We evaluated the impact of a resident-led patient safety council in an internal medicine residency program. We assessed change in resident perception of safety issues over 3 years, scholarship activities, and behavioral choices to participate or lead patient safety activities after residency.The Stony Brook Internal Medicine Residency Program formed the Patient Safety and Quality Council (PSQC) in 2014, consisting of fifteen peer-nominated residents serving a three-year term. Surveys were distributed annually from 2014 to 2017 to measure resident council members’ perception of patient safety. The number of safety-related abstract/publications were tracked during and one year after graduation. Additionally, graduates from the council were surveyed to assess the influence of the council on post residency involvement and leadership in safety activities.A total of 18 residents have participated in the council from 2014 to 2017. Overall, resident perception of safety culture improved. A total of 17/18 (94%) PSQC resident members demonstrated scholarship activities in safety during residency: 8/18 (44%) were engaged in an independent Quality Improvement (QI) project, 5/18 (27%) achieved a quality improvement leadership role post residency. A total of 15 of 18 (83%) recent graduates suggest that involvement with the safety council during residency fostered future involvement in patient safety.Implementation of a resident-led safety council can help to improve the safety culture, generate scholarly activities, and encourage continued participation in patient safety after graduation. Historically, resident participation in departmental and institutional-based patient safety and Quality Improvement (QI) has been limited . To addrThe call for physician leaders who are skilled in QI and patient safety is rising across the nation . AlthougWe implemented a resident-led safety council that generated scholarly activities and encouraged continued participation in patient safety after graduation, using the Kirkpatrick evaluation model for educational intervention to demonstrate both learning satisfaction and behavioral influence.Stony Brook University Hospital is an academic medical center and serves as the tertiary care center of Suffolk County, New York. The internal medicine residency program consists of approximately 96 trainees from Post-Graduate Year (PGY) one through three. A resident-led Internal Medicine Residency Patient Safety and Quality Council (PSQC) was formed in August 2014. The main objectives and mission of the PSQC include: to serve as ambassadors of patient safety and QI; and to address safety concerns brought up by the residents. At its inception, the scholarly goals related to quality and safety of the council were discussed and agreed upon. Specifically, the council’s goals included: participate in patient safety/quality day, generate abstracts and publications from the quality initiatives encountered, and hopefully motivate council members to become involved in QI after residency completion.Fifteen residents from all post-graduate years 1 to 3 (five from each year) of training were peer-nominated and recruited to join the newly formed PSQC. The goal was to form a small committee with adequate representation from each resident PGY level. Recognizing that physicians alone cannot adequately address safety, interdisciplinary faculty representatives volunteered to also serve as the leaders of the PSQC. The council members consisted of a patient safety officer from the institution, a quality nurse, pharmacist, informatics personnel and various faculty members. Meetings took place on a monthly basis for one-hour duration on the last Wednesday of the month at 6 pm. PSQC residents determine a monthly agenda based on reported safety issues brought up by the medicine residents through either in-person communication or via a PSQC medicine email inbox. Safety or quality issues are identified by residents during their routine practice on the wards or in the clinic setting. Based on the issue, respective department representatives are invited to help address the specific safety issue. The members of the council conduct group-based QI projects using the Plan-Do-Study-Act (PDSA) methodology as they tackle the safety issues. SMART  aim statements are developed during the meeting and group members continue to work on QI projects on their own time with faculty mentorship outside of the meetings.A survey was created to assess council members’ perceptions of patient safety within the institution. The surveys were distributed on the first day of council inception and were redistributed at the end of each academic year . An excel spreadsheet was developed to track abstract presentations and publications generated from the PSQC initiatives. An additional survey was emailed to the PSQC graduates who had completed their training in 2018 to assess the impact of the