Muscular variations of the ventral thoracic wall are generally common and of great clinical interest.An unusual muscular variation of the ventral thoracic wall was observed and dissected in a West-European female body donor.An interclavicularis anticus digastricus muscle was observed and studied. It originated from the manubrium sterni and inserted bilaterally to the clavicles. Both muscle bellies were interconnected by a tendon on the ventral surface of the manubrium sterni. The muscle was innervated by branches of the lateral pectoral nerve.The interclavicularis anticus digastricus muscle is a muscular variation of the ventral thoracic wall of unknown prevalence. This variation might be of clinical interest in orthopaedics and thoracic surgery. It is also a vulnerable structure during infraclavicular insertion of a subclavian vein catheter or fractures of the clavicle. The ventral thoracic wall is built by various bones, muscles, and connective tissue. Multiple muscular variations of the ventral thoracic wall are known, and variations of pectoral muscles are said to be more frequent than variations of any other muscle group , 7 VariaSupernumerary muscles of the ventral thoracic wall   were claAn unusual muscular variation was observed in a 90-year-old West-European female who died of gastric cancer. We lack any further clinical information. The woman was part of the body donation program of the Anatomical Institutes of the Johannes Gutenberg-University, Mainz, Germany. She donated her body voluntarily for medical education and research. The specimen had been fixated via arterial perfusion with formaldehyde and subsequent formaldehyde immersion within a humidity chamber. Dissection was performed during the routine dissection class for undergraduate medical students at the Institute for Microscopic Anatomy and Neurobiology in the winter term 2020/2021. For morphometrical analysis, the muscle was removed carefully. Measurement was performed using a calliper. Inkscape project  was used to create the Fig. During dissection of the ventral thoracic wall, we observed an IADM, a special bilateral condition of a SAM. This muscle originated from the ventral surface of the manubrium sterni. The muscle inserted bilaterally with one muscle belly each on the inferior surfaces of the acromial ends of the clavicles. The two muscle bellies showed an interesting asymmetry: on the left side, the muscle belly was spindle-shaped and lay beneath the medial third of the clavicle Fig. a. It insSupernumerary clavicular muscles are numerous but uncommon. They were classified by Testut into four groups: 1. muscles sterno-chondro-scapulaires (sternochondroscapular muscles), muscles sterno-claviculaires (sternoclavicular muscles), muscles scapula-claviculaires (omoclavicular muscles), and muscles cleido-aponévrotiques  .The sternoclavicularis anticus muscle  is a rare muscular variation of the ventral thoracic wall , 32, 33.In rare cases, a bilateral SAM was found , 25, 29.There is a great variety of other supernumerary clavicular muscles that must be distinguished from SAM and IDAM. Hubert Luschka first described a supraclavicular muscle  which connects the suprasternal ossicles and the interclavicular ligament with the superior surface of the clavicle. Bilateral forms of this muscle are known , 19. In In the present case, we could confirm that the IADM receives its nerve supply from small branches of the lateral pectoral nerves from the brachial plexus. The lateral pectoral nerves arise from the lateral cord of the brachial plexus and contain fibres from the cervical segments 5 to 7 .The occurrence of a SAM or an IADM seems to coincidence with variations of the clavicular portion of the pectoralis major muscle. Variations of the pectoralis major muscle are common in general. Its most common variation is the absence of the sternocostal head . AbsenceSince the IADM correlates with muscular variations of the pectoralis major muscle and is innervated by the same nerve, both muscles may share the same developmental origin. Embryologically, the pectoralis muscles are hypaxial muscles. The pectoralis blastema splits into a cranial part, which is the anlage of the clavicular head of the pectoralis major muscle, and a caudal part, which is the primordium of the pectoralis minor muscle and the sternocostal head of the pectoralis major muscle . The subThere are only putative functions of the IADM. It may stabilize the sternoclavicular joint or lead to a weak protraction of the clavicle in the sternoclavicular joint. In case of common clavicular fracture , this muscle might influence the displacement of the bony fragments. The clavicular part of the pectoralis major muscle has an important role in arm flexion and medial rotation [In this case report, we used the terms sternoclavicularis anticus muscle and interclavicularis anticus digastricus muscle since these terms were introduced by Gruber in his original description of these variations , 13. AltThe interclavicularis anticus digastricus muscle is a rare muscular variation of the ventral thoracic wall of unknown prevalence. Physicians should be aware of this rare muscular variation during operative treatment of clavicle fractures or insertion of a subclavian vein catheter.


Goal-directed behavior often involves temporal separation and flexible context-dependent association between sensory input and motor output. The control of goal-directed behavior is proposed to lie in the frontoparietal network, but the computational architecture of this network remains elusive. Based on recent rodent studies that measured and manipulated projection neurons in the frontoparietal network together with findings from earlier primate studies, we propose a canonical scheme of information flows in this network. The parietofrontal pathway transmits the spatial information of a sensory stimulus or internal motor bias to drive motor programs in the frontal areas. This pathway might consist of multiple parallel connections, each controlling distinct motor effectors. The frontoparietal pathway sends the spatial information of cognitively processed motor plans through multiple parallel connections. Each of these connections could support distinct spatial functions that use the motor target information, including attention allocation, multi-body part coordination, and forward estimation of movement state . The parallel pathways in the frontoparietal network enable dynamic interactions between regions that are tuned for specific goal-directed behaviors. This scheme offers a promising framework within which the computational architecture of the frontoparietal network and the underlying circuit mechanisms can be delineated in a systematic way, providing a holistic understanding of information processing in this network. Clarifying this network may also improve the diagnosis and treatment of behavioral deficits associated with dysfunctional frontoparietal connectivity in various neurological disorders including Alzheimer’s disease. Our behavior flexibly changes depending on the desired goal. Approaching the same intersection, we may prepare to turn left or right depending on our current goal . Faced with the same dessert at the supermarket, we may choose to put it in our shopping cart or not depending on our desired goal . Brain areas supporting such flexible goal-directed behavior include the posterior parietal cortex (PPC), frontal premotor cortex (PMC), and prefrontal cortex (PFC), collectively forming the frontoparietal network . NumerouOne way to unravel the flow of information processing in a network is to identify the information content transmitted from one area to another. The direct characterization of inter-areal information flows requires the examination of the activity of projection neurons. For instance, an early study examined the activity of neurons projecting from the PPC to the frontal eye field (FEF) in the frontal lobe and found strong and prevalent visual activity in those neurons , implicaRecent scientific advances have made the study of projection neurons in the frontoparietal network more tractable. At the technical front, a diverse set of tools has been developed and become readily available for large ensemble recording and manipulation of projection neurons in specific pathways in rodents. At the biological front, studies have demonstrated that the frontoparietal areas in rodents, similar to primates, are involved in the control of goal-directed behavior (see later sections) . The simAll cortical functions rely on long-range connectivity to exchange information between brain areas and support hierarchical and distributed neural processing . Thus, tin vivo two-photon calcium imaging  and identify the spike activity upon direct activation of the cell bodies/somas  or antid imaging  with ret imaging . The thi imaging . When prInformation flow from one area to another also can be manipulated in order to demonstrate its causal role in specific neural processing or even a behavior. Activation can be applied to test gain-of-function, and suppression can test loss-of-function. A pathway of interest can be activated optogenetically by illuminating axon terminals of projection neurons that are infected with virus expressing channelrhodopsin . AlternaInformation flow from one area to another is carried by projection neurons, and the projection neurons, in turn, receive inputs from presynaptic neurons in multiple brain areas. Such a series of information flows can be examined by a new technical approach that can visualize presynaptic neurons of specific projection neurons  . This meSome of these powerful techniques have been applied in pathway-specific investigations of the frontoparietal network, providing important clues into the computational architecture of this network, as detailed in the following sections.What information is transmitted from the parietal to the frontal areas? Insights into this question may be gained by examining the known features of the primate and rodent PPC. The primate PPC is parceled into multiple subregions, each projecting to selective frontal premotor regions and organizing actions involving specific motor effectors; the parietal reach region (PRR) projects to the PMd for arm reaches, the lateral intraparietal area (LIP) projects to the FEF for oculomotor behavior, and the anterior intraparietal area projects to the ventral premotor cortex for hand grasping . The PRRA, and part of VRL and VAM , which largely overlap with the posterior-lateral PPC where M2-projecting neurons are prevalent  neurevalent , and (3)revalent . Overallrevalent .What is the functional purpose of the information flow in the parietofrontal pathway? Although Itokazu et al. did not investigate the behavioral impact of inactivating PPC neurons projecting to the M2, a separate study examined these behavioral effects . This stTaken together, these two mouse studies found that the parietofrontal pathway transmits the spatial information of both sensory stimuli and internal bias. These findings raise an intriguing question of whether the same population of PPC neurons encodes both the