However, limited research has been conducted on recent, rapid telehealth implementation and expansion initiatives regarding facilitators and barriers surrounding the provision of quality patient care. Our rapid review evaluated the literature specific to rapid telehealth implementation during the current COVID-19 pandemic from three research databases between January 2020 and May 2020 and reported using preferred reporting items for systematic reviews and meta-analyses (PRISMA). The results indicate the rapid implementation and enhanced use of telehealth during the COVID-19 pandemic in the United States surrounding the facilitators and barriers to the provision of patient care, which are categorized into three identified themes: (1) descriptive process-oriented implementations, (2) the interpretation and infusion of the CARES Act of 2020 telehealth exemptions related to the relaxation of patient privacy and security (HIPAA) protocols, and (3) the standard of care protocols and experiences addressing organizational liability and the standard of care. While the study limitation of sample size exists ( Telehealth can be as rudimentary as a provider-to-patient phone call regarding their current health status or take a more advanced approach, including synchronous webinars, the sharing of digital patient information, and associated administrative tasks. Since 2007, the World Health Organization (WHO) has defined telehealth as [While telehealth is a much broader term used in the industry that includes both clinical and non-clinical services provided remotely, the term telemedicine refers specifically to the provision of remote clinical (non-administrative) services ,3. Both Telehealth technology continues to increase in usage across all health care industry segments and is becoming more accepted by many organizations and patients alike. The use of telehealth technologies to support health care organization reach, accumulation, and the communication of health care information has recently been enhanced by the COVID-19 global pandemic . An incrWith the rush to expand or even initiate telehealth services, the use of this technology continues to be adapted to decrease the number of patients who do not have the proper access to care while also supporting pandemic physical distancing requirements. Exacerbated by the ongoing updates regarding vulnerable populations, those seeking medical care from their provider and medical team members during a global pandemic can be supported by telehealth. This technology is often deemed the solution for a wide range of routine and other acuity levels of care. Recognized as a solution to the challenges presented by the pandemic, alterations to previous telehealth policies include a relaxing of HIPAA standards, increased waivers from the Center for Medicare and Medicaid Services (CMS) to expand eligible services, and even billing/reimbursement clarifications to support the utilization of telehealth services (Wavier-1135) [The disruption in health care practice caused by COVID-19 continues to raise the demand for telehealth, and its use in the industry is projected to increase by 64.3% by the end of 2020 [The purpose of this rapid review is to identify the main underlying constructs (themes) in telehealth implementation and utilization during the COVID-19 pandemic (January 2020 through to May 2020) to assist with ongoing and early-adopter experiences regarding telehealth implementation. The rationale behind this rapid review is to provide a framework for future research as ongoing telehealth initiatives continue to be implemented and adapted to the United States health care environment. This review and the identified underlying themes should help the health care industry’s ongoing goals to provide quality care, while also addressing rapid implementation facilitators and the barriers identified during the early stages of the COVID-19 pandemic.The research process began with a review of the research team’s intent and associated health care terms and research protocols per the PRISMA review standard. Three main research databases were utilized . The PubMed/MEDLINE database was utilized in this study because “telehealth” is a recognized vocabulary term in the MeSH  controlled vocabulary thesaurus, which is utilized for indexing articles for PubMed and clearly identified in the research. CINAHL is a health database that indexes nursing and allied health literature from a range of topics highly applicable to the research topic. The ScienceDirect database was also included based on its contribution to the initial search criteria sample size via its Novel Coronavirus Information Center, providing free access to timely health and medical research publications that align with the research question.Study search terms and Boolean operators generated the database search string that resulted in the identification of current telehealth research in response to the COVID-19 pandemic. The identification of key terms for the research databases continued with the use of “telehealth” while also adding “virtual care” to broaden this perspective and associated health care technology research articles. The sample was further qualified with the use of “Coronavirus”, “COVID-19”, and “2019-ncov” (as suggested by the EBSCO database search engine) search criteria keywords using Boolean search operators. The initial search results were 3128 articles published between 1 January 2020 and 26 May 2020. This date range was incorporated into the rapid review criteria to help ensure that only telehealth implementation and enhancement initiatives related to the COVID-19 global pandemic were included to support the research objective. The initial database query and identification of the article sample was conducted by the researchers in May 2020 and the results/analysis was conducted in June 2020.Studies in this review were eligible if telehealth implementation was specifically addressed and reported in quality journals (peer-reviewed) and also met the January–May publication date range. Limited studies reported patient outcomes as a result of rapid telehealth implementation. Therefore, the research objective was to focus primarily upon the rapid implementation facilitators/barriers of telehealth during the pandemic. As long as telehealth implementation facilitators and/or barriers were addressed and other search criteria were met, the article was included in this rapid review. The decision to include a wide range of study methods in the sample was made by the authors to help improve the sample size of the rapid review, primarily due to the recent nature of the global pandemic and the relevant nature of the research topic.To produce focused, applicable results meeting the research objective, additional filters were applied to the research database findings, based upon each database’s online search platform filter options. For CINAHL, in addition to the 2020 publication date criterion, full-text, English only, and academic journals only criteria were applied, resulting in 29 articles. For PubMed, in addition to the publication date criterion, scholarly peer-reviewed journals only, linked full-text only, and English only criteria were applied, resulting in 16 articles. For ScienceDirect, in addition to the publication date criterion, research articles that were open access status only were queried and yielded 5 articles. A rigorous review of the 29 (CINAHL), 16 (PubMed), and 5 (ScienceDirect) articles was conducted by the authors by reading the full manuscripts of each article. This was accomplished by the six reviewers splitting into two separate groups to review the assigned articles to identify the underlying themes related to rapid telehealth implementation and expansion . ArticleOverall, 19 articles were removed from CINAHL, 10 articles were removed from PubMed, and zero articles removed from ScienceDirect based on applicability to the research objective and germane to the overall study initiative. Specifically, the remaining items had to meet the research objective of the study and meet all the inclusion criteria by qualifying as peer-reviewed publications in academic journals and also directly addressing the implementation of telehealth during the COVID-19 pandemic. For example, while many articles met the exclusion criteria, during full-text screenings it was observed that several studies (9) were not targeted or primarily focused toward COVID-19 and the implementation or improvement of telehealth resources. Furthermore, seven (7) articles were also excluded from the study for not providing facilitators or barriers related to the implementation of telehealth during the pandemic (required data items to be observed by the research team during the article screening process). The rapid nature of this review regarding the rapid implementation of telehealth during the pandemic restricted the researchers’ efforts in data item observations to identify facilitators and barriers only in an effort to assist the medical community with the implementation and ongoing facilitation of telehealth efforts. Article selection bias was addressed through a series of consensus meetings (via webinar) that focused on each of the 10 article sets  reviewedn = 21) with a description of the study participants , the coding of the study design strength per the Johns Hopkins Nursing Evidence-Based Practice Model (JHNEPB) protocol listed at the end of the table, and a summary of the facilitators and/or barriers to rapid telehealth implementation identified by the researchers. Based upon these results, researchers were then able to identify and code all the underlying themes demonstrated in the sample. While (patient) outcomes were part of the researchers’ initial review process, this variable was found to not specifically be addressed beyond the implementation and facilitator/barrier findings with regard to telehealth. As a result, positive outcome findings were limited to the organizations’ abilities to conduct a rapid implementation and/or continuous improvement of telehealth services as an initiative to provide access to quality care during the pandemic.The identified studies’ quality, as assessed through the use of the JHNEBP study design coding methodology, demonstrated that the majority of the literature  falls within the level 4 category . The remaining literature in the sample demonstrated a study design interpreted as level 3, non-experimental, qualitative, or meta-synthesis studies (4 articles) and 1 quasi-experimental (level 2) study design. While the strength of evidence regarding this review’s literature sample (primarily consisting of level 4 study designs) is important to note, the researchers came to the conclusion that this observation was possibly due to the nature and timeliness of this rapid review. A limited ability to conduct true experimental and/or randomized control trial (RCT) studies concerning the implementation of telehealth to date potentially exists. Finally, while a level 5 study (expert opinions not based on any research evidence) was identified earlier on in the researchers’ review process, this study was excluded because it was a letter to the editor or similar type of manuscript .The health care organizations referenced in the literature were primarily located in the United States (19 of the 21 articles in the sample). Of the remaining two articles, only one specifically addressed telehealth implementation facilitators/barriers observed across multiple countries  . The resn = 21), each researcher read assigned articles in the sample and all six reviewers worked to establish a consensus on the