council on post-graduation engagement and leadership in patient safety and QI. The impact of the council on process improvements was specifically assessed and published in a prior study .Results from the annual survey demonstrate that the PSQC has had a positive impact on the culture of safety within the residency program . CouncilResident-led PSQC is extremely valuable in not only promoting resident engagement in process improvement but can effectively serve as a venue for QI scholarship and dissemination in a residency program. Residents at our institution completed a formalized longitudinal QI curriculum during their ambulatory weeks as part of residency training. The QI projects conducted by the PSQC residents supplemented their training and further developed their motivation to continue QI initiatives. Using the Kirkpatrick evaluation model for educational intervention, we used survey data on the perception of the council to demonstrate learning satisfaction, and data on recent graduate involvement in safety roles as a marker of behavioral influence.Our study has several limitations. This study particularly focuses on the committee’s success as a function of QI scholarship and influence on QI engagement and leadership after graduation from residency, relying on self-reported resident perception of the safety culture of the residency program. We also did not measure prior data for comparison of QI scholarly output prior to the inception of the PSQC; therefore, we cannot make a strong conclusion that there is abstract productivity as a direct result of the PSQC. Further studies can use a better approach to assess the impact of the council on scholarship productivity by comparing the scholarly output of the PSQC group versus a non-PSQC group.We noted an initial rapid rise followed by an apparent decreasing trend in mean number of abstract and publication from 2015 to 2017. A surge of enthusiasm and interest at the inception of the council followed by a slight decline is a potential explanation for the observed trend. This highlights the importance of sustainability planning  to maintain outcome achievements in resident QI projects. Finally, we studied a single departmental, single institution intervention with a small group of residents.We believe that the success of PSQC forum is reliant on three important factors: 1) peer selection of residents; this promotes identification of safety champions who are accountable for representing and promoting safety for their respective peers, 2) the support and endorsement of the Residency Program Director/Vice Chair of Education, and the Department Chair; they provided a small budget for dinners during the monthly meetings, 3) using scholarship (abstracts and publications) as a dissemination strategy to motivate residents to conduct spontaneous and voluntary QI.Implementation of a resident-led safety council can help to improve the safety culture, generate safety/QI scholarly activities, and encourage continued participation in patient safety after graduation. More importantly, a PSQC has the potential to generate future QI leaders that can continue to generate independent QI projects even after transition to a new role and institution.EMR, electronic medical record; ER, emergency room; MRI, magnetic resonance imaging; MICU, medical intensive care unit; CAUTI, catheter-associated urinary tract infection; ACGME, accreditation council of graduate medical education.


Bolosaurus from North America and Belebey from Russia, utilizing a combination of histological and tomographic data, reveals unusual patterns of tooth development and replacement. The data confirm that bolosaurid teeth have thecodont implantation with deep roots, the oldest known such example among amniotes, and independently evolved among much younger archosauromorphs (including dinosaurs and crocodilians) and among synapsids . High-resolution CT scans were able to detect the density boundary between the alveolar bone and the jawbone, as confirmed by histology, and revealed the location and size of developing replacement teeth in the pulp cavity of functional teeth. Evidence provided by the paratype dentary of Belebey chengi indicates that replacement teeth are present along the whole tooth row at slightly different stages of development, with the ontogenetically more developed teeth anteriorly, suggesting that tooth replacement was highly synchronized. CT data also show tooth replacement is directly related to the presence of lingual pits in the jaw, and that migration of tooth buds occurs initially close to these resorption pits to a position immediately below the functional tooth within its pulp cavity. The size and complex shape of the replacement teeth in the holotype of Bolosaurus grandis indicate that the replacement teeth can develop within the pulp cavity to an advanced stage while the previous generation remains functional for an extended