stimulus and internal bias information. Multiple scenarios can be conjectured. First, the two lines of input information, the external stimulus and internal bias, might be integrated in the same population of PPC neurons and utilize an overlapping pathway for motor control. Second, distinct PPC neurons might encode each type of information but converge and feed into the same M2 neurons. Third, distinct PPC neurons encoding each type of information might project to distinct subpopulations or subregions in the M2. This scenario suggests that the multiple parallel parietofrontal pathways might be segregated based on the type of information , similar to primates and humans, each controlling a specific effector such as saccade, reach, or grasp . Such paWhat information is transmitted from the frontal to the parietal areas? Before delving into this question, we first review our current understanding of the frontal cortical regions that are strongly interconnected with the parietal regions in primates and rodents. In primates, the PMd is reciprocally connected with the PRR and the two areas show very similar neuronal response properties . In a deIn parallel to the close link between the PMd and PRR for reaching movements, the primate FEF in the frontal lobe and the LIP are reciprocally connected for eye movements and attention . Note thWhether and where rodents have brain areas homologous to the primate PFC is an unsettled matter . This isNotwithstanding the above caveat, the dorsal part of the rodent medial frontal areas includes part of a region referred to as the M2, which shows similar, albeit not identical, anatomical connections and electrophysiological properties as the primate PMd and FEF . First, Given the functional and anatomical similarities between the rodent M2 and the primate PMd/FEF, the current review addresses the question of what information is transmitted from the frontal to the parietal areas, focusing on the rodent M2 and the primate PMd/FEF. One of the first rodent studies that directly examined this question is the aforementioned study by The explicit purpose of the motor target information flow from the M2 to the PPC has yet to be characterized, but decades of primate research offer some compelling hypotheses. Research has shown that intracortical microstimulation of the FEF in macaques activates the LIP in the PPC and visual areas, consistent with the anatomical connectivity . FurtherIntriguingly, perceptual enhancement can also occur for sensory stimuli at planned movement targets, indicating a link between movement planning and attention processing . Thus, oIn addition to attention processing, the PPC has been implicated in various other functions that may utilize motor target information originating from the frontal areas . Such fuBased on the recently identified pathway-specific information flows in mice and extensively characterized neural response properties in primates, we propose the following canonical organization of information flows in the frontoparietal network . The parDysfunction of the frontoparietal network could underlie many neurological/neuropsychological diseases including Alzheimer’s disease (AD). The role of the frontoparietal network has been underappreciated in AD; traditionally, AD pathology has been characterized as neurodegeneration in the medial temporal structures  and memory impairments have been the most representative AD symptoms. However, recently AD symptoms in sensory and motor systems began to gain more and more attention . Two linFirst, the neuropathology of AD  is frequently observed in the sensory and frontal areas at an early disease phase prior to cognitive decline , in someSecond, AD is increasingly viewed as a disconnection syndrome, where the long-range cortical interactions are impaired . The eviin vivo imaging and cell-type-specific labeling of monosynaptic long-range inputs, as discussed above, will provide key information regarding the relationship between reduced functional connectivity and the cognitive and goal-directed behavior deficits in AD.It is reasonable to speculate that the reduced functional connectivity in AD patients might reflect impaired long-range connectivity . Yet, thThe frontoparietal network might have evolved from the pressure to support goal-directed behavior, allowing context-dependent flexible association and temporal separation between sensory stimuli and motor responses. The parietofrontal pathway transmits bottom-up sensory-driven information to drive automatic or default responses similar to reflexes. The bottom-up responses can be enforced, temporarily withheld, or canceled in context-dependent manners through interaction with the frontal areas specialized for the computation of cognitive rule-based responses. The frontoparietal pathway transmits cognitively processed responses so that it can be used by the parietal areas specialized for spatial information processing for attention allocation, multi-body part coordination, and forward models. We hope this canonical scheme of parallel information flows in the frontoparietal network provides holistic insights into the dynamic information processing in this network and guides future research delineating the computational hierarchy and supporting circuit mechanisms in a systematic way. Furthermore, a detailed understanding of the frontoparietal network can shed light on the neural basis of impaired goal-directed behavior in various neurological and psychiatric disorders including AD.EH, TRS, and TKS: conceptualization and writing. TRS and TKS: funding acquisition. All authors contributed to the article and approved the submitted 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Minimally invasive tissue sampling (MITS), an alternative to complete diagnostic autopsy, is a pathology-based postmortem examination that has been validated in low- and middle-income countries (LMICs) and can provide accurate cause of death information when used with other data. The MITS Surveillance Alliance was established in 2017 with the goal to expand MITS globally by increasing training capacity, accessibility, and availability in LMICs. Between January 2019 and May 2020, the MITS Surveillance Alliance convened a multidisciplinary team of technical advisors to attain this goal.This article describes the process used to develop criteria and identify an optimal location for a MITS training hub, establish a cadre of LMIC-based trainers, refine standardized MITS sample collection protocols, develop a training program, and release a telepathology platform for quality assessment of MITS histological samples.Results include the creation of a training hub and curriculum, with a total of 9 pathologists and technicians trained as part of the training of the trainers. Those trainers trained 15 participants from seven MITS projects representing 6 LMICs trained in MITS sample collection. The 15 participants have gone on to train more than 50 project-level staff in MITS sample collection.Lessons learned include an appreciation for using an iterative process for establishing standardized procedures, creating opportunities for all stakeholders to deliver critical feedback, and highlighting the importance of complementing in-person trainings with ongoing technical assistance. Accurate mortality data are needed to prioritize health programs and guide health policies. As a result of limited pathology and laboratory resources and insufficient numbers of adequately trained personnel to conduct postmortem investigations in low- and middle-income countries (LMICs), there is inadequate use of the complete diagnostic autopsy (CDA), the gold standard for postmortem assessment of cause of death . In low-To support the expansion of pathology-based mortality surveillance, in 2017 the MITS Surveillance Alliance was established as a global multidisciplinary consortium of researchers to expand the use of MITS. The Alliance catalyzed the expansion of MITS by initially funding 12 grants to implement small-scale postmortem studies using MITS, all in LMICs. Most grant recipients lacked previous experience performing MITS sample collection and thus required training.To date, training on the MITS sample collection technique has been limited and tailored to each study’s specific objectives. Researchers from the Barcelona Institute for Global Health  as part of the Cause of Death using Minimally Invasive Autopsies (CaDMIA/CaDMIA Plus) projects, organized a training program for the Child Health and Mortality Prevention Surveillance (CHAMPS) Network . The traThe MITS Surveillance Alliance built on this prior research to establish a new training hub with the goal to expand MITS training capacity and increase accessibility and availability, specifically in LMICs. It is important to acknowledge that although implementing MITS in new contexts requires expertise across a variety of domains including pathology, histology, microbiology, social and behavioral sciences, and cause of death assignment, the primary objective of the training hub was to build capacity in MITS sample collection. MITS sample collection primarily involves the practice and acquisition of new skills; for this reason, training with ample opportunity for skills practice and expert feedback was prioritized. Fundamental to this goal was creating a standardized training program for adult learners that maximized skills practice and acquisition and prepared trainees to cascade the training to additional team members within their awarded projects.This article describes the MITS Surveillance Alliance strategic approach to expanding MITS sample collection training, including identifying a new MITS training hub, establishing a cadre of LMIC-based MITS trainers, improving standardized collection procedures, developing a detailed training curriculum, and providing ongoing technical assistance to trainees following in-person trainings .The MITS Surveillance Alliance Training technical working group (TWG) was convened in January 2019 for the purpose of developing a plan to expand the use of MITS globally. The TWG consisted of a diverse group of technical advisors from ISGlobal, Research Triangle Institute (RTI) International, and the US Centers for Disease Control and Prevention’s (CDC’s) Infectious Disease Pathology Branch . To idenFollowing the selection of the training hub location, a training of the trainers (TOT) curriculum was developed based on a traditional TOT training model in which members of the TWG conducted a training for pathologists, pathologists in training, and pathology technicians, establishing a regionally based cadre of MITS trainers. Learning objectives for the TOT were developed and agreed upon by the TWG. The objectives were then mapped to the MITS Sample Collection training curriculum implemented by ISGlobal for prior MITS projects. In addition to content directly related to collecting MITS samples, objectives specifically targeting best practices in training professional adults were identified; sessions addressing the principals of adult learning, skills for effective facilitation, and methods for supporting multiprofessional