major themes (constructs) identified from their individual research initiatives. Each article was coded based on the theme(s) identified by the group, as shown in The rapid review process identified very recent, highly appliable telehealth publications that include the COVID-19 pandemic challenge to the health care system from a variety of health care organizations and the implementation and expansion of telehealth services. Of the total sample . Standard of care was the next common theme identified in the review, evident in 42% of articles in the sample. The maintenance of privacy standards was the third concept identified as most common in the review, with only five articles (24% of those reviewed) focusing on this important initiative. The identified themes  were not mutually exclusive, and therefore it was common for multiple constructs to be identified within any single article.The COVID-19 pandemic has led to many paradigm changes within the health care environment. One such change is the need to provide patient populations with high-quality health care services at a safe distance. The implementation of various virtual care modalities has been forced to take place at a rapid pace, causing many health care systems to either develop or restructure existing virtual care programs. Historically, health care programs have been slow to develop telehealth programs despite telehealth being known to reduce cost and increase patient access . ProgramSimilarly, most rapid implementations of virtual health have also involved the identification of appropriate computers, laptops, tablets, and smart phones for both patient and provider usage . In the The rapid implementation of telehealth services has also provided patient populations with a safe and effective treatment modality during the COVID-19 pandemic. Patient safety is a factor in the implementation of virtual visits. By having a virtual visit at a distance, patients feel that they are being cared for while in the safety of their own home . While tDuring the implementation of telehealth throughout COVID-19, health care systems encountered barriers to rapid implementation. Barriers such as low internet connectivity, lack of device access, elderly patient populations, and general technology difficulties slowed virtual visit implementation . HoweverSince the onset of the COVID-19 pandemic, concerns surrounding the standard and liability of care formalities have heightened. Clinicians and policy makers have expressed inevitable controversy considering the legal liabilities associated with the current health care crisis ,21,22. WWhile the utilization of non-HIPAA compliant videoconference solutions has increased during the pandemic, significant concerns regarding patient privacy and private health information confidentiality remain a concern . Mental The adaptation of health care information technology to advance the use of telehealth capabilities comes with a growing need for proper privacy and security use and regulations. With the onset of the COVID-19 pandemic, delivering health care has come with new physical distancing and requirements, which telehealth is credited with enhancing ,27. ThouAdditionally, the research supports an interesting finding related to the other extreme: too much health privacy as a result of the implementation of telehealth ,27. ThisThis rapid review presents research limitations that are common in similar review studies. An intended limitation of this research was rating bias, which existed within individual researcher reviews of the sample articles. This limitation was addressed by group-level decisions and consensus was attained surrounding the thematic coding of each article. Research database findings will continue to change (therefore increasing the number of studies meeting the inclusion criteria) as research/publications continue to occur during the pandemic. The limited use of the database search criteria timeframe is also a study limitation. While sample size is an important limitation of the study, the focused research topic that identified initial themes as related to recent telehealth implementation and service expansion do support ongoing research surrounding identified constructs. As a result, the qualification and categorization of study design and related results as compared to a control group were limited in the available literature reviewed.Changes are occurring in health care due to the COVID-19 global pandemic. Telehealth is continuing to adapt to environmental and industry needs in order to provide the highest quality of care for a variety of patients, while also assisting with physical distancing mandates and other public health measures. This research was initiated to rapidly identify underlying constructs in recently published literature related to the use and implementation and expansion of telehealth as applicable to the COVID-19 pandemic. Ongoing research surrounding the implementation of best practices, privacy concerns, and industry-specific  best practices is recommended to assist with the ongoing implementation and increased utilization of telehealth services. The patient experience of care and the specific health outcomes of care delivered via telehealth during the COVID-19 pandemic would also be opportune areas for future research. Health care organizations are encouraged to continue to infuse telehealth initiatives to support patient care and related outcomes during the COVID-19 pandemic with ongoing attention and efforts directed towards implementation/process improvement of best practices, controlling organizational liability by maintaining standards of care, and the maintenance of altered privacy standards during this challenging pandemic time period.


Introduction. Due to the complex interaction between the underlying disease, psychosocial factors, and the high-dose hormonal therapy, transgender patients pose a therapeutic and diagnostic challenge, especially during emergencies. This case presents one such clinical dilemma using the example of a case of myocardial infarction.  A 35-year-old transgender male presented to our clinic with an acute inferior wall myocardial infarction. For the past 6 years, he was receiving high-dose testosterone therapy for the maintenance of hormone levels after female-to-male gender conversion. The emergency coronary angiography revealed a distal right coronary artery occlusion. Recanalization of the vessel was achieved by catheter-driven direct thrombectomy and subsequent intracardiac lysis. The appearance of the remaining coronary arteries bore no angiographic evidence of advanced coronary artery disease. We suspected a thromboembolic origin as the primary cause of the myocardial infarction. The presentation also fulfilled the proposed National Cerebral and Cardiovascular Center criteria for the clinical diagnosis of coronary embolism. In the diagnostic work-up, the most common causes of coronary embolism like atrial fibrillation, cardiomyopathies, endocarditis, and intracardiac tumors could be ruled out. The screening for hereditary thrombophilia was also negative. Likewise, the presence of a haemodynamically relevant right to left shunt could be excluded. In the end, the high-dose testosterone therapy seemed to be the most likely cause.  Following major thromboembolic cardiovascular events, we believe that transgender males treated with high-dose testosterone therapy should receive oral anticoagulation, preferably with a DOAC, especially keeping in mind that the discontinuation of the hormone therapy is not always possible due to the various underlying psychosocial factors. A transsexual 35-year-old Caucasian male without known relevant medical history of cardiac disease presented to the emergency room with a sudden onset of typical anginal chest pain. Physical examination revealed a hemodynamically stable patient with resting pulse of 70/min and blood pressure of 110/70 mmHg, with no signs of acute cardiopulmonary decompensation. Cardiac examination was uneventful with normal heart sounds without pathological murmurs. Respiratory, abdomen, and neurological examinations remained normal. Active smoking accumulating to 20 pack years and a history of daily alcohol consumption were significant risk factors. Drug history revealed a hormonal therapy with intramuscular testosterone undecanoate for gender conversion over the past 6 years, with an initial dosage of 1000 mg per month over a period of 1 year from 2011 to 2012 and later at a dose of 1000 mg every 3 months to date. An electrocardiogram showed sinus rhythm with ST-Segment elevation in the inferior leads .An emergency coronary angiography revealed normal coronary arteries with an occlusion of the distal right coronary artery . The appSubsequently, investigations were conducted with the aim to identify an underlying cause for the suspected embolic myocardial infarction. The transthoracic echocardiography did not reveal intracardiac thrombus or valve vegetations as evidence for infective endocarditis. A deep venous thrombosis could also not be detected by ultrasonography, and the D-Dimer levels were negative.The initially performed transoesophageal echocardiography under sedation (Midazolam) raised the suspicion of a possible small persisting foramen ovale (PFO). We performed a second contrast-enhanced TOE without sedation. No crossover of microbubbles over to the arterial circulation were observed even under Valsalva manoeuvre. Thus, a haemodynamically relevant right to left shunt could be ruled out.No evidence of paroxysmal atrial fibrillation was reported in a 72 h Holter-ECG Monitoring. Cardiac embolic sources were thus deemed unlikely.Other manifestations of atherosclerotic vessel diseases could not be seen in the colour-coded Doppler Ultrasound scans of the extracranial arteries or pelvic/lower limb arteries.Laboratory tests for Antiphospholipid Syndrome (APS), Factor-V Leiden, Protein C and Protein S deficiency, Antithrombin III deficiency, and Hyperhomocysteinemia as possible causes for a hypercoagulable state were also negative.In conclusion, the work-up for the definitive cause of the infarction remained inconclusive. The drug history of the patient with the use of high-dose hormonal therapy with testosterone for gender conversion was one of the significant factors in the patient's history.This background of high-dose testosterone therapy for the purpose of gender conversion and its procoagulant associations led us believe this to be the factor leading to the coronary embolism.A follow-up of the patient was performed at 3 months and 1 year. The echocardiography and ECG showed no signs of long-term detrimental effects following the myocardial infarction with resolution of the initial wall motion disturbances.Transgender patients undergoing sex change therapy pose a unique challenge with a complex interaction of underlying disease, psychosocial factors, and the additional high-dose hormone therapy. With the number of cases of gender conversion gradually increasing , the altIn this case, we present one such diagnostic and therapeutic dilemma. At initial presentation, our patient met the diagnostic criteria for an acute inferior wall ST-elevation myocardial infarction (STEMI). Except for a significant smoking history accumulating to 20 pack years, there were no other known risk factors in the patient's past history. Due to the young age of the patient and the medical history, we thought of an alternative explanation rather than an atherosclerotic disease as the underlying cause for the acute myocardial infarction. The coronary angiogram supported our uncertainty with evidence of normal