time, reminiscent of the condition seen in other amniotes with occluding dentitions, including mammals.Permian bolosaurid parareptiles are well-known for having complex tooth crowns and complete tooth rows in the jaws, in contrast to the comparatively simple teeth and frequent replacement gaps in all other Paleozoic amniotes. Analysis of the specialized dentition of the bolosaurid parareptiles  Belebey vegrandis,Bolosaurus, the smaller Bo. striatus  and Be. vegrandis  from X-ray and Neutron energy sources, this paper reconstructs the patterns of tooth development and replacement in Belebey and Bolosaurus. This combination has rarely been applied with such high resolution to a targeted examination of teeth, dental tissues, and the associated jawbone  has visible wear and past the apex of the cusp. The thickness of the enamel varied with a maximum extent of 205 µm related to the amount of visual occlusion and could be seen through histology and CT. The second tooth is broken on its mesial side, exposing the pulp cavity. This tooth did not have an extensive enamel covering, but this may have been the result of breakage. The final and most massive tooth is in the best condition, and also shows evidence of light wear. Neither method was able to reveal tissue that could confidently be associated with cementum in ROMVP 83327.The lingual side of a right dentary fragment of VP 83327 ] is dama grandis . CompariBolosaurus grandis . Both the labial and lingual walls of the tooth roots are equally long, in contrast to the asymmetry between the labial and lingual sides commonly found in early amniotes . All theIn histological sections, the alveolar bone surrounding each tooth is separated from the jawbone by a distinct reversal line  and 5C, Bo. grandis , the 14th tooth in Bo. grandis is significantly smaller and thinner with a different morphology from the neighboring teeth  also allows us to reconstruct the dynamics of tooth replacement in bolosaurids  shows replacement pits along the lingual side of every single tooth locus, but no shed teeth (One specimen of ed teeth –3E. The ed teeth  and 4K. ed teeth –2C. The Belebey (IVPP 15104) and Bolosaurus (OMNH 52311) revealed an unusual tooth replacement pattern for bolosaurids. The presence of regularly arranged tooth gaps in fossil reptiles represent a period in the replacement cycle in which the functional tooth has been shed, but the replacement tooth had not fully erupted at the time of death (Belebey (IVPP 15104) shows replacement teeth at nearly the same stage of development along the jaw (Belebey (IVPP 15104) and Bolosaurus (OMNH 52311) reveal that, unlike most other polyphyodont amniotes, bolosaurids underwent a single replacement wave at a time, passing from the front of the jaw to the back (Belebey is incrementally more developed from the front of the jaw to the back. This single-wave model also explains why in OMNH 52311, there is no evidence of resorption pits in the anterior 10 teeth, tooth 11 has been shed, and posterior tooth positions 12 and 13 were still undergoing replacement. The replacement wave in this specimen had already passed through the first 10 teeth, while tooth 11 had recently been shed. Meanwhile, positions 12 and 13 have very large and well-developed replacement teeth and were likely nearing the tooth shedding phase (The presence of replacement teeth in of death . At firs the jaw . It is p the jaw  and woulthe back –4. Each ng phase . As oppong phase .The enamel of bolosaurid teeth is thick and well ornamented . The creDiadectes (Bolosaurids truly are a unique group of early reptiles with an unusual patchwork of dental characteristics. They exhibit not only strong heterodonty and extensive tooth-on-tooth wear but also have deeply implanted, thecodont teeth that are ankylosed to the jaw. Bolosaurids apparently maintained tooth-on-tooth wear over prolonged periods of time through specialized tooth replacement cycles. Although it appears that tooth development is nearly synchronous, our CT- and histology-based analyses show that the anterior teeth were replaced earlier than the larger posterior teeth in what appears to be a single tooth replacement wave, passing from the front of the jaw to the back. As in the stem amniote iadectes , the the