learning were integrated into the TOT curriculum  8]..8].Members of the TWG conducted a 7-day TOT for 3 pathologists and 5 pathology technicians onsite at KNH in July 2019. Two of the 3 pathologists participating in the TOT had previous experience with MITS. The first 2 days were focused on didactic content and adult learning principles. The subsequent 5 days focused on MITS sample collection. Each day started with a skills practice session followed by a short didactic lesson and concluded with a debrief.Central to establishing a standardized training program was the adoption and refinement of a standard operation procedure (SOP) for MITS sample collection. Using aspects of SOPs for MITS sample collection already created for other studies, the TWG developed a draft SOP that was piloted over the course of the TOT , 9. The The daily debriefing sessions consisted of collecting structured and unstructured feedback from both TWG members and trainers about the training process and curriculum organization. In addition, a comprehensive summary feedback session to review all final suggested changes to the curriculum and SOP was held on the last day of the TOT. Outcomes of the feedback sessions included converting some of the in-person content to online asynchronous e-learning modules and increasing the total amount of training time dedicated to skills practice. The feedback sessions also led to the development of the customized MITS Specimen Collection form see  and the In September 2019, trainers trained as part of the TOT began conducting MITS sample collection training for MITS Alliance grant awardees . TraineeTWG members attended the first and second trainings to provide supportive supervision to the trainers. The supportive supervision included joint daily debriefings to share observations from the day, support to the trainers in preparations for the subsequent day of training, and documentation of observations about the curriculum and training materials. This iterative approach allowed trainers to revise and fine-tune the curriculum over the course of the initial trainings. In addition to TWG members, a pathologist with extensive expertise in MITS training from the CaDMIA/CaDMIA Plus projects in Mozambique was invited to attend a training. This external expertise and feedback offered trainers a different perspective and established a strong foundation for future South-South cooperation.All trainees completed an evaluation on the final day of the training program see . This evFollowing the conclusion of the in-person trainings, the TWG and trainers collaborated to provide additional technical assistance intended to complement the in-person training. Activities included conducting implementation site visits and establishing a telepathology platform to enable remote quality assessment of MITS sample collection.The site visits were designed to reinforce training and support trainees in MITS implementation and to further strengthen the capacity of trainers following the in-person training. Sites were identified based on complexity of the study, whether the site had previous experience conducting MITS, observations of skill acquisition by the trainers over the course of the in-person training, and the level of existing resources available at the site. Assessment criteria for the site visits were prepared and included prerequisites for the visit, a description of the goals and objectives of the site visit, and a proposed agenda see . Using aSite visits were initially planned for 5 projects. Ultimately, 3 of the 5 were carried out in person, but the remaining 2 were conducted virtually because of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first site visit was conducted by members of the TWG over 4 working days in December 2019. Each site visit focused on observations and feedback of MITS sample collection procedures and techniques and the review of already processed histological MITS samples. The TWG observed trainees’ MITS sample collection and provided real-time feedback with suggestions for improving technique and accuracy. The review of processed histological MITS samples as part of the implementation visit emphasized the value in providing feedback and troubleshooting challenges in MITS sample processing. Trainees were encouraged to incorporate suggestions made by the TWG over the course of the visit, and as a result the TWG witnessed immediate improvements at the sites.After the SARS-CoV-2 pandemic was declared, travel was not feasible, and the remaining 2 site visits were conducted via videoconference. In preparation for these “virtual” visits, prior to the meeting date trainees were asked to create and share videos and photos of their facilities including a detailed mapping of the expected workflow and sample storage. The materials provided by the sites were reviewed by the TWG members in advance of the scheduled videoconference. During the live videoconference, TWG members provided feedback to the site and helped troubleshoot and identify solutions for potential issues related to implementing MITS sample collection locally.TWG members collaborated in the design and development of an online telepathology platform aimed at supporting trainees in ongoing quality improvement of MITS sample collection and processing for histopathology. The telepathology system was largely based on CDC’s Infectious Diseases Pathology Branch telepathology approach for supporting CHAMPS and other MITS studies , 10. TraFollowing the self-evaluation, CDC pathologists used the same criteria to evaluate and document overall case and image-specific feedback. After a case was evaluated, trainees were able to view evaluator feedback and comments.During the site visits, trainees were oriented to the telepathology system and practiced uploading images and completing the self-evaluation with support from the TWG. Discussion during the site visit subsequently informed the creation of a User Guide and Frequently Asked Questions document.The MITS Surveillance Alliance convenes quarterly meetings to provide ongoing support to trainees. These meetings have helped sites troubleshoot MITS related challenges, address specific topics such as how SARS-CoV-2 is impacting their ability to conduct MITS, and serve as a forum for sharing experiences and learning. Trainees also participate in monthly virtual domain-specific TWG meetings which create unique opportunities for trainees to interface with peers and more experienced MITS researchers. All trainees have access to a private chat group to connect and interact in real time.This article describes the approaches used to increase the global availability and accessibility of MITS training by successfully establishing a training hub in an LMIC. We describe in detail the activities carried out to identify a training hub site, conduct a TOT to establish a cadre of MITS trainers, implement MITS sample collection training, and provide post-training ongoing technical support to trainees. There were several valuable lessons learned as part of establishing this training hub.One lesson was the importance of engaging an experienced and multidisciplinary group of experts with a commitment to expanding the use of MITS at the outset. Prior to the establishment of the training hub, there had been little published on MITS training, few models for implementing MITS training, and only a handful of individuals capable of building new capacity in MITS sample collection. By establishing a Training TWG consisting of individuals from different institutions and disciplines, we were able to capitalize on the collective experience and knowledge regarding MITS sample collection training to establish a well-prepared training hub, refine the standardized sample collection procedure, and launch a comprehensive training curriculum.A second lesson learned was that there is value in continued communication and support for the trainers following the TOT. This allowed the TWG to identify and promptly address any gaps in knowledge or resources needed to implement MITS sample collection trainings. By observing the KNH team while conducting the first MITS sample collection training, the TWG facilitated the trainers in identifying both successes and areas for improvement. Frequent communication between the TWG and trainers also supported iterative development and revision of the MITS sample collection training curriculum. This approach empowered the trainers to adapt the curriculum based on their observations and assume increasing ownership over trainings.Similarly, providing ongoing opportunities for technical assistance in MITS implementation to trainees was important and reinforced the skills learned as part of the in-person training. Site visits helped trainees refine and perfect their MITS sample collection technique and improve the quality of sample processing. The telepathology platform established a durable channel for trainees to receive expert feedback on the quality of MITS sample collection and processing.And lastly, by creating enduring training materials including the didactic lessons adapted to self-paced e-learning modules and a well-illustrated SOP, the initial impact of training was extended to support trainees to expand MITS sample collection capacity within their sites and train additional members of their project team.Until March 2020, plans for further utilizing the MITS training hub included conducting the remaining site visits for trainees and supporting additional trainings. However, the global SARS-CoV-2 pandemic has significantly curtailed planned activities. Curriculum modifications to support remote learning have been made and include utilizing new methodologies. A complete series of comprehensive step-by-step training videos teaching MITS sample collection was created by the trainers. The videos and didactic content are discussed in depth via a series of interactive videoconferences. Trainees use mobile devices and hotspots to demonstrate and record their MITS sample collection technique. Trainers review each recording and share feedback, troubleshoot challenges, and debrief with trainees in advance of the next skills practice over videoconference. The other methods for supporting MITS training, including the TWGs, the telepathology platform and regular meetings with trainees, continue without interruption. The TWG will continue to innovate and adapt to expand MITS training accessibility and availability within existing limitations.Accurate mortality data are needed to prioritize health programs and interventions to guide health policies. The SARS-CoV-2 pandemic highlights the urgent need for pathology-based cause of death determination. MITS is comparable to CDA and can be implemented in LMICs with lower costs and fewer resources. By establishing a training hub and cadre of trainers for MITS sample collection, MITS training capacity and accessibility has been expanded, making pathology-based postmortem examination more attainable, especially within LMICs.Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at ciab765_suppl_Supplementary_MaterialsClick here for additional data file.