coronary arteries and with no evidence of underlying atherosclerosis. Other invasive coronary imaging modalities like optical coherence tomography or intravenous ultrasound were not performed in this patient, although these modalities would have helped in definitively ruling out significant atherosclerotic plaques. Other signs of systemic atherosclerotic vessel disease could also be ruled out in the subsequent colour-coded Doppler ultrasound scans of the extracranial arteries and pelvic/lower limb arteries.The myocardial infarction was hypothesized to be of embolic origin, due to a coronary embolism. The subsequent successful treatment with catheter-directed thrombectomy and intracardiac lysis with Tirofiban, along with no evidence of plaque rupture, underlined the case for an embolic origin of the episode. The clinical case satisfying one major criteria with angiographic evidence of coronary embolism without atherosclerotic component and two minor criteria with <25% stenosis on angiography, except for the culprit lesion and the presence of an embolic risk in the form of hypercoagulable state in our case, of the proposed National Cerebral and Cardiovascular Center criteria for the clinical diagnosis of coronary embolism by Shibata and coworkers [Our further work-up was aimed at finding a causative link for the coronary embolism. Literature search showed the most common factors leading to coronary emboli in the order of descending significance to be (a) atrial fibrillation, (b) dilated cardiomyopathy, (c) endocarditis, and (d) intracardiac tumors . Other sGiven the known history of smoking and alcohol consumption of our patient , he possFinally, the search for the cause for the coronary embolism failed to clearly identify the underlying aetiology of the event. An important factor at this point seemed to be the high-dose testosterone therapy for gender conversion causing the activation of the thrombotic cascade in the arterial circulation, leading to formation of thrombotic material (white clots).Recent published reports have suggested an increased cardiovascular mortality associated with testosterone therapy. The effects of testosterone and its association with increased myocardial infarction and stroke in cisgender men under testosterone therapy for age-related hypogonadism were issued recently as an FDA Warning in accordance with recent studies . It was On the other hand, these evidences and risks associated have also been widely disputed with contrasting evidence. Morgentaler and colleagues found no convincing evidence of increased CV risk with testosterone therapy in hypogonadism .In contrast, patients on testosterone therapy for gender conversion, like the one in our case, receive significantly higher doses in comparison to that used in hypogonadism. There have been reports of increasing risk of venous thromboembolism under testosterone therapy used for gender conversion . A worseThese factors led us to believe that testosterone therapy for gender conversion might have led to a general hypercoagulable state favoring intraarterial thrombus formation. Our patient in this case had a history of hormonal therapy with intramuscular testosterone undecanoate for gender conversion over the past 6 years. An interaction of factors like (a) vascular stasis due to episodes of paroxysmal AF, along with the (b) procoagulant tendency under high-dose testosterone therapy, and (c) endothelial injury due to the excessive smoking could also have led to the intraarterial activation of the clotting cascade leading to thrombus formation, possibly in the left atrial appendage. This is in accordance to the Virchow's triad of factors contributing to thrombus formation. The embolization of this thrombus into the coronaries could have been the cause for the acute myocardial infarction.2DS2-VASc-Score for risk stratification in cases of paroxysmal atrial fibrillation in this subpopulation might be misleading.We believe this subpopulation of patients demand an individualized approach to further therapy. A guideline-based approach is not available here due to the very low research base. A generalized approach to therapy with the otherwise conventional CHADue to the high risk of recurrence of coronary embolism after the first episode, consideration was given to treating the patient with an oral anticoagulant. Despite the increased risk of recurrence, stopping of the testosterone therapy is a very delicate decision and is almost always not acceptable to the patient due to the various psychosocial factors bound with this decision.The risk of major bleeding episodes under DOAC therapy increases with age. We believe that the risks associated with major bleeding episodes in a younger patient, like the one in this case, are tolerable compared to the risk of recurrence of the coronary embolism. Keeping all this in mind and after discussion with the patient about the potential risks, we decided to treat the patient with an oral anticoagulation—in this case with Apixaban. Regular follow-ups were advised due to the increased risk of recurrence. After 3 months and 1 year, the patient remained asymptomatic with no evidence of similar episodes under continuing testosterone therapy, as well as no major bleeding complications. However, if the patient would have reliably stopped smoking and one could manage to optimally address cardiovascular risk factors, it could have also been justifiable to omit anticoagulation or to replace it by antiplatelet therapy. But, again, evidence is low, and the decision has to be reached individually.


Near field scanning optical microscopy exploiting differential interference contrast enhancement is demonstrated. Beam splitting in the near field region is implemented using a dual color probe based on plasmonic color sorter idea. This provides the ability to illuminate two neighboring points on the sample simultaneously. It is shown that by modulating the two wavelengths employed in exciting such a probe, phase difference information can be retrieved through measuring the near field photoinduced force at the difference of the two modulation frequencies. This difference in frequency is engineered to correspond to the first resonant frequency of the cantilever, resulting in improved SNR, and sensitivity. The effect of both topographical and material changes in the proposed near field differential interference (NFDIC) technique are investigated for CNT and silica samples. This method is a promising technique for high contrast and high spatial resolution microscopy. However differential interference contrast (DIC) microscopy has not been yet applied to SNOM.High resolution imaging, beyond the conventional diffraction limit has lead to the development of near-field microscopy (SNOM), in which the evanescent waves containing high spatial harmonic frequencies are collected in the near field region. Near-field microscopy, in its conventional form, delivers insufficient image contrast due to evaluating only field intensity as the image information. Inspired from far-field microscopy several contrast-enhancing techniques, including phase contrast6. Therefore, DIC provides the ability in visualizing weakly scattered samples which have low contrast images in conventional intensity contrast microscopy. The same is true for sharp imaging of edges on the samples. Several challenging issues have prohibited the implementation of DIC in SNOM. These include high resolution excitation of the two neighboring points on the specimen, near-field interference of the two scattered beams from the specimen, and detection of very low phase changes resulting from nanometric changes of optical path length during the near field scanning of the specimen’s topography.DIC microscopy, relying on detection of the phase change resulting from either topological or refractive index changes, is a powerful tool to provide high-contrast images using the phase information provided by the interference signal. In a conventional optical far field DIC system Fig. , the bea7. In spite of a great deal of work in designing innovative aperture10 and apertureless13 SNOM probes, none of them are capable of beam splitting in the near field region. Previously reported nanoantenna probes have been generally exploited to generate large near-field enhancement and optical confinement at the probe’s tip, as well as large optical throughput and detection efficiency of the probes. However, diffraction-unlimited excitation of the two neighboring points can be done through utilizing the novel SNOM probes reported in our previous works14, a new category of SNOM probes known as dual color probe. This kind of near-field plasmonic probes, relying on generating two hot spots at well-defined locations on the sample surface, is an excellent tool for splitting the beam of the light source in the near field region. The underpinning mechanism of this energy/frequency beam splitting is the hybridization of the plasmon modes due to the symmetry breaking of the nanoantenna structure on top of the probe15. It is worth mentioning that our proposed plasmonic dual color probe also has additional advantages features, including improvement in accuracy and speed of imaging, while doing its main job as a plasmonic nanoantenna probe providing large enhancement, and confinement of the illuminating field7.Here, we demonstrate the implementation of a near-field differential interference contrast microscopy (NFDIC) technique by the means of combining a dual color SNOM system and a photoinduced force microscope (PiFM). Diffraction-unlimited excitation of two neighboring points can be performed utilizing novel SNOM probes18, in which optically-induced localized polarizability of the specimen is measured by mechanical detection of the force gradient generated due to the interaction between a sharp polarizable tip and the specimen. Since in the PiFM the detection is carried out in the near-field region, it can be employed in our proposed NFDIC system to interfere non monochromatic scattered fields from the sample  experienced by the tip19:S is an arbitrary surface enclosing the tip, β direction  and generated by the αth hot spot, in Eq.  of the probe with two specific wavelengths . Figure I(x) and Iref are normalized output signal at the desired point and reference point  analysis technique. In the simulations, Johnson and Christy dielectric function data