Moreover, two clinical cases of brain tumors impinged on MdLF territories are reported to further discuss the anatomical results in light of previously published data on the functional involvement of this bundle. The main finding is that the MdLF is consistently organized into two layers: an antero-ventral segment (aMdLF) connecting the anterior STG  and the extrastriate lateral occipital cortex, and a posterior-dorsal segment (pMdLF) connecting the posterior STG, anterior transverse temporal gyrus and planum temporale with the superior parietal lobule and lateral occipital cortex. The anatomical connectivity pattern and quantitative differences between the MdLF subcomponents along with the clinical cases reported in this paper support the role of MdLF in high-order functions related to acoustic information. We suggest that pMdLF may contribute to the learning process associated with verbal-auditory stimuli, especially on left side, while aMdLF may play a role in processing/retrieving auditory information already consolidated within the temporal lobe.The middle longitudinal fascicle (MdLF) is a long, associative white matter tract connecting the superior temporal gyrus (STG) with the parietal and occipital lobe. Previous studies show different cortical terminations, and a possible segmentation pattern of the tract. In this study, we performed a post-mortem white matter dissection of 12 human hemispheres and an  This white matter pathway has received less attention and is one of the most puzzling bundles because its morphology and function are still poorly understood.in vivo studies are reported. This may be partially due to the fact that MdLF was first recognized in monkeys, where it interconnects the superior temporal gyrus (STG) with the inferior parietal lobule (IPL)  . Howeverle (IPL) . Interesle (IPL) . Nonethele (IPL) .Moreover, in humans, posterior terminations of MdLF are not limited to the parietal lobe, as they are also directed toward the extrastriate occipital cortex  and cuneus (Cu). This occipital terminations of the MdLF have not been described in monkeys indeed .Middle longitudinal fascicle anterior terminations at the level of the STG and temporal pole (TP) are also controversial, as some authors found these terminations to reach the most anterior cortex of STG and TP , while oFinally, there is a lack of agreement regarding MdLF segmentation. While DTI studies showed several subcomponents (up to six) of the MdLF , white mThe functional role of the MdLF is even less understood than its morphology. Some authors, on the basis of the cortical terminations, speculated that this bundle might be a connection between the dorsal and ventral stream of the language network , while oHowever, cortical stimulation during awake surgery  or lesioin vivo DTI tracking. In addition, we aimed to discuss quantitative and anatomical results of this bundle in two clinical cases of tumors that involved the MdLF.The first aim of this study was to investigate the MdLF anatomical connectivity between temporal, parietal and occipital regions using white matter fiber dissections of post-mortem human brains. Second, the analysis of the connectivity patterns of the MdLF was used to acquire anatomical information on MdLF subcomponent derived from Twelve normal cerebral hemispheres (six right and six left) obtained from six human cadavers  donated to the Department of Medical Cell Biology, Section for Anatomy Studies at Uppsala University, Sweden, were studied. All individuals had no history of neurological diseases and death cause was not related to brain diseases. All donating individuals had given written consent for use of the whole cadaver for biomedical research and education in a testimonial donation letter. The study protocol was filed with the application for ethical vetting of research involving humans to the Regional Ethical Vetting Board in Uppsala, Sweden (Dnr 2014/468).Each brain was fixed with an intra-carotidal injection of 12% formalin within the first week after death. The brains were carefully extracted and put in 10% formalin for 24 h. The pia mater, arachnoid membrane and vascular structures were then carefully removed under microscopic magnification and the hemispheres were frozen at −15 to −20°C for 6–10 days, then slowly defrosted for 12 h .Before the start of dissection, the superficial anatomy of the sulci and gyri was studied in detail. The specimens were dissected in a stepwise manner, from lateral surface to the medial structures with a modified Klingler’s technique , b, 2017https://db.humanconnectome.org.Twenty-four subjects  were acquired from the Human Connectome Project (HCP) database. The subjects were selected because of the older age group, high quality structural images including T1 and T2 sequence and high angular resolution diffusion imaging (dMRI). The 1200 Subject release Diffusion data acquisition and preprocessing are included in the 1200 Subject release and are summarized below. The 1200 Subjects Data Release Reference Manual provides full technical documentation and can be found freely downloadable at b-values 1000, 2000, and 3000 s/mm2), each shell with 90 diffusion sampling directions. The in-plane resolution and slice thickness were 1.25 mm, with TR = 5500 ms, TE = 89 ms, flip angle = 78 degrees using a multiband factor of 3.HCP data were acquired using a Siemens Skyra 3.0 T with a 32-channel head coil  according to the HCP Study Protocol . T1w imab-value/b-vector deviation  which includes; EPI distortion correction using FSLs TOPUP algorithm, eddy current