A defective nutrient foramen in the fovea capitis femoris was hypothesized to reflect the blood circulation pattern of the femoral head, leading to insufficient blood supply and causing osteonecrosis of the femoral head.Normal and necrotic femoral head specimens were collected. The necrotic femoral head group was divided into a non-traumatic and traumatic subgroup. 3D scanning was applied to read the number, the diameter, and the total cross-sectional area of the nutrient foramina in the fovea capitis femoris. Chi-squared tests and independent t-tests were used to detect any differences in the categorical and continuous demographic variables. Logistic regression models were used to estimate the odds ratio (OR) for non-traumatic and traumatic osteonecrosis in different characteristic comparisons.A total of 249 femoral head specimens were collected, including 100 normal femoral heads and 149 necrotic femoral heads. The necrotic femoral head group revealed a significantly higher percentage of no nutrient foramen (p < 0.001), a smaller total area of nutrient foramina (p < 0.001), a smaller mean area of nutrient foramina (p = 0.014), a lower maximum diameter of the nutrient foramen (p < 0.001), and a lower minimum diameter of the nutrient foramen (p < 0.001) than the normal femoral head group. The logistic regression model demonstrated an increasing number of nutrient foramina , a larger total area of nutrient foramina , a larger mean area of nutrient foramina , a greater maximum diameter of the nutrient foramen , and greater minimum diameter of the nutrient foramen  significantly associated with reduced odds of osteonecrosis of the femoral head (ONFH). The necrotic femoral head group was further divided into 118 non-traumatic and 31 traumatic necrotic subgroups, and no significant difference was observed in any characteristics between them.Characteristics of the nutrient foramen in the fovea capitis femoris showed a significant defect of necrotic than normal femoral heads, and significantly reduced odds were associated with the higher abundance of the nutrient foramen in ONFH. Therefore, the condition of the nutrient foramen might be the indicator of ONFH.The online version contains supplementary material available at 10.1186/s13018-021-02564-6. Osteonecrosis of the femoral head (ONFH) is a complex disease with ill-defined etiology and pathogenesis. About 70–80% of the patients with ONFH progress to secondary hip arthritis. Both operative and nonoperative treatments, including core decompression (CD) and other joint preserving treatments, have been performed and described with variable success rates –3. EarlyThe causes of ONFH include traumatic and non-traumatic. ONFH mainly occurs after direct trauma, such as femoral neck or head fracture, acetabular fracture, hip dislocation, severe sprain, or hip contusion. The pathogenesis of non-traumatic ONFH is unclear, and the main risk factors include systemic steroid administration –8, alcohONFH was characterized by the death of osteocytes and the bone marrow and might be caused by the inadequate blood supply to the affected segment of the subchondral bone , 11. MosDefects of fovea capitis femoris in the femoral head are the anatomical basis for the occurrence and development of a vascular necrosis of the femoral head. This concept has never been described and proven in the previous reports. For patients with femoral neck fractures, bleeding on the fracture surface reduces the blood supply to the femoral head and aggravates ischemia. For patients with avascular necrosis of the femoral head, lack of blood flowing into and out of the fovea of the femoral head aggravates the metabolic disorder of the femoral head. It is vital to understand the rules and changes of blood supply in evaluating and managing femoral neck fractures for personalized treatment. Complete information of the epidemiological and clinical characteristics is implemented for developing and establishing appropriate treatment strategies.This study hypothesized that the defect of the nutrient foramen in fovea capitis femoris would reflect the blood circulation pattern of the femoral head, which would impact the repair of the blood supply under the action of risk factors, and then cause osteonecrosis of the femoral head. The nutrient foramen in the necrotic femoral head was compared with that in the normal femoral head to clarify the relationship between fovea capitis femoris and ONFH.This study collected femoral head specimens comprising intact normal femoral heads and necrotic femoral heads. The dry bone specimens of the femoral head were used as the normal femoral head group, which were obtained from our published study . The speThe femoral head surface was scanned using Micro-CT-100  and output with a DICOM image for 3D surface reconstruction. The necrotic femoral head specimens with damaged fovea capitis femoris due to the collapse of the femoral head were excluded, and only femoral head with complete fovea capitis femoris and normal femoral head specimens were analyzed. The nutrient foramina in the fovea capitis femoris of the femoral head were analyzed on the 3D reconstruction specimens  for categorical variables and mean ± SD for continuous variables. Baseline characteristics were compared between groups using chi-squared tests and independent t-tests to detect any differences in the categorical and continuous demographic variables. Logistic regression models were used to estimate the odds ratio (OR) and 95% confidence intervals (CIs) for non-traumatic and traumatic osteonecrosis in different characteristic comparisons. Data management and statistical analyses were conducted using SAS version 9.4 software . A two-sided P-value of < 0.05 was regarded as statistically significant.A total of 249 femoral head specimens were collected, including 100 normal femoral heads and 149 necrotic femoral heads. The characteristics of nutrient foramina in the fovea capitis femoris of normal femoral heads and necrotic femoral heads are shown in Table The logistic regression model demonstrated that increasing number of nutrient foramina , larger total area of nutrient foramina , larger mean area of nutrient foramina , greater maximum diameter of the nutrient foramen , and greater minimum diameter of the nutrient foramen  were significantly associated with reduced odds of ONFH , total area, mean area, maximum diameter, and minimum diameter of the nutrient foramen. The defect of nutrient foramina in necrotic femoral heads was significantly higher than the normal. Among 31 specimens of traumatic femoral head necrosis, 77.4% had no nutrient foramina. Besides, the abundance of nutrient foramen was significantly associated with low odds of ONFH. The defect of nutrient foramina at the femoral head could result from vascular foramina defect in this area, suggesting a clear association between the nutrient foramina and ONFH.The avascular necrosis of the femoral head has been reported as a type of osteonecrosis due to disruption of blood supply to the proximal femur and can occur due to various causes, either non-traumatic or traumatic in origin , 14. TheKusumbe et al. reported that the role of type H vessels in bone formation is revealed . Type H Displaced femoral neck fracture patients were reported to have a higher risk of vascular necrosis than non-displaced femoral neck fracture ones, which might be due to the blood supply to the femoral head is disrupted after displacement . HoweverAn osteotomy was a treatment for ONFH by changing the spatial position of the necrotic portion of the femoral head. However, Quaranta et al. have reported that approximately one-third of the osteotomies performed in cases of ONFH were converted to THR over 7 years . The infWith the assistance of high-resolution CT scanning, information about the presence of nutrient foramina in the fovea capitis femoris might be expected as one of the monitoring indicators of ONFH risk. For the elderly lacking nutrient foramina in the fovea capitis femoris, artificial hip replacement would be suggested. For the young and middle-aged patients suffering from femoral neck fractures, drilling from the greater trochanter, the neck of the femur, and the fovea capitis femoris combined with internal fixation is recommended. For patients with femoral neck fractures and lacking nutrient foramina in the fovea capitis femoris, or patients with non-traumatic ONFH, this might be a treatment option. This anatomical phenomenon enriches the etiology of ONFH and provides an alternative strategy for the individualized treatment options for femoral neck fractures, especially the internal fixation treatment of femoral neck fractures in young people.A significant defect of the nutrient foramen in the fovea capitis femoris of necrotic femoral heads was observed in this study, and a higher abundance of nutrient foramen was significantly associated with reduced odds of ONFH. Therefore, the information from high-resolution CT scanning relating to the nutrient foramina in the fovea capitis femoris might be a monitoring indicator of the ONFH.Additional file 1: Supplemental Figure S1. The 3D reconstruction picture of the femoral head specimen shows the nutrient foramina in the fovea capitis femoris of the femoral head.Additional file 2: Supplemental Figure S2. The zoom-in picture presents the fovea capitis femoris of the femoral head.Additional file 3: Supplemental Figure S3. The enlarged nutrient foramina, indicating that the nutrient foramina penetrate the bone, and the contour of the cancellous bone in the femoral head can be observed from the nutrient foramina.