Background. Diabetic retinopathy is a microvascular disease, it is associated with changes in peripapillary retinal nerve fiber layer thickness, these changes being more pronounced in PDR (Proliferative diabetic retinopathy) patients undergoing laser photocoagulation.Objective. To assess changes in peripapillary retinal nerve fiber layer thickness in proliferative diabetic retinopathy patients using optical coherence tomogram (OCT).Methods. The database search was conducted in June 2018 and continued until October 2018. The search engines used included Pubmed, Medline, OVID and Google Scholar. A meta-analysis of weighted mean difference and standard deviation was conducted.Results. A total of 10 studies containing 377 eyes of PDR patients were selected. The analysis of the included studies revealed no significant effect of PRP on average retinal nerve fiber layer thickness  using OCT. Conclusion. Hence, to conclude, our meta-analysis revealed that there was no significant effect of PRP on RNFL thickness and the impact of PRP could vary. Measurement of peripapillary RNFL thickness may yield erroneous and unpredictable results in this subgroup of patients, further confounding the evaluation of nerve fiber layer damage and its progression. Diabetic retinopathy (DR) is the leading cause of blindness worldwide, especially in individuals between 20 and 65 years old. The backbone of treatment of diabetics is disability limitation, and, to an ophthalmologist, this implies prevention of the visual complications due to DR and once developed, prevention of their progression. According to the early treatment of diabetic retinopathy study (ETDRS), pan-retinal photocoagulation (PRP) is the treatment of choice for proliferative diabetic retinopathy (PDR) and severe non-proliferative diabetic retinopathy (severe NPDR). PRP reduces chances of profound vision loss by half in these types of patients .If laser intensity is too high, it can destroy the entire retinal layer including ganglion cells, leading to a decrease in RNFL thickness. Mild retinal edema can result immediately after PRP, due to increased retinal inflammation caused by increasing vascular permeability .It is imperative to critically evaluate the impact of PRP on the RNFL layer in patients with diabetic retinopathy [14-20]. RNFL imaging can be performed using optic disc cube protocol that images an area of 6 mm x 6 mm with 200 x 200 scans. The inbuilt software recognizes the center of the optic nerve by utilizing a graph-based method and a circle of 3.46 mm is positioned automatically around the optic disc center to generate average and clock hour parapapillary RNFL measurements. In this meta-analysis, only the average RNFL thickness was evaluated, and only the studies with signal strength of seven or more were included for analysis , the mean and was recorded in the form of continuous variables, and the difference in the weighted mean and standard deviation was then calculated.All the studies were arranged according to the year of publication in ascending order . These studies reported an initial increase in RNFL until six months after photocoagulation, with RNFL thickness measurements becoming the same as at baseline at one year. They have then reported a significant drop at two years follow-up . Some of the newer studies have used SD-OCT for the evaluation of RNFL thickness.Various authors have used the TD-OCT to report a significant decrease in average RNFL two years after the photocoagulation .Although the effect of diabetes on retinal nerve fiber layer thickness has been studied in literature in past and few studies have reported decrease in thickness of RNFL even in the absence of a history of PRP . Therefore, due to such inconsistent and variable results using the same tool of OCT, we planned to perform a meta-analysis.It is noteworthy that this observation has not been consistently reported by authors who have used the OCT to measure RNFL [31]. In addition, the reduction in the RNFL thickness by apoptosis of neuronal cells, and the damage due to glycosylation end products of diabetes also play a role [32-35]. The interplay of these heterogeneous factors which results in the final impact of PRP on the RNFL, in any individual patient, was possible. Authors have variably postulated that this fluctuation in RNFL thickness can be attributed to the PRP induced retinal inflammation and edema in the early post-PRP phase and subsequent degeneration of RNFL by retinal cell loss in the late–post-PRP phase. An increase in leukocyte rolling and subsequent augmentation of vascular permeability, resulting in retinal edema after PRP. On the other hand, Tso et al. have demonstrated that the high-intensity laser beam results in the damage of the entire retinal layer, including the retinal ganglion cells [Hence, to conclude, our meta-analysis revealed that there was no significant effect of PRP on RNFL thickness and the impact of PRP could be variable. The RNFL thickness, often tends to yield erroneous and unpredictable results in this subgroup of patients, further confounding the evaluation of nerve fiber layer damage and its progression. Therefore, clinicians should keep in mind these points when interpreting the thickness in diabetics who have received PRP. It makes sense that diabetics undergoing PRP require more attention regarding neurodegenerative changes of the retinal nerve fiber layer and the resultant damage to vision. Multicenter studies, with a larger sample size may help understand the complexity of RNFL changes following PRP. Limitation of the studyThere are certain limitations in this meta-analysis. Even though we did not limit our analysis to location or evaluation methods during our database search, we included only those studies that were in English. We did not limit our analysis to the type of OCT used, and studies using both TD- and SD-OCT have been included in the analysis. Also, we did not restrict ourselves to scanning circle of 3.4 to 3.6 mm as done in other studies, because this was not defined in the two studies. Additionally, the type of diabetes mellitus, duration of disease and glycemic control could be possible confounding factors, none of which has been considered in this analysis.Conflict of InterestThe authors declare no conflict of interest.The study was conducted according to the Declaration of Helsinki.No funds were used to perform the study.


Estimating the depth of image and egomotion of agent are important for autonomous and robot in understanding the surrounding environment and avoiding collision. Most existing unsupervised methods estimate depth and camera egomotion by minimizing photometric error between adjacent frames. However, the photometric consistency sometimes does not meet the real situation, such as brightness change, moving objects and occlusion. To reduce the influence of brightness change, we propose a feature pyramid matching loss (FPML) which captures the trainable feature error between a current and the adjacent frames and therefore it is more robust than photometric error. In addition, we propose the occlusion-aware mask (OAM) network which can indicate occlusion according to change of masks to improve estimation accuracy of depth and camera pose. The experimental results verify that the proposed unsupervised approach is highly competitive against the state-of-the-art methods, both qualitatively and quantitatively. Specifically, our method reduces absolute relative error (Abs Rel) by 0.017–0.088. Vision-based environment depth and egomotion estimation are essential for autonomous vehicle perception and infrastructure-less robot navigation . At presI to Most unsupervised learning methods estimate depth and camera egomotion by minimizing a photometric error . The phoIn addition, the dynamic objects and occlusion also violate the photometric consistency. To overcome the problem of dynamic objects, the unsupervised method struct2depth  segmenteOur contributions are as follows.1. We propose feature pyramid matching loss (FPML) capturing local and global information, which is more robust than SAD and SSIM and can solve the problem of photometric inconsistency caused by brightness change.2. The proposed occlusion-aware mask (OAM) addresses, for the first time, the problem of photometric inconsistency causing by occluded pixels in the image with the consideration of novel relationship between two adjacent masks.3. Furthermore, OAM solves the problem of dynamic objects by balancing the photometric error and the regularization term of the mask and improve the accuracy of depth and camera egomotion.The development of deep learning has facilitated the application of supervised and unsupervised methods. We briefly overview some supervised depth estimation methods and introduce current SOTA unsupervised methods for single view depth and egomotion estimation.The supervised learning methods establish the relationship between image and corresponding depth through CNN. Eigen et al.  first prThe above-mentioned supervised methods need a large number of ground truths during training, but acquiring ground truths is difficult in practice. Using synthetic data is a good alternative, but these data cannot simulate the physical world accurately .Compared with the supervised methods, the unsupervised learning methods do not need labels; thus, the latter methods overcome the disadvantage of the supervised learning relying on labels. Unsupervised depth and camera egomotion estimation only needs raw video sequences. These methods refines the model from the video gathered from a new scene ; thus, iGarg et al.  proposedSfmLearner  only useMost of these methods are based on photometric errors and assume constant brightness and Lambertian surface of objects. However, meeting these conditions is difficult in real scenes. To handle the problem, ,13,28,29Our method uses single-view depth and multiview pose networks, with a loss based on warping the adjacent frames to the current frame using the computed depth and pose. In this work, we propose a framework containing three networks: a depth prediction network (DepthNet), a camera egomotion network (MotionNet) and an occlusion-aware mask network (MaskNet). The networks will be trained together due to the loss function but can be applied independently at test time. The framework of the networks and loss functions are shown in P represents a point in 3D space, K is the given camera intrinsic parameters, and The warp process is to find the corresponding point in the adjacent frames through the depth map of the current frame and the camera egomotion, and then synthesize the current frame. The warping process is divided into two steps: coordinate transformation and interpolation reconstruction. According to the pinhole camera model,  process , where PThe process of interpolation reconstruction is to synthesize the pixel value of  network  to obtain indexes are considered over different depth map scales. The photometric error, the OAM and the FPML elaborated in The loss we propose includes a photometric error Under the assumption of surface Lambertian and static rigid scenes, the brightness of the same object under different views should be consistent. Therefore, the current frame ty index ; Mf and In order to make the depth smooth and the edge of it sharp, we also use the following image gradient  based dePhotometric consistency assumes that the scene is static and the objects are nonoccluded. However, dynamic objects and occlusion usually occur in real scenes. As shown in We assume a object is visible in the current frame. Depending on whether the corresponding pixel on adjacent frames is visible, there are four cases of the corresponding pixel as follows: visible in all adjacent frames, occluded in all adjacent frames, occluded in the past or occluded in the future. The case that a pixel occluded in all adjacent frames rarely occurs in practice is discarded.The input of MaskNet is the current and adjacent frames Similar to SfmLearner , we add In other words, the loss prevents the mask to always be zero, since most points in the scene meet the photometric consistent. We also introduce the smoothing loss of the mask to ensure that the pixels in the neighborhood have the similar state, that is,lth current feature map lth adjacent feature map lth feature map lth feature maps as follows,To consider both global high-level and local detailed information, we extract feature pyramid from images and construct FPML for reducing the effect of brightness change and non-Lambertian surface. The total FPML function isDepthNet and MaskNetThe DepthNet and MaskNet we proposed based on encoder-decoder architecture, in which the decoder part can share the shallow information of the encoder part through skip connections.The encoder part adopts the standard ResNet18 , which cIn the decoder modules, ELU  is adoptd et al.  in