and motion correction using FSLs EDDY algorithm, gradient non-linearity correction and calculation of eviation . HCP difapproach  with a dPrior to reconstruction, all included datasets were thoroughly examined to ensure the quality and integrity of diffusion data using the built-in quality control in DSI studio and by visual examination .2), which utilizes a generalized streamline fiber tracking method (We performed deterministic fiber tracking using DSI Studio software (DSI Studiog method . Parametg method  dropped g method .DSI Studio was used to place and draw regions of interest (ROIs) and anatomical landmarks. The manual ROIs were placed on T1-weighted maps with locations according to the anatomical findings in the white matter dissection. The visual steps to identify and segment the MdLF and its subsegments are displayed in a priori knowledge gained from the dissection. Connectivity matrices were generated by the Connectivity Matrix function in DSI Studio for each segment   , step 10U-test for independent samples was used for comparison between groups for tract metrics  for all MdLF components. The symmetry coefficient of each tract metric and MdLF component was calculated, based upon the formula (L – R)/(L + R) as have been reported in previous studies  was used for the statistical analysis.To further discuss the MdLF functional role we selected two clinical cases where STG was involved by a low-grade glioma that could illustrate a lesion model of MdLF. Pre- and post-operative clinical, neuropsychological and neuroradiological data of the two cases are provided. These clinical cases were retrospectively retrieved by a database containing clinical and radiological data of patients with suspected low-grade gliomas operated on at the Department of Neurosurgery, Uppsala University-Hospital, Uppsala, Sweden, who had detailed pre- and postoperative neuropsychological and speech evaluation as a part of a larger research project. The regional ethics committee, Regionala Etikprövningsnämnden Uppsala, approved the study protocol (Dnr 2015/210). An informed consent from patients included in this study was acquired.The dissection started from the lateral surface of the hemisphere  with theThe central segment of the MdLF lies underneath the AF at the level of the STG . Its fibThe MdLF is part of the sagittal stratum (SS) described by Sachs, a deep white matter structure of the temporo-parietal occipital region, organized in three layers: fibers of the splenium , optic radiations (OR)  and the association pathways  . Since iBoth fiber dissection and fiber tracking confirmed an intimate anatomical relation of the MdLF with the AF/SLF, ILF, IFOF, and ORs.Vertical SLF and AF are more superficial and perpendicularly intersect the MdLF at the level of the temporo-parietal junction . VOF, loThe IFOF is part of the external capsule and crosses from the frontal to the temporal lobe at the level of the limen insulae. Its fibers run on the roof of the temporal horn of the lateral ventricle in a deeper layer in respect to the MdLF fibers. The two bundles form an angle of about 40° at this level . PosteriWithin the superior temporal gyrus, the pMdLF shows close relationship with the superficial fibers of the AF laterally, and with the acoustic radiation which is located medial and caudal, underneath the aTTG (not displayed in our figures). The aMdLF runs instead parallel to the ILF within the temporal region until their division in the anterior and caudal part of the superior temporal gyrus and sulcus , 4 as prThe technique we used for virtual dissection reproduced our anatomical findings in the white matter dissection, and following the same step-by-step anatomical criteria, the MdLF was successfully isolated in all subjects. The first and more lateral white matter bundles like the vSLF were subtracted, showing the course of the AF, which is lateral and posterior compared to the MdLF in its temporal component, and represented the landmark for the identification of the MdLF stem within superficial layer of the sagittal stratum together with the ILF fibers . The ILFThe whole MdLF did not show quantitative differences in terms of volume, length or tract metrics between left and right hemisphere. The aMdLF and pMdLF displayed similar volume, length or tract metrics without any significant difference in lateralization. Tract metrics were analyzed to exclude differences between sub segments which might have resulted in artifacts especially in regions like the sagittal stratum  where many kissing and crossing fibers can be tracked. A summary of descriptive and statistical results is displayed in A connectivity analysis at group level for the two subcomponents of the MdLF on both sides was performed with three-dimensional reconstruction of the illustrative pathways. A circle diagram was chosen to show the connectivity between the selected regions from the Harvard-Oxford