Bacteria can adapt promptly to environmental changes using regulatory switches which work at both transcriptional and post-transcriptional levels. Translational control offers a rapid and precise response to different stresses insofar as the signals are processed to get immediate proteome remodeling. The players of this regulation are mRNAs, tRNAs, nucleic acid binding proteins, regulatory sRNAs, and the ribosome itself. Depending on the state of the cell, they can establish different regulatory networks via direct interactions, structural changes, and RNA modification states. Translation initiation, involving ribosome loading on the mRNA start codon is most often the step subjected to regulation. The accessibility of several mRNA signals, including Shine-Dalgarno (SD) sequences, A/U rich tracts recognized by ribosomal RNA chaperone bS1, and the start codon, can be regulated in response to environmental clues, interactions with proteins, sRNAs or metabolites ppGpp alarmones are produced in response to the binding of an uncharged cognate tRNA to the A-site of stalled ribosomes under a variety of stress conditions, including starvation for an essential amino acid. Notably, (p)ppGpp can target the assembly of translation initiation complexes in a mRNA dependent way. Finally, a combination of mRNA structures and RNA chaperone proteins orchestrates translation during cold shock.The review by Pourciau et al., describes the role played in Gammaproteobacteria by CsrA and its homologs. CsrA is the global regulator of carbon metabolism in the stationary phase, also coordinating virulence and motility. This RNA-binding protein establishes regulatory loops including its own autoregulation. To do this CsrA operates at different levels using different mechanisms, including translation repression or activation, promotion of transcription termination, and RNA stabilization.Maksimova et al., reports a systematic approach, including kinetics and thermodynamics studies, to investigate the effects on different stages of protein synthesis of Amicoumacin A, an antibiotic that targets the 30S ribosomal subunit. The results provide insight on its original mechanism of action, involving stabilization of the mRNA and the 30S initiation complex.The article from Samatova et al. discuss the surprising world of translation pausing, reviewing the most recent advancements in this field. The pauses of elongating ribosomes during translation can affect both translation rates and protein folding. Different factors can contribute to translational pausing, namely the cis-acting elements of mRNAs , the chemical modification and the availability of aa-tRNAs, as well as the interactions between the wall of the polypeptide exit tunnel of the ribosome and the nascent peptide.Translation regulation does not finish with the initiation step. Müller et al., describes in structural detail the various rescue mechanisms which are critical to release both ribosomes and tRNAs sequestered in the no-go and non-stop complexes, to make them available for new rounds of translation.The prolonged stalling of the ribosome on intact mRNAs or on chemically damaged mRNAs can produce the so-called no-go complex. Ribosomes can also stall on mRNAs which lack the stop codon . The review from Carrier et al. review common and uncommon sRNA-mediated mechanisms of translation regulation, mainly focusing on gram negative bacteria. sRNAs can do different jobs, from the classical inhibition of translation by targeting Ribosome Binding Sites (RBSs), to less canonical mechanisms of action which entail base pairing of the sRNA with the 5'UTR or the coding region of the target mRNA, a situation which may favor translation initiation by producing local structural rearrangement on the mRNA.The sRNA word is very fascinating both for the wide range of mechanisms which control translation and for the questions still open in this field. Staphylococcus aureus antisense small RNAs (asRNAs) are often involved in the control of plasmid copy number, as described in the original research paper of Guimarães et al. The natural plasmid pSA564 produces an asRNA (named RNA1) from a promoter located on the reverse strand of the replication initiation gene (repA). As observed for other RepA_N family members, base-pairing between RNA1 and the 5'UTR of repA could favor a specific conformer of the 5'UTR which reduces both repA transcription and translation. The rapid degradation of RNA1 is probably ensured by the host exoribonucleases RNase J1 and J2.In In conclusion, this Research Topic highlights a selection of original research and review articles representing the current progress in our understanding of the diversity of molecular mechanisms of translation regulation in response to changing environmental conditions or antibiotic treatments. We hope that the readers will enjoy these works as much as we have.AMG and SM have made 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.


Bursaphelenchus xylophilus, causes strong worldwide economic and ecological impacts. Direct control is performed through trunk injection of powerful nematicides, however many of these (hemi)synthetic compounds have raised ecological and human health concerns for affecting non-target species and accumulating in food products. As sustainable alternatives, essential oils (EOs) have shown very promising results. In this work, available literature on the direct activity of EOs against PWN is reviewed, as a contribution to advance the search for safer and greener biopesticides to be used in sustainable PWD pest management strategies. For the first time, important parameters concerning the bioassays performed, the PWNs bioassayed, and the EOs used are summarized and comparatively analyzed. Ultimately, an overview of the chemical composition of the most active EOs allowed to uncover preliminary guidelines for anti-PWN EO efficiency. The analysis of important information on the volatile phytochemicals composing nematicidal EOs provides a solid basis to engineer sustainable biopesticides capable of controlling the PWN under an integrated pest management framework and contributes to improved forest health.The impacts of a rapidly changing environment together with the growth in global trade activities has promoted new plant pest pandemic events in forest ecosystems. The pinewood nematode (PWN),  Bursaphelenchus xylophilus (Steiner & Buhrer 1934), is classified as one of the top 10 PPNs with the highest global economic and scientific importance  methyl-3,4-dihydro-6,7-dimethoxy-isoquinolinium chloride, capable of controlling PWN and acting as a fungicide, which has the advantage of debilitating PWN and limiting its fungal food source [50 values to its original compounds [Research on EOs with activity against PWN has evolved progressively, starting with screening a wide range of plants and plant parts, known for the high biological activity of their EOs, and focusing on the chemical characterization of compounds and/or compound interactions responsible for the highest anti-PWN activities. Currently, laboratory screening methodologies for phytochemicals are being improved with the aid of in vitro culture techniques that allow testing compounds in an infection condition where both the host and the parasitic nematode are present ,102. Thed source . The appompounds . Future The use of natural compounds for the biological control of important pests is extremely advantageous, since it provides eco-friendly biodegradable alternatives to dangerous synthetic chemicals, whose study leads to the development of derivatives with increased activity or specificity; brings recognition to the diversity of natural resources; and promotes sustainable pest management strategies that stimulate the recovery of ecosystem diversity. Against PWN, a high number of EOs have been screened and several have been proven effective. The summarization of the methodologies used to assess the nematicidal activity of EOs permitted determining the most utilized and successful bioassay conditions, and is presented here in detail as a guideline towards a standardization of direct contact bioassays against the PWN. Linking the composition of EOs to their nematicidal activity allowed for uncovering the compounds with the highest nematicidal potential. From the reported EOs, those rich in sulphides or oxygen-containing compounds showed the lowest effective concentrations and are candidates for in vivo testing, under infection conditions, in order to assess efficiency against PWD. The application of the latest developments on anti-PWN EO research allied to the optimization of current methodologies can provide an innovative strategy to establish sustainable pest management practices against PWD.