bordeMotionNetThe input of MotionNet contains RGB images of the current frame and adjacent frames, and the outputs are camera poses of the current frame and adjacent frames. MotionNet consists of a ResNet18 and four convolution layers. The parameter of ResNet18 input layer is In this section, we compare results of our method with existing state-of-the-art approaches on depth and camera egomotion estimation.Implementation detailsOur models are implemented with PyTorch  and traiptimizer  with β1=KITTI datasetWe use the KITTI  dataset Evaluation metricD represent the ground truth and estimated depths respectively.We use the depth evaluation metric of Eigen et al. . The expWe use absolute trajectory error (ATE)  to evaluQuantitative comparison results of our method and previous methods are shown in edian(D)  for compedian(D) ,39 and uedian(D) ,17,40,41edian(D) , which uOur DepthNet and MotionNet are the same as those of methods in literature ,13, so tIn Our method is compared not only with the traditional visual SLAM method  but alsoWe measure the impact of each contribution on performance and show the results of ablation study in We propose an unsupervised learning framework that achieves monocular depth and egomotion estimation via FPML and OAM. The introduced FPML captures the local and global information and reduces the influence of brightness variation and non-Lambertian surface. In addition, the proposed OAM predicts not only dynamic objects but also occluded pixels in an innovative manner according to change of masks. As a result, FPML and OAM address the problem of photometric inconsistency and improve accuracy of depth and camera pose estimation. On the KITTI dataset, our results are better than the state-of-the-art unsupervised methods and even some supervised methods, both qualitatively and quantitatively. Especially, compared with previous methods, our method reduces Abs Rel by 0.017–0.088, which is the most important metric in the literature.In our future works, we will estimate the 3D motion of the dynamic rigid object in the image to help the robot better understand the 3D environment. Furthermore, the camera and LiDAR information will also be fused to achieve real-time accurate depth estimation, which is used for localization and mapping.


They also represent critical water resources for areas around the globe, with the potential for far-reaching effects in a warming world. Advancements to understand and model glacial changes and the variables influencing them are therefore paramount. Many glacier models fall into one of two endmembers: either highly complex transient models requiring careful tuning of multiple parameters to individual glaciers, or basic empirical correlations of glacier area and length with few considerations for local and regional variations in characteristics. Here we detail a physical steady-state model for alpine glaciers relating directly to glacier mass balance  while retaining the simplicity of other morphology methods, and simultaneously including error estimates. We provide custom MATLAB functions as a user-friendly and generally-applicable method to estimate glacier equilibrium line altitudes from only a limited number of glacier bed topography and glacier width measurements. As a test of the model’s efficacy, we compare the model results for present-day glaciers in the Swiss Alps with previously published estimates of equilibrium line altitudes and intermediate model outputs. Specifications tableChanges in glacier size and extent are fundamentally related to the mass balance of the glacier. An annual mass surplus (when net accumulation exceeds ablation) leads to glacier growth, while a deficit leads to glacier retreat. Such transitions can be visually drastic, with some glaciers changing by kilometers in response to minor perturbations in climate. A more comparable measure of the glacier response to climate change than glacier area or length changes is the concept of the equilibrium line altitude (ELA). The ELA is the boundary between the accumulation and ablation zones on a glacier and represents the elevation at which the annual amount of mass added through accumulation exactly equals the annual amount of mass lost through ablation The most accurate method to determine the ELA is direct measurements of the distribution of accumulation and ablation on a glacier. Such measurements, however, are only available for a small subset of modern glaciers, and entirely absent for paleoglaciers. Several empirical proxy methods have therefore been developed to estimate ELA when direct measurements of mass balance are not possible. Some of the more widely used are the accumulation area ratio (AAR), the toe-to-headwall altitude ratio (THAR), the area-weighted mean altitude (AMA), and the median elevation of the glacier (MEG) This manuscript presents a method to reconstruct ELA estimates based on continuity equations, while only requiring estimates of bed topography, glacier length, and glacier width. The ELA model also generates intermediate results of continuous modeled bed topography, ice surface elevation, and glacier width along the length of the glacier . An addeThe presented model is largely derived from a simple linear glacier-length model presented in The ELA model also provides analytical constraints on the error associated with model outputs. Such uncertainties are fundamental in determining the significance and reliability of results, but rigorous physical uncertainties of ELA estimates are rarely presented in paleo-glacier research, either because such uncertainties are difficult to assign for geomorphic methods like THAR and AAR or because higher order models are sufficiently complex to challenge error propagation. Uncertainty estimates in this study are calculated based on Monte Carlo simulations of bootstrapped residuals of the input parameters. These uncertainties give insight into the range of plausible ELA values based on both uncertainty of input parameters and the ability of the model assumptions to accurately represent those inputs.TM spreadsheet to calculate the ice surface profiles of a former mountain glacier or ice cap, given bed topography and a yield stress. Pellitero et al. Other computational methods exist to estimate the ELA of paleoglaciers. Benn and Hulton Similar to The fundamental basis of the ELA model is an integrated balance formula  for stea and ELA .(2)ELA=∫We then estimate each of the three components  on the initial parameter estimates to optimize the fit to the input width estimates , with v0.1.0 the particular version used in this manuscript. In brief, the ELA model function ELA_calc.m requires two dataset inputs  and the number of Monte Carlo simulations to perform. Approximately ten quasi-equally spaced points along the length of the glacier are often sufficient, though the optimum number depends on the length and complexity of the bed topography and glacier geometry. To avoid issues of model extrapolation , both the toe and the head of the glacier should be included in these measurements. The ELA model input data should be provided as a MATLAB structure with four fields, as summarized in The complete ELA model MATLAB code is publicly available . Moreover, the validation glaciers show variation in overall area, length, width, and elevation extent, thereby providing a range of possible glacier geometries . As the LANDSAT 5 imagery has a horizontal resolution of The Silvretta and Gries glaciers have the best-constrained mass balances with  50 years of published data for each The model results, including bed topography, ice thickness, plan-profiles, and ELAs, are summarized in Modeled ELA estimates for the four validation sites and comparisons to corresponding observed ELAs are presented in Likely sources of error to explain discrepancies between the observations and modeled results involve more complex considerations not accounted for with the simple ELA model. For instance, more complex bed topographies, differences in shading/shielding by valley walls, debris cover, and accumulation through avalanching can all affect the recorded ELA in mass balance measurements, none of which are considered in the ELA model. It is important to note that the model is particularly sensitive to errors in bed topography, as these values influence estimates of slope, ice thickness, and width and therefore can potentially strongly affect the final ELA estimates. Differences in steady-state assumptions may also be an important factor in differences between modeled and measured modern ELAs. The ELA model assumes steady-state conditions, whereas the annual mass balance reflects emergent climate conditions. Glaciers typically have either an annual mass surplus or deficit in a given year, complicating comparisons of our results to measured ELA values. Such a limitation, however, is inherent to all morphology-based ELA models. For instance, all methods significantly underestimate the ELA for Gries glacier, suggesting this glacier could be strongly out of equilibrium. Overall, the presented results show a high degree of confidence in the model’s ability to estimate glacier ELAs  from relatively few geomorphic inputs, supporting the use of the presented ELA model for simple valley glaciers across a wide spectrum of bed slope geometries, glacier shapes, glacier widths, and elevation extents.F factor relates the frictional lateral drag to the glacier cross-sectional area and perimeter length of the ice-topography contact F factor implementation could be incorporated into the ELA model in the future, potentially improving the ELA estimates for valley glaciers. In light of the sensitivity of the model to bed slope, using a non-parametric interpolation method for bed topography estimates could improve the ELA estimates, but would also require more complex modifications of the model to avoid discontinuous step changes in ice thickness and other parameters.The incorporation of additional variables and modeling components could address some of these limitations and improve the overall effectiveness of the model. For instance, the methods presented in The model described here accurately estimates ELAs from Alpine valley glaciers of varying size, topography, and areal distribution while utilizing a small set of easily-obtained measurements. The model provides errors based on the physical uncertainties of model inputs, a crucial factor for determining the significance and importance of results. We validate the model on a set of glaciers in the Alps spanning a variety of characteristics . The model performs at least as well as traditional empirical methods of ELA estimation while minimizing reliance on optimized empirical coefficients, adding uncertainty estimates, and providing insight for the sensitivity of individual glaciers to model inputs. Based on these validations and the physics-based nature of the model, this ELA model should serve as a robust, easily applicable, self-consistent method for ELA glacier reconstructions in varied areas, including the broader European Alps, alpine regions of the Arctic, the Southern Alps in New Zealand, and similar glaciated locations. The model should also be readily applicable to paleoglacier reconstructions based on preserved moraine sequences, permitting rapid and consistent comparisons of glacier changes through time and across diverse regions. Such studies will permit enhanced insight into the mechanisms of climate change in the past, and help us to better understand present and future changes to critical glacial and water resources in a warming world.The Authors confirm that there are no conflicts of interest.