Cortical Atlas .Analysis at the group level showed that the aMdLF connects the aSTG and the PP with the occipital region in both right and left hemisphere . Within The pMdLF displayed a constant connection between the posterior portion of the superior temporal gyrus (pSTG), the aTTG and PT and the parieto-occipital region . The mosA 34-year-old patient was admitted to our clinic because of seizures in 2016. MRI investigation detected a suspected low-grade glioma in the aSTG on the right side . SeizureThe retrospective analysis of white matter bundles involved by the tumor area and postoperative resection revealed that the aMdLF was mainly involved within the aSTG but even the most anterior portion of ILF was invaded in the TP .This 39-year-old patient was referred to our clinic because of cognitive impairment involving learning, memory, and concentration. An MRI investigation revealed an expansive lesion in the pSTG on the left side, without contrast enhancement . At the Despite being a long associative tract, MdLF has been object of debate since its first description. Indeed, different descriptions of MdLF cortical terminations, possible subdivisions and functional role have been reported in the scientific literature. Our work is placed in the context of such controversial debate and we tried to analyze each of the above aspects of the MdLF.in vivo virtual dissection, DTI-based, techniques  and contiguous secondary (“belts” and “parabelts”) cortical areas are located at the level of the STG, is thought to be organized into parallel streams encoding the information “what” , “where,” “when,” and “how”  . These aPosterior-MdLF could be related to the “where” and “what” auditory functions. Similar potential functional role have been suggested by other anatomical studies . The cauAccording to The strong connection between both primary and secondary auditory areas in the STG and secondary visual areas in the occipital lobe also supports the role of the MdLF in visual-auditory integration processes .The anterior part of secondary auditory cortex, including the PP and the aSTG, is believed to process the properties of an auditory object that are not dependent upon spatial location or attention . Higher-Our connectivity analysis demonstrated that the LOC may be an important hub common to both MdLF branches . This important region has been recently suggested to be a key site for the storage of multisensory memory representations with semantically congruent elements . The LOCBased on our anatomical results, we can hypothesize that the predominantly perceptual associations in congruent memories and the mainly conceptual associations in incongruent memories are encoded by the higher-order occipital cortex and the lateral temporal cortex, respectively. The aMdLF may then play a crucial role within this network for retrieval of memories that are congruent and already consolidated into visual-associated categories.The two clinical cases described in our study, provided a lesional model with new possible insights into the functional implications of the MdLF. In case # 1, the tumor was located at the aSTG and TP on the right side , 11a. MuThe most important postoperative change regarded the semiology of the hallucinations, namely the onset of musical obsessions, an uncommon but previously described finding . The relDespite the interesting association between MdLF and auditory hallucinations, it is mandatory to interpret these results with caution because the postoperative clinical situation in our patient may be also related to other psychological/psychiatric causes not related to postsurgical structural modifications.“intermittent whistling sound inside my head”), confirming the common origin for this phenomenon within the STG  was still intact at the neuropsychological examination. This case demonstrates how the AF and the MdLF pathways may work, processing in parallel auditory information with differences in functional domains. We believe that the pMdLF, connecting primary auditory areas and parieto-occipital regions, may play a key role within auditory “what and where” integration processes, which are necessary for consolidation of cross-modal inputs during verbal learning.This case shows a different anatomical substrate for verbal and visual learning abilities. The selective impairment of auditory processing, with an intact visual memory and learning both pre- and post-operatively, indicates that the pMdLF is a specialized pathway within the auditory network.We believe that verbal learning impairment was then correlated with a damage of dorsal auditory network including primary afferent fibers to aTTG, the pMdLF and its connections with the SLF, IFOF, and AF within the temporo-parieto-occipital area on the left side.Our study has some limitations. The first one concerns the anatomical comparison between diffusion tensor tractography (DTT) in young healthy volunteers