Infertility is a common problem in modern societies with significant socio-psychological implications for women. Therapeutic interventions are often needed which, depending on the cause, can either be medical treatment, surgical procedures or assisted reproductive technology (ART). However, the treatment of infertility is not always successful due to our limited understanding of the preparation of the lining of the uterus, the endometrium, for pregnancy. The endometrium is of central importance for successful reproduction as it is the site of placental implantation providing the interface between the mother and her baby. Due to the dynamic, structural and functional changes the endometrium undergoes throughout the menstrual cycle, it is challenging to study. A major advancement is the establishment of 3D organoid models of the human endometrium to study this dynamic tissue in health and disease. In this review, we describe the changes that the human endometrium undergoes through the different phases of the menstrual cycle in preparation for pregnancy. We discuss defects in the processes of endometrial repair, decidualization and acquisition of receptivity that are associated with infertility. Organoids could be utilized to investigate the underlying cellular and molecular mechanisms occurring in non-pregnant endometrium and early pregnancy. These studies may lead to therapeutic applications that could transform the treatment of reproductive failure. The World Health Organization describes infertility as a ‘disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse’ . In womeChlamydia trachomatis or Neisseria gonorrhoea. Suboptimal function of the endometrium, the mucosal lining of the uterus, failing to achieve optimal decidualization and become receptive are a major cause of primary infertility , environmental (endocrine disruptors) and lifestyle (chronic stress and delayed childbearing) influences that can affect reproductive function . Up to 3vice versa does not seem to significantly change the live birth rates    and rodeThe physiology of the endometrium is a determining factor in the establishment and maintenance of pregnancy as it provides the site of implantation and early nutrition to the conceptus during the first few weeks of pregnancy  expression is highest during this phase in both the epithelial and stromal compartments where maximal levels of mitoses are seen , epithelial cells at the surface epithelium (LGR5+), stem cells likely to be pericytes , stromal fibroblasts from menstrual blood, endometrial and decidual side-population cells  and bone marrow-derived cells  that facilitates their subsequent regrowth has not been addressed. Transcriptomic approaches allow the generation of reference datasets to identify the different epithelial populations in vivo and infer their potential roles in the function of the endometrium. For example, single-cell RNA sequencing analysis of organoids has identified a putative stem cell population that decreased when they were treated with oestrogen, progesterone and cyclic AMP (cAMP)  into single cells using the CRISPR/Cas9 technology  occurs spontaneously, unlike in mice. Following ovulation (day 14), the endometrium undergoes substantial remodelling of all cellular elements to become receptive for implantation in the mid-secretory or luteal phase . Initialet al. 2019). On the contrary, genetic signatures and molecular biomarkers of receptivity are more promising. An endometrial receptivity array can be used to classify endometrial biopsies according to their transcriptomic profile, based on which women can then undergo personalized embryo transfer (The window of implantation (WOI) (days 20–24) marks the phase during which the endometrium is receptive and the implantation of the blastocyst can occur . Althouget al.Decidualization is mediated by hormonal signalling through oestrogen and progesterone. Oestrogen acts through the oestrogen receptor α (ESR1) to enhance the expression of progesterone receptor (PGR) allowing the endometrium to respond to the elevated levels of progesterone during the secretory phase . PGR is SOX9, PROM1, AXIN2 and LRIG1) . The corpus luteum involutes with decreasing progesterone levels resulting in menstruation . The relin vivo features of early trophoblast and secrete placental-specific peptides and hormones, including chorionic gonadotropin  cells make up ~70% of CD45arteries . The exaarteries . This fuarteries . uNK celarteries . CurrentBesides organoids, culture methods for human embryos, together with transcriptomic and bioengineering technologies, provide additional experimental approaches for the study of early human development . AlthougAltered function or regulation of endometrial progenitors and their niche are likely to be responsible for some endometrial disorders. Dysregulated proliferation is seen in endometriosis, hyperplasia and carcinomas or during the insufficient growth of the endometrium  but not R-spondins are expressed by organoids explaining the requirement for external addition of R-spondin but not WNT3A . Organoids from endometrial low-grade tumours also highly express WNT target genes   and endometrial cancer (RSPO1) which could bind WNT receptors in epithelial cells  , a progesterone-regulated gene, was downregulated in the organoids at different stages of endometriosis. On the contrary, SOX9 was upregulated further supporting the hypothesis that an altered progesterone response and enhanced proliferation is driving endometriosis  genes and their cofactors between eutopic and ectopic organoids and tissues from women with endometriosis  , the anterior pituitary gland  and the ovaries . Endocrine-disrupting chemicals  are commonly used in Western societies with concerns about their impact on female infertility (Lactobacillus spp.) in the uterine mucosa that does not respond to hormonal changes and remains stable during the menstrual cycle  and the activation of progesterone receptors  . DiffereEndometrial regeneration after menstrual breakdown is unusual as it occurs without the fibrosis normally seen following ulceration of a mucosal surface. Scarring does develop if the basal layer is removed following uterine infection or surgery . The fibrous scarring can lead to intrauterine adhesions that are unresponsive to hormones and often asymptomatic. However, they can cause hypomenorrhoea/amenorrhoea, recurrent miscarriages and possibly infertility, which are all symptoms characteristic of Asherman Syndrome (AS). Attempts to lyse the fibrotic lesions are of questionable efficacy, with a high risk of recurrence , uterine disorders , altered immunological niche  and lifestyle factors  – affect fertility, understanding how these conditions affect endometrial epithelial behaviour is still limited. Generating organoids from healthy and pathological endometrium opens up opportunities to address these essential questions as well as promote personalized medicine approaches with tailored hormonal therapies and regenerative therapies for the treatment of infertility.Infertility is a complex, multifactorial disorder and ~30% of cases still remain unexplained. The endometrium is the site of implantation and source of nutrition for the developing conceptus and its altered function is a major cause of infertility. However, because of the lack of physiologically relevant The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.K N was supported by the Wellcome Trust Investigator Award to A Moffett (UNS13724) and is now supported by a PhD fellowship from the Centre for Trophoblast Research. M Y T is supported by the Royal Society Dorothy Hodgkin Fellowship (DH160216) and has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. [853546]).K N and M Y T conceived and wrote the manuscript. K N prepared the figures.


The circular bioeconomy has undoubtedly gained global momentum during the last few years. The bioeconomy envisions “3R”, the goal of 3R  is to implement in circular economy preventing excessive and unnecessary wastes. The circular bioeconomy emphasizes the best use of all sorts of available bioresources through the reduction of generated wastes during product formation, recycling of generated wastes, and reuse of valuable by-products and residues. Biotechnology could be useful in utilizing the resources to the optimum and therefore the role of biological agents and bioprocesses is of prime importance. In this review, we highlight the paramount importance of beneficial strains of microorganisms, macro, and microalgae in the bioeconomy. Microorganisms are universally recognized for the notable production of a vast array of secondary metabolites and other functionalities with possible use in various sectors. The application of potential strains in industries and modern agriculture practices could progressively improve the effective yield of food and feed, including fertilization of arid soils, bioconversion of by-products from industrial processes, and agriculture wastes. The valuable properties of specifically selected biological agents typically make them suitable candidates for their efficient contribution to circular bioeconomy without hampering the environment. The marketable products conventionally considered as economic waste in a linear economy can be reprocessed for maximum utilization. A circular bioeconomy typically focuses on the optimal use of bioresources in diverse sectors and extensive use of biotechnological tools for the processing of goods, economic modernization of essential services, and generation of sustainable energy 1.1.In this study, we seek to highlight the possible scope of biosystems in the circular bioeconomy, which lacks extensive studies to date. It is important to understand the types of different economies viz. linear economy, circular economy, bioeconomy, and circular-bioeconomy through literature search. Further, the role of microorganisms, micro, and macroalgae in the circular-bioeconomy has been discussed.1.2.Linear economy or conventional system primarily involves the extensive use and improper disposal of materials made by industries, where the raw materials typically enter the system at the start of the complex process, and the by-products are improperly disposed of. The linear economy results in the considerable loss of valuable resources in the production line and eventually adversely affects the environment 1.3.The circular economy aims to regenerate and carefully redesign the industrial systems by preserving and enhancing its capital, optimizing the ideal yields, and promoting the overall effectiveness of the system. This can be achieved by several factors:1. Using renewable sources of energy,2. By eliminating the use of toxic and hazardous chemicals,3. Reducing or eliminating generated wastes by utilizing the correct starting raw materials,4. By implementing innovative process designs and effective models,5. Recycling and using of wastes generated during the production, or even after the consumption of several types of products The maximization of the use of the raw materials in the production line and minimization of their loss with time is the basis of a circular economy. Carefully designed models in circular economy help in reducing wastes through personal interaction involving humans, which is important during continuous production and sustainable consumption of products. In comparison to the conventional linear models, the circular economy considers a product as a resource even at the end of its life-cycle, rather than a waste product The innovative idea of a new product formulation should involve a creative process and methodical approach through which all the wastes are sufficiently reduced at each step. Major principles of circular economy involve recycling of by-products and end-products as well as helping in utilizing resources sensibly and eliminating wastes. Such an approach eventually becomes a beneficial contribution to the global economy 1.4.There has been considerable interest around the globe for the conversion of the conventional system of utilizing bioresources to sustainable ones. The process generally encompasses the employment of materials derived from biological sources or biomass obtained from wastes generated from different industries The bioeconomy aspect involves three main factors 1. The efficient utilization of renewable biological reserves.2. Significant transformation of valuable resources.3. Recycling waste products into beneficial products.et al. The vision of the bioeconomy has been classified into two main categories by Bugge 1. Biotechnology vision in bioeconomy typically assigns