The hair cells that reside in the cochlear sensory epithelium are the fundamental sensory structures responsible for understanding the mechanical sound waves evoked in the environment. The intense damage to these sensory structures may result in permanent hearing loss. The present strategies to rehabilitate the hearing function include either hearing aids or cochlear implants that may recover the hearing capability of deaf patients to a limited extent. Therefore, much attention has been paid on developing regenerative therapies to regenerate/replace the lost hair cells to treat the damaged cochlear sensory epithelium. The stem cell therapy is a promising approach to develop the functional hair cells and neuronal cells from endogenous and exogenous stem cell pool to recover hearing loss. In this review, we specifically discuss the potential of different kinds of stem cells that hold the potential to restore sensorineural hearing loss in mammals and comprehensively explain the current therapeutic applications of stem cells in both the human and mouse inner ear to regenerate/replace the lost hair cells and spiral ganglion neurons. The inner ear is a sophisticated and sensitive sensory organ of the body. It contains three well-known functional structures: the cochlea for sound perception, the vestibule, and the semicircular canals for maintaining body equilibrium. The cochlea is responsible for understanding mechanical voices by transducing incoming sound vibrations into electrical impulses using hair cells (HCs) and then transmits these electrical impulses to the brainstem via spiral ganglion neuron cells (SGNs) –5. The cOne way to restore hearing loss is to produce new functional HCs to replace the lost HCs in the cochlea. Regeneration of HCs and SGNs after damage could possibly yield a treatment for sensorineural hearing loss , 38. SteHearing research science is primarily focused on formulating the best therapeutic strategies to renew the hearing cells (HCs and SGNs), thus restoring the natural hearing function and producing comfort to the millions of patients affected by this widely growing disorder . Also, tStem cells are better called the principal cells of the body that maintain their undifferentiated and unspecialized state in order to either directly transform into specialized cells or pursue the mitotic division to form new stem cells. Stem cells are used to restore cellular damage and recover the cell loss. Adult stem/progenitor cells, spiral ganglion-derived neural stem cells (SGN-NSCs), embryonic stem cells (ESCs), and inducible pluripotent stem cells (iPSCs) are kind of stem cells that are commonly used in therapeutics . Adult sESCs are pluripotent stem cells, obtained from the inner cell mass and hold the limitless potential to proliferate as well as to differentiate to form all three germ layers: ectoderm, mesoderm, and endoderm. Yet, the mouse ESCs have been more deeply investigated as compared with the human ESCs. ESCs have been widely used for in vitro culture system to deliberately induce the formation of different cell types such as liver cells, neuronal cells, cardiac cells, and pancreatic cells –73. ThusThe iPSCs are the adult differentiated cells that are genetically reprogrammed to form pluripotent stem cells. They hold a novel therapeutic ability to replace and repair the hearing cells (HCs and SGNs) in the inner ear. The mature skin fibroblast cells were the first reprogrammed iPSC generated by deliberately introducing the four crucial transcription factors including Klf4, Sox2, c-Myc, and Oct3/4 . In therThe use of stem cell therapy in the inner ear is a promising approach to rescue the HC damage and to reestablish the hearing function. There are two possible stem cell-based approaches to treat deafness. The first is the restoration of existing stem cells in the inner ear by stimulating the resident stem cells within the organ of Corti, therefore allowing stem cells to replace the damaged HCs and rehabilitate the normal hearing mechanism. However, the basic difficulty with this approach is the insufficient number of resident stem cells in the inner ear that are not capable to restore hearing. The second is the exogenous supply of stem cells (stem cell transplantation) into the inner ear . This apThe presence of endogenous stem/progenitor cells in the adult human sensory epithelium was evident, when the pure population of cells was marked with the stem cell marker ABCG2+ve isolated from dissociated human cochlear cells via flow cytometry. These dissociated human cochlear cells also form spheres in the in vitro culture system. However, the number of spheres generated in the experiments was inadequate to further characterize these spheres for the ability to regenerate functional HCs . More reMultiple studies have attempted the transplantation of embryonic stem cells in the inner ear in order to regenerate HCs in vitro. There were few studies that reported on the use of human embryonic stem cells (hESCs) to differentiate to form HC-like cells. In one of the studies, the hESCs were triggered to differentiate under particular signals mandatory for the specification of the early otic placode and obtain otic progenitors that differentiate into HC-like cells displaying HC-specific marker, immature stereociliary bundles. These HC-like cells also showed the electrophysiological characteristics suggesting that they are functional HCs. Some other otic progenitors differentiate to form neuronal cells exhibiting specific neuronal markers and having electrophysiological properties, suggesting that these cells are also able to generate functional auditory neuronal cell fate . The genTo overcome this nonfunctionality of matured HC-like cells, the three-dimensional culture system has been successfully used to generate the inner ear organoid from hESCs. The inner ear organoid has the genuine cytoarchitecture of HCs, SCs, and neuronal cells as expressive of the native inner ear sensory epithelium . In vitrThe capability to generate SGNs from stem cells is a compulsory requirement to develop stem cell therapy for SNHL. A group of researchers developed a protocol that allows the differentiation of hESCs into a pure population of otic neuronal progenitors (ONP) and SGN-like cells. Interestingly, the newly differentiated SGN-like cells express the specific SGN genotypic and phenotypic markers as well as extend their neurites towards the cochlear nucleus suggesting that the hESC-derived SGNs can closely replicate the features of functional human SGN . Moreoveβ through the use of the differentiated monolayer culture system [There are some ethical concerns on the experimental utilization of human embryonic stem cells, and since then, much attention has been paid on the experimental generation of iPSCs from somatic cells to further transform to generate HC-like cells. Multiple strategies have been formulated successfully to first generate human iPSCs (hiPSCs) and then stepwise induce the differentiation of hiPSCs into the human inner ear HC-like cells . There ae system , 88. TheThe correction of gene mutation in iPSCs stimulated from somatic cells of diseased persons is a promising way to treat hereditary SNHL. In two different studies, researchers begin iPSC formation from a deaf patient carrying Myo7a and Myo15 mutations that are mainly responsible for deafness. CRISPR/CAS 9 gene-editing tool is used to genetically rectify the Myo7a and Myo15 mutations and observe that the HC-like cells derived from the corrected iPSCs exhibited the recovered organization of the stereociliary-like structures and complete morphological and functional restoration of HCs , 90. MorOne main concern regarding the use of iPSCs is their genetic integrity, as the use of viral vectors during reprogramming of these cells might cause the insertional mutagenesis. To address this query, Boddy et al. proposed a nonintegrating mRNA-based reprogramming of human-induced pluripotent stem cell (hiPSC) lines. The integration-free hiPSC lines were allowed to culture in the presence of FGF3 and FGF10 that trigger the process of hiPSC line differentiation into otic progenitors as confirmed by the detection of otic markers Pax2, Pax8, Sox2, and Foxg1. Subsequently, the purified otic epithelial and neuroprogenitors were differentiated to generate HC-like cells and neurons .In addition, the iPSCs also served as a resource for the replacement therapy of neurons in the damaged cochlea. A study demonstrated that the hiPSC-derived neurons innervate with the developing HCs and form presynaptic connections in the in vitro coculture system. Those hiPSC-derived neural progenitors cocultured with HCs at an earlier stage of differentiation displayed a higher innervation potential as compared to the other neural progenitors . HoweverBarhl1 is a deafness gene expressed in the developing hair cells. It plays an important role in the differentiation of mouse embryonic stem cells (mESCs) into HC-like cells. The targeted disruption of Barhl1 hindered the differentiation of mESC-derived HC-like cells in vitro [The embryonic stem cells derived from mice were first used in an experiment to produce HC-like cells in vitro by formulating a proper stepwise differentiation strategy. These differentiated HC-like cells showed the full