and white matter dissection of post-mortem brains. The different age spans of the two populations represent a limitation when interpreting the results. Hence, a quantitative comparison between these two techniques may be difficult to achieve and was beyond the aim of this paper. Our aim was to determine, in post-mortem brains, the organization of MdLF fibers and provide evidence for a better orientation within the temporo-parieto-occipital connections. In addition, despite the classical limitations of white matter dissection and the high risk of artifacts during the dissection of regions in which the fibers intermingle or overlap , the information provided by the dissection is consistent with other studies using the same technique and high-quality specimens .Further, using normalized anatomical ROIs and results in a group analysis may create false results. In our opinion, the use of atlas-based regions to create connectivity maps minimizes the risk for incongruent/inconsistent anatomical results. We decided to use normalized percentage of streamlines within the regions and display them with a cut-off of 5% to remove possible artifacts. However, the risk of incomplete reconstruction or the effect of kissing/crossing fibers in complex anatomical region such as temporo-parietal-occipital region or the SS cannot be excluded with the current techniques. This may create tractography “contaminations,” with resulting overestimation of volume and difficulties to determine cortical terminations. Indeed, despite we performed a meticulous microdissection and used a strict, advanced tractographic method, we cannot exclude that the absence of MdLF terminations at the IPL represents a false negative from both techniques. On the other hand, the intrinsic advantage of high angular diffusion tensor imaging (DTI) and proved optimal quality of cadaver specimens may be reduce the risk of false or incomplete results. Nonetheless, our findings seem to strengthen previous findings that report a lack of significant MdLF connections with the IPL (SMG and AG).Finally, the use of two clinical cases to support anatomical-functional results can raise criticism because of the inter-individual variability in patients with low-grade gliomas. Even though the lesions  may result in minimal anatomical differences compared to patient-specific space, we believe that these two cases support complement anatomical information regarding the MdLF anatomy with functional/clinical implications  from language/neuropsychological examinations. Aware of the low level of evidence provided by only two neurosurgical cases without direct cortical subcortical mapping, we invite the reader to carefully interpret our inferences regarding the functional implications of MdLF. On the other hand, we believe that the results from a very extensive preoperative and postoperative assessment support the role of MdLF in auditory networks in the presented cases. Since the scientific community is still lacking a validated intraoperative test to demonstrate the on-line inhibition of MdLF, we believe that our result may encourage further studies to develop one or more dedicated tests for intraoperative mapping of auditory functions. Further studies with larger populations of selected cases and tailored intraoperative functional tasks would be able to confirm our theories on the functional role of MdLF.in vivo DTT, and clinical cases revealed a clear, constant, and detailed organization of the MdLF fibers in the temporo-parieto-occipital region. The main body of the MdLF is formed by an anterior-ventral segment (aMdLF) and a posterior-dorsal segment (pMdLF). The anatomical connectivity pattern and quantitative differences between the MdLF subcomponents support a pivotal role of the MdLF in supporting high order functions related to acoustic information. Due to the anatomical position and connectivity, the posterior portion, especially on left side, is possibly involved in learning process for verbal-auditory cross-modal integration. The anterior portion is on the other hand possibly involved in processing/retrieving auditory information already consolidated.Our results from post-mortem white matter dissection, subject-by-subject The datasets for this article are not publicly available due to privacy and ethical restrictions. Requests to access the datasets should be directed to the corresponding author.The studies involving human participants were reviewed and approved by Regional Ethical Vetting Board in Uppsala, Sweden (Dnr 2014/468). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.FL, GT, MF, and MR contributed to the experimental design and its implementation. FL, GT, and MF contributed to the analysis and interpretation of the data. All authors contributed to writing the manuscript at draft and any revision stages, read and approved the final version.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.