significance to Biotechnology research, this involves commercialization and efficient utilization of products derived through the effective use of Biotechnology in various sectors.2. Upgrading and efficient processing of biological resources, formation of innovative value chains as the prime focus of Bioresource vision of bioeconomy.The Bioeconomy vision attributes considerable importance to the optimal use of valuable resources, including energy and essential nutrients. Sustainability can be promoted by active upgrading of biological diversity, the apparent reduction in mono-cultures and appreciably reducing the degradation of productive soil. Some of the expected targets of circular economy and bioeconomy are somewhat similar. Both the economies depend on the widespread use of sustainable resources and prevent the use of fossil fuels, which supports to deal with climate change and the greenhouse effect. The circular economy approach typically counts on the extensive use of reprocessed materials and effective systems and technologies, whereas the bioeconomy recommends the large use of energy derived from a natural and renewable source such as agriculture, food industry, forests, and marine biomass 1.5.An effective bioeconomy aims to generate stable and balanced products from available bioresources and its efficient value addition in circular bioeconomy (CBE) The successful development of the bioeconomy currently represents a global trend to ensure paramount safety and adequate access to proper food, raw materials, energy-source, water, and their efficient use. The major principles of circular bioeconomy are shown in A circular bioeconomy typically involves treating waste products as valuable resources. Intentionally burning of crop residues is traditionally practiced in some places of the world to prepare the cultivated field for the next continuous cycle of specific crops. This deliberate act of burning of the residues results in an adverse effect on human health and the environment along with a considerable economic loss to the prospective farmers. Instead, biochar produced from wheat-straw along with specific nitrification-inhibitor sourced from neem plants with the recommended dose of synthetic fertilizer could significantly improve soil nutrition for good maize crops. This highlights the vital importance of agriculture waste as a valuable resource in the circular bioeconomy 2.Bioprocesses employing microorganisms could help in the recycling of industrial wastes and play an important role in the circular bioeconomy. There are several projects undertaken globally by researchers for such studies. 2.1.Paenibacillus genera was found to be suitable for bioleaching copper, cadmium, sodium, and lead from electronic wastes viz. video card and random-access memory card Acidithiobacillus ferrooxidansSulfobacillus thermosulfidooxidans, Aspergillus niger, Penicillium simplicissimum, A. thiooxidans, and A. ferroxidans. Such approaches were applied through several mechanisms, such as acidolysis, redox reactions, bioaccumulation, and the complexation of metals 2 and save water resources Structural modeling was conducted to assess the use of microorganisms for the extraction of metals from electronic wastes through biotechnology. Bioleaching of metals employing microorganisms is an eco-friendly approach in the extraction of metals from electronic waste. A bacterial species belonging to the 2.2.Synechocystis salina was employed for the biosynthesis of poly-hydroxybutyrate, along with the production of useful by-products, such as feeds for animals, bio-pigments, biomethane, and fertilizers. Such a process contributes to decreasing the carbon footprint in the environment Chlorella pyrenoidosaRhodobacter sphaeroides B-3059 to achieve another type of biofuel, the hydrogen, bioconverting the valuable organic load present in the distillery wastewater Biomolecules produced by cyanobacteria and microalgae could be used as material for the synthesis of bioplastics. The methane generated during the process could be used as a precursor molecule for resynthesis 2 into valuable by-products, which provides an insight into the extensive use of microorganisms in circular bioeconomy et alActinobacillus succinogenes for biofuel after evaluation of thermal characteristics of the bacterium. With a higher combustibility index than lignite coal and almost similar to biochar and bio-oil, the bacterium could be developed as fuel and play a part in the bioeconomy. Thus, specialized microorganisms could be used for biobased products from the sequestration of CO2, to ease climate change along with the production of value-added products Electrosynthesis using specific microorganisms involves the use of microbial cells to accept electrons and reduce carbon dioxide that could be useful for recycling CO2.3.Some of the key characteristics of microorganisms make them ideal candidates for use in organic farming practice. A diverse number of microorganisms have been isolated that display antimicrobial potential against phytopathogens and some produce molecules with bio fertilization properties Neotyphodium lolii may cause a negative effect on plant growth and induce dwarfism in Lolium perenne[56], the potential of beneficial microorganisms, such as endophytes in plant growth promotion outranks its adverse effects on plants. In a study conducted to assess the effect of grazing on non-toxic tall fescue infected with novel endophyte, improvement in the rate of calving, production of milk, and growth of calf were observed Microorganisms secrete siderophores that chelate iron molecules present in the surroundings and thus severely inhibit the continuous growth of pathogens by limiting the essential nutrients. Some of the microorganisms promote plant growth in several ways, supplying chelated or sequestered iron to the host plant 2.4.viz. absorption, uptake and accumulation of metals, precipitation of metals outside the cells, oxidation, and reduction of pollutants through enzymatic activity Pollution of valuable fertile soil has become a common careless practice in many countries. Some synthetic or natural compounds are present in the contaminants, which require efficient approaches for their removal. Biotreatment of such pollutants through the strategy of microbial-assisted remediation is one of the effective and cost-effective methods. An array of mechanisms is involved in microbial remediation of pollutants 3.in vitro-biosynthesis of enzymes, which are of importance for their application in several industries, such as amylase 3.1.There is a possibility of isolating a considerable number of beneficial microorganisms from this habitable planet. Some of the strains have scientifically proven beneficial due to their capabilities to biosynthesize a range of bioactive compounds, which are secreted in their stationary growth phase as secondary metabolites with their possible use in various industrial processes. Effective use of microorganisms could prove beneficial in the synthesis of those molecules, which were traditionally derived from other expensive and non-sustainable sources in vitro studies. Modern genome mining and metabolomics approach using biotechnological tools could be properly employed to mine for such specific genes and sequencing could positively enhance the characterization process Microorganisms could efficiently perform a significant role in the bioprocessing of valuable materials in modern industries. Mining novel biocatalysts isolated from exotic habitats could prove useful at diverse levels of cascading processes in key industries. The diverse biotechnological approaches that could be profitably employed to harness the optimum potential include i) Meta-transcriptomics, Meta-proteomics, and Metabolomics; ii) Profiling of crude samples from the diversified environment through whole-genome sequencing techniques; iii) Possible reconstruction of metabolic pathways Microbial processes could be a valuable strategy in circular bioeconomy with their extensive application: 1. at the start of the complex process for efficiently generating specific products, 2. during the process, and 3. after the end of products lifecycle by naturally decomposing the used products/byproducts into environment-friendly components.3.2.The development of biorefineries based on the accepted varieties of macroalgal strains have shown the prospects of generating novel products 3.3.The application of microalgae for a wide range of products has proved it as a sustainable renewable bioresource support system for circular bioeconomy Aphanizomenon flos-aquae, Arthrospira platensis, Chlorella luteoviridis, Chlorella pyrenoidosa, Chlorella vulgaris, Tetraselmis chuii, and Odontella aurita, have been included in the list of foods and ingredients authorized in the European Union. Several bioactive compounds produced by microalgae have been approved as food ingredients by EFSA, some are biopigments like β-carotene from Dunaliella, phycocyanin from A. platensis, Docosa-hexaenoic acid from Crypthecodinium cohnii, and Astaxanthin from T. chuii and HaematococcusMicroalgal strains Oreochromis niloticus. Researchers substituted fishmeal with a protein-rich defatted biomass of Nannochloropsis oculata, which was available as a useful leftover after the extraction of oil for nutraceuticals); whereas the fish oil could be substituted using whole cells of Schizochytrium sp. as a source of docosahexaenoic acid The manufacturers of aquafeed have been successful in reducing the contents of fishmeal and fish oil by cost-competitive replacements. Two commercially available microalgae have been studied to produce a high-performing fish-free feed for the world's second-largest group of farmed fish Yarrowia lipolytica, and microalgae Isochrysis, Nannochloropsis, and Tetraselmis have shown their ability to produce PUFAs. Among types of PUFA, omega-3  and omega-6  are two essential fatty acids for human health Microorganisms are economical agents contributing to circular bioeconomy, though their activities can be utilized through several routes as discussed in previous sections, however, the biosynthesis of polyunsaturated fatty acids (PUFA) is another economical proposition. The organic residues and wastes generated in many industries are valuable carbon-load-containing resources to be used as the growth media for the cultivation of PUFA producing microorganisms 4.There has been considerable progress in the exploration of microorganisms isolated from various habitats across the globe for their employment in bioprocesses. However, a large part of the planet remains unexplored to date. Investigation of microorganisms from deserts, alpine regions, mangrove forests, flooded grasslands, etc. may reveal the array of novel functionalities [120]5.The conventional economic system that typically involves the key concept of use and throw of products undoubtedly puts considerable pressure on valuable resources and in turn, it causes a detrimental effect on our precious environment. The circular economy expects the adaptive reuse of valuable resources and it progressively reduces wastes through well-designed strategies. The bioeconomy naturally implies the extensive use of renewable sources of energy and relies on the proper use of natural substances as raw materials. The circular bioeconomy adjoins the circular economy and bioeconomy together. However, accurate identification of fortes and potential weakness at the regional level is a must for a favorable and successful transition.The principal importance of beneficial microorganisms, micro and macroalgal species in the circular bioeconomy has been highlighted in this short review. Biological agents have the ability to recycle and positively transform an impressive array of valuable materials including wastes produced from various modern industries. The microorganisms are laden with immense potential, which has remained mostly unused to date in this sector. Biotechnological tools could undoubtedly enhance their unique abilities to improve the continuous production of food and feeds. Through proper recycling and reuse of agriculture and food wastes, a range of bioactive metabolites and industrially significant enzymes can be produced. The renewable raw materials and industrial wastes can be transformed for the maximum utilization of limited resources while employing a greener approach towards the circular bioeconomy. The active role of biological systems is of prime importance in circular bioeconomy through widening the application spectra of the beneficial microorganisms, macro, and microalgal species.