expression of HC-specific markers observed via gene expression profiling and immunostaining . The Barin vitro . Moreovein vitro . On accoin vitro .EGFP/+ cells were used for inner ear organoid formation to understand the otic induction. The results displayed the higher expression of Pax2 and active stimulation of ERK downstream of the FGF signaling pathway in inner ear organoid development. The expression of Pax2 was persistent throughout the formation of sensory HCs, and the cochlear neurons established synaptic connections with HCs in the organoids [Despite the use of the feeder cell layer, some other strategies such as three-dimensional (3D) cultural systems have also been used to transform mESCs into HC-like cells, SCs, and neuronal cells. The advantage of the 3D cultural system is that the neuronal cells established synaptic connectivity with the HCs. Furthermore, the aggregate of mESCs in the 3D culture system has been guided to mimic the normal development by sequentially generating the nonneural ectoderm expressing multiple marker genes , preplacodal ectoderm, and otic placode (expressing PAX2 and PAX8 genes) –101. Alsrganoids , 104.Gfi1, POU4f3, and Atoh1, directly stimulates the genetic programming in mESCs that leads to the sensory HC generation in vitro. The newly generated HCs express various HC-specific markers and revealed the polarized membrane protrusions on the HC surfaces similar to the stereociliary bundles [In addition, there is a novel exploration of transcriptional machinery that controls the HC fate and differentiation of mESCs. The simultaneous overexpression of three transcription factors,  bundles . The dif bundles , 107. Al bundles . In cont bundles –111.Until now, in vitro studies regarding both human and mouse ESCs and iPSCs demonstrated that the specific culture conditions allow the stem cells to differentiate and achieve the desired cell fate such as HC-like cells and SGNs , 113. ThHearing research is mainly focused on developing different strategies to design therapeutics that help to initiate the HC regeneration/replacement process in the inner ear to ultimately recover hearing loss. Multiple studies on the animal model have been successfully conducted that allow the clinical applications of endogenous and exogenous stem cells in order to regenerate/replace HCs in the mammalian inner ear. However, there are numerous challenging questions that need to be dealt with before executing these therapeutic strategies in humans. Some of them include the risk of tumorigenesis after implanting the stem cells, possible detrimental effects to the patients, and appropriate and controlled growth of stem cells at the site of cell transplantation in the cochlea. Also, the high cost of stem cell therapy makes it unreachable for a large number of hearing loss patients. In addition, the success rate of stem cell therapy is not high enough yet. Regardless of these limitations, stem cell therapy is still a promising future strategy to start HC regeneration/replacement in the adult mammalian cochlea to recover sensorineural hearing loss.


Verticillium spp. The increased resistance of mycorrhizal plants is mainly due to the improved nutritional and water status of crops and to enhanced antioxidant metabolism and/or increased production of secondary metabolites in the plant tissues. However, the effectiveness of AMF in protecting their host plants against Verticillium spp. may vary depending on the environmental factors. Some environmental factors, such as the concentration of carbon dioxide in the atmosphere, the availability of soil water and the air and soil temperatures, are predicted to change drastically by the end of the century. The present paper discusses to what extent the climate change may influence the role of AMF in protecting crops against Verticillium-induced wilt, taking into account the current knowledge about the direct and indirect effects that the changing environment can exert on AMF communities in soils and on the symbiosis between crops and AMF, as well as on the development, incidence and impact of diseases caused by soil-borne pathogens.The association that many crops can establish with the arbuscular mycorrhizal fungi (AMF) present in soils can enhance the resistance of the host plants against several pathogens, including  Mycorrhizal fungi are terrestrial fungi that coinhabit the rhizosphere with many saprotrophic and pathogenic fungi, interacting with one other . MycorrhFusarium oxysporum in strawberries [Phythium aphanidermatum in pawpaws [Armillaria mellea in grapevines [Phytophthora parasitica in tomatoes [Aphanomyces euteiches in peas [Rhizoctonia solani. Several mechanisms, acting together or separately, have been proposed to explain the bioprotection conferred by AMF to crops against soil-borne pathogens: enhanced plant nutrition, damage compensation, alterations in the root anatomy and longevity, competition between AMF and soil-borne pathogens for the colonisation sites in roots and for host photosynthates, activation of plant defences and changes in the populations of rhizospheric microorganisms [Among all the benefits that arbuscular mycorrhizal fungi (AMF) can provide to their host plants is worth noting the protection against different pathogens and, especially, against soil-borne pathogens. There are numerous reports on the alleviation of damage caused by soil-borne necrotrophic pathogens, such as wberries , cucumbewberries  and chicwberries ; Phythiu pawpaws ; Armillaapevines ; Phytophtomatoes  or Aphan in peas . Guillon in peas  also obsrganisms . Moreoverganisms .Verticillium spp. are soil-borne ascomycete fungi with a very broad spectrum of host plants around the world. Although initially these fungi show biotrophic behaviours and do not produce severe reductions in plant performance, at later stages, they become necrotrophic and alter the hormonal balance, induce the synthesis of hydrogen peroxide and nitric oxide and cause the activation of defence genes in the plant, leading to the death of host cells [Verticillium-infected annual and perennial crops. Despite some exceptions [Verticillium attacks. Those benefits can be specified in reduced disease development and severity [Verticillium-infected plants cultivated in pots  a susceptible plant, (b) a pathogen able to cause disease and (c) a favourable environment, which includes factors affecting the plant, the pathogen or even additional organisms, such as vectors. However, the environmental changes occurring nowadays are steadily shaping the relationship between plant growth and the associated diseases. In the case of diseases caused by pathogenic fungi, it has been demonstrated that the triangle shape is becoming skewed because of the pressure of the environmental component on plant growth, physiology and yield , which aPhytophthora infestans, white mould produced by Sclerotinia sclerotium and wilt caused by Verticillium albo-atrum in tomatoes. In agreement with this point of view, Zhou et al. [Fusarium oxysporum f. sp. raphanin and Rhizoctonia solani in Arabidopsis did not change under different concentrations of CO2 in the atmosphere. However, as these last authors commented, in a global context of climate change, disease incidence will also be affected by other parameters, such as elevated ozone, humidity, drought and increased temperature. Even some agronomic practices, such as fertilisation, can modulate the effects of environmental parameters. In a study performed with potatoes infected with Phytophthora infestans, Osswald et al. [2 (700 ppm) enhanced the resistance of a susceptible potato cultivar towards P. infestans due to an increased C/N-ratio in the leaves, N fertilisation nullified the enhanced resistance as a consequence of a reduced C/N ratio. It is expected that higher CO2 concentrations in the air will induce the accumulation of carbohydrates in plant tissues and the reduction in the levels of proteins and amino acids in the tissues of many plants, thus increasing the C/N ratio. This enhanced C/N ratio may improve the tolerance of crops against soil-borne pathogens but can also diminish the nutritional quality of crops. Increased CO2 in the air may also modulate the crop resistance against V. dahliae through changes in the balance between the jasmonate (JA) and salicylic acid (SA) signalling pathways. It has been observed that an elevation of the atmospheric CO2 concentration can suppress the JA pathway in favour of the SA pathway [V. dahliae quickly activate the JA pathway in order to strengthen the defences detriment to growth. However, V. dahliae can counteract the priority for the JA signalling in order to favour the development and reproduction of plants instead of their defence [V. dahliae stimulates the host JA functions in order to promote host cell death, which suggests that the effect of V. dahliae on the host JA pathway may depend on the stages of the disease cycle. In summary, the effect that increased CO2 could exert on the tolerance of plants against V. dahliae appears uncertain; while an increased C/N-ratio could enhance plant resistance, the suppression of the JA pathway could reduce the ability of plants to fight against V. dahliae in the early stages of the infection.Predictions on the possible incidence of climate change on