In this report, we describe a case of timely gas vitrectomy to displace a moderate submacular hemorrhage from the submacular space without tPA, release vitreoretinal traction along the borders of a posterior retinal tear, and analyze postoperative multimodal imaging findings in a 34-year-old male patient whose right eye was injured by a stone. The patient underwent a successful nontissue plasminogen activator gas vitrectomy 3 days after the accident. A multimodal evaluation with spectral-domain optical coherence tomography (SD-OCT), 10-2 and 30-2 campimetry, microperimetry, multifocal electroretinography (mfERG), and visual evoked potentials was performed 6 months after the accident. The multimodal imaging tests yielded abnormal foveal SD-OCT patterns, with a fibrous sealed tear in the retinal pigment epithelium. Campimetry showed low levels of retinal sensitivity; microperimetry and mfERG revealed a subnormal retinal response and a reduction in the N1 and P1 wave amplitudes. The visual evoked potential responses were normal. Multidisciplinary examination at 6 months postoperatively revealed a structurally and functionally abnormal macula. The retina remained attached. Our functional findings indicate that submacular hemorrhage should be treated in a timely manner to minimize photoreceptor damage. Closed-globe blunt ocular trauma mechanisms can rupture the vascular choroid and result in central vision-threatening submacular hemorrhage (SMH) . This coPostcontusional choroidal rupture usually runs vertical and temporal to the optic nerve disc and sometimes runs through the foveal center, with different and significant amounts of secondary hemorrhagic macular detachment in 66% of cases, resulting in poor visual outcomes, particularly when the SMH persists for several days , 3.Here, we describe the case of a patient with a trauma-related SMH complicated with a large tractional posterior paramacular retinal tear; these two posttraumatic lesions were not connected or tunneled together at the level of the subretinal space since this would have facilitated its simultaneous surgical approach to treat this condition only with gas vitrectomy pneumatic displacement of the blood and release of the vitreoretinal traction complemented with laser retinopexy, without the use of tissue-plasminogen activator (tPA) to avoid additional potential retinal toxic damage. We would like to emphasize the efficacy of our simplified surgical approach and the importance of timing in surgical intervention to achieve adequate anatomical and functional recovery with minimal sequalae at the subclinical level as demonstrated by the multimodal imaging structural and functional evaluations.Instituto de Oftalmologia Hospital, Mexico City, Mexico, provided authorization and released the electronic clinical record pertaining to this case report. This study adhered to the tenets of the Declaration of Helsinki and received approval from the institutional ethics committee . Written informed consent was obtained from the patient in accordance with the institutional guidelines. Data are available from the imageology and psychophysics laboratory at the Retina Department of the Institution.The Retina Department at the A 34-year-old man presented with reduced central vision in his right eye 3 days after experiencing blunt trauma due to being struck by a stone. The preoperative best-corrected visual acuity (BCVA) was 1/200 in the affected eye. The intraocular pressure was 10 mmHg, and there was a pupillary sphincter rupture. On biomicroscopy assessment, the vitreous cavity showed partial posterior detachment with vitreoretinal traction around the edges of an irregular posterior retinal tear, with a very shallow subretinal fluid-like appearance and neuroretinal whitening around the tear. The rest of the retina was completely attached, and no communication between the posterior retinal tear and the SMH was documented on optical coherence tomography (OCT). The macula was dome-shaped and elevated because of the presence of a moderately thick SMH Figures . Cross-sAlthough only injection of an expansible gas bubble was considered the finding of a large posterior tear in the relatively young man, with traction of a nonliquefied vitreous cortex around the edges of the tear, allowed us to decide on the use of surgery as treatment modality. It is important to emphasize that it was not possible to drain the submacular hemorrhage through the retinal tear by avoiding concomitant retinal detachment. This would have facilitated the total transoperative removal of the submacular blood on the third day, when surgery was performed. However, it was decided not to use tPA because of its potential retinal toxicity, leaving only gas followed by strict postoperative prone position to achieve the pneumatic displacement of the blood.3F8). Postoperatively, the patient was instructed to strictly remain in the prone position for 5 days and follow the protocol for recovery recommended for this type of blunt trauma treated with pneumatic submacular blood displacement. Local and systemic antibiotics were administered after the surgical procedure.Under local anesthesia and sedation, the patient underwent a pneumatic submacular blood displacement procedure, which involved a gas pars plana vitrectomy and the release of vitreoretinal traction around the retinal tear. Subsequently, central vitrectomy was performed with removal of the cortical vitreous body from the retinal surface, using a silicone-tipped cannula and active suction. The surgeon was careful to obtain a free and mobile posterior hyaloid membrane. Laser retinopexy was performed around the retinal tear, and an air-fluid exchange was conducted at the end of the surgical procedure using a mixture of nonexpandable 10% perfluoropropane gas , the fixation pattern was found to be stable, and the fixation location pattern was documented as foveocentral. The retinal sensitivity analysis map showed abnormal macular integrity with reduced sensitivity, mainly in the center of the fovea, as well as reduced sensitivity over the choroidal rupture. There was no correlation between the reduced retinal sensitivity locus and the corresponding retinal thickness on OCT . The visHere, we have reported a case in which early treatment with gas vitrectomy yielded successful displacement of the submacular blood as well as release of vitreoretinal traction at the margins of the posterior tear. Moreover, a strict prone positioning regimen allowed the sealing of the tear, preservation of the retinal anatomical structure, and displacement of the submacular blood outside the central area of the macula; all the previous facts have also been demonstrated in other studies , 3, 4, 63F8 and received no tPA, which has been used previously [The main aspect to consider when managing this condition is rapid blood displacement . The pateviously , 6.This patient showed choroidal rupture temporal to the fovea, similar to what was described in others studies , and didThe natural course of SMH varies according to the etiology, duration, diameter, and thickness of the hemorrhage . It has Numerous approaches have been described for the displacement of SMH, including vitrectomy with the use of intravitreal or subretinal recombinant tPA (r-tPA), intravitreal gas tamponade, postoperative positioning , and pne3F8 pneumatic displacement of limited traumatic SMH with excellent anatomical results and final visual acuities attributed only to gas injection and patient positioning, without surgery or the use of tPA.In 1991, Peyman et al.  first reIn cases complicated by posterior retinal tears, we consider that the release of vitreoretinal traction is of paramount importance and the pneumatic displacement without tPA injection followed by a strict prone position, in cases complicated by posterior retinal tears such as the one reported here, is less invasive and potentially less toxic than the tPA-assisted surgical drainage of the SMH. The mechanism involves moving the blood away from the subfoveal space by using the long-acting gas buoyancy effect to displace the blood from the submacular foveocentral photoreceptors , 7, 11.In this report, photoreceptor dysfunction was considered to be the result of blood pooling under the macula and contact with the central photoreceptors, although pneumatic displacement occurred within the first 3 days. We considered that the OCT changes in this case Figures  were conWe acknowledge the several inherent limitations and shortcomings of this case report. However, based on the analysis of our results as well as other findings reported on the literature, we can confirm that early non-tPA pneumatic displacement could be achieved without severe visual damage. Prospective and multicenter protocols are needed to improve the approach in severe or complicated cases of SMH, similar to the one reported here.In summary, this report confirms that early removal of blood from beneath the macula within the first few days is important in cases of SMH. This case was complicated by the presence of a large posterior retinal tear and vitreoretinal traction, but vitreoretinal release and gas vitrectomy were sufficient to displace the submacular blood and maintain the retinal attachment with good anatomical and functional results. A few subclinical and consequently not significant abnormalities since they do not affect the quality of binocular vision were detected at the 6-month multimodal functional evaluation only with sophisticated diagnostic tools.Our findings suggest that SMH should be treated as soon as possible to minimize photoreceptor damage. With early displacement of the hemorrhage, only subclinical damage ensues. We emphasize that if the blood stays in contact with the photoreceptors for a long time, the damage will be greater, with loss of vision and clinical sequelae. This report suggests retina surgeons to perform timely surgical techniques to allow displacement of blood from the submacular space and, thereby, open an innovative path to developing new drugs that could reduce the toxic effects of blood catabolism seen with the drugs currently in use.


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