soil-borne pathogens and the incidence of the diseases they cause in crops are not clear. Gioria et al.  argued tu et al.  found thd et al.  observed pathway . Gao et  pathway  observed defence . More re defence  postulat2, other environmental factors linked to the climate change are erratic and extreme rainfalls and increased air and soil temperatures. The vulnerability of crops to the attacks of soil-borne pathogens can increase after the extreme drought and rainfall events, in part due to the reduction of the natural capacity of soil to suppress pathogens, a fact verified when plants infected with fungal species belonging to Fusarium and Verticillium genera have faced drought conditions [V. dahliae. Although the findings arisen from the assays performed under controlled conditions do not clarify the consequences of climate change on the diseases caused by soil-borne pathogens, a real fact is that the incidence of Verticillium wilt affecting sunflowers in the field has risen since 2013–2014 in several European countries, including Bulgaria, France, Italy, Spain and Ukraine [Together with increased atmospheric COnditions . Similarnditions  were notnditions  found th Ukraine . This ob Ukraine , most in2 in the air for the development, incidence and impact of crop diseases.The information, currently available and obtained from both field studies and assays under controlled greenhouse conditions, indicates that the rainfall regime and temperature may be more determining factors than the high CO3 and atmospheric CO2 on mycorrhizal fungi seem to be completely indirect, the influence of warming, extreme rainfall events and nitrogen deposition can be both direct and indirect [Changing environmental conditions can affect mycorrhizal fungi both directly and indirectly through modifications induced in the physiology and metabolism of their host plants. While the effects of tropospheric Oindirect . Vice veindirect .2 in the atmosphere often reduces the abundance of AMF belonging to the Gigasporaceae and promotes the presence of Glomeraceae, thus changing the structure of the mycorrhizal communities present in soils. The reduction or exclusion of Gigasporaceae from agricultural soils will also represent a loss of functional diversity for crops, being the nutrient uptake and the consequent increase in plant vigour some of the aspects most negatively affected, which could be in detriment of the compensation of damage caused by pathogens [2 can also indirectly promote the mycorrhizal colonisation of plant roots as a consequence of the enhanced carbon allocation to roots [2 on root colonisation and the growth of extra-radical fungal hyphae has been mainly found in studies carried out in greenhouses rather than in the field [To date, there is not conclusive information on the effect that elevated tropospheric ozone may exert of AMF in the soils. More long-term studies are needed to conclude the accumulative effects of ozone on the composition and activity of AMF communities in the soils. By contrast, many studies  warming can induce the growth of the extraradical hyphae in the soil  by increasing the direct competition between AMF and V. dahliae for soil resources and root entry points, (b) by enhancing the uptake of water and soil minerals by roots, thus benefiting crop growth  and (c) by allowing in the field belowground interactions between individuals thanks to the mycelium shared by the roots of neighbouring plants. These common mycorrhizal networks (CMN) represent a promising tool for the biocontrol of crop pests, because they increase the bioactive zone for allelochemicals and volatile compounds in the soil  elevated COthe soil . If so, oil  will be damaged. The disruption of the belowground fungal network can severely impair both the uptake of water and minerals and the exchange of signals between plants for increasing their resilience against pathogens. Moreover, the reduced size of the soil pores under compaction will impair the diffusion of volatile compounds.Another aspect to highlight is the big air phase in the dried soils, which facilitates the interactions between microorganisms via volatile organic compounds . It has Verticillium spp. Lignin deposition in root xylem can be induced under drought [V. dahliae [V. dahliae [As previously commented, extreme drought can reduce the natural capacity of soil to suppress pathogens, thus increasing the vulnerability of crops to the attacks of soil-borne pathogens . Neverth drought , a mecha dahliae . Similar dahliae . This inV. dahliae) will predominate in flooded soils.The erratic rainfall related to the climate change can also trigger flooding, which will strongly influence the antagonistic interactions between pathogens and other soil microorganism in the soil . As expl2, drought or high temperature) applied to a dual interaction plant-pathogen or plant-AMF. The interactions between several climatic change parameters acting together or sequentially can strongly influence the final result. Moreover, in the field, there are many rhizospheric interactions among microorganisms  and fauna, which can modulate the behaviour of the triple-interaction ‘crop-Verticillium spp.-AMF’.The current scientific evidence offers an incomplete and fragmentary view on the role that AMF may play as bioprotectors agents of crops against Verticillium wilt under scenarios of climate change. Most of the conclusions were obtained from studies performed in a greenhouse and only managing one parameter related to climate change  for long periods.Genetic resistance is considered as the most economical approach to crop protection, so that the search of naturally occurring resistances has been a recurrent subject of investigation. The success of many genetic engineering programs focused on increasing the resistance of crops to diseases is highly subject to public acceptance. In a way, the association of the crop species with AMF represents a natural way of altering the gene expression, which can enhance crop tolerance against pathogens and environmental constraints.


A 72-year-old male was diagnosed with a duodenal mass and underwent extensive surgical resection. The patient's post-op course was complicated by an anastomotic leak that was first treated conservatively; however, his condition continued to deteriorate. An upper endoscopy was performed, which showed misplacement of drain forming a fistulous track through the lumen of the bowel. We removed the drain and used argon plasma coagulation to de-epithelize the lumen and closed the fistula with hemostasis clips. The patient's clinical status improved significantly. Our case emphasizes the success of endoscopic techniques as an alternative option in the management of postsurgical anastomotic leaks and fistulas in the right clinical setting and patient population. Postsurgical anastomotic leaks and fistulas are a serious complication after major abdominal surgery resulting in significant morbidity and mortality . Its occHistorically, the mainstay of treatment has been either conservative management such as prolonged bowel rest with total parenteral nutrition (TPN) or surgical interventions. Lately, endoscopic treatments have emerged as an alternative option for the management of anastomotic leaks/fistulas with better clinical outcomes .We present a case of a postsurgical anastomotic leak and enterocutaneous fistula formation after an extensive small bowel resection who deteriorated with conservative/surgical interventions and had successful outcomes with endoscopic treatment.A 72-year-old male presented to the emergency department with complaints of four-day history of epigastric abdominal pain, nausea, vomiting, constipation, and inability to tolerate oral diet. He reported early satiety and 24 pounds of unintentional weight loss in the last four months. He was hemodynamical stable on presentation. Abdominal examination revealed mild epigastric tenderness with moderate abdominal distention. The basic laboratory workup was within normal limits. However, computed tomography (CT) abdomen and pelvis with intravenous and oral contrast showed eccentric thickening of the third and fourth part of the duodenum . A magne38The endoscopic management of postsurgical intestinal anastomotic leaks and fistulas serves as an alternative to conservative and surgical treatment options. These techniques have the advantage of being minimally invasive that results in a shorter length of stay and antibiotic therapy. Different endoscopic modalities used have unique mechanisms and are used in combination or alone .The use of self-expandable metal stents (SEMS) allows the diversion of the gastrointestinal contents away from the site of leakage to provide a stable environment for healing , 8. ExtrHemostatic clips including through the scope (TTS) clips and over the scope (OTS) clips are used in closing the GI defects . TTS clin = 47; 38.5%), fistulas , leaks , and perforations . The immediate clinical success was ascertained in 79.5%, and long-term clinical success was noted in 78.8% after a mean follow-up of 68 days [Endoscopic suturing devices can also be used in the management of GI defects depending upon the location and type of the lesions. The Overstitch device (Apollo Endosurgery) is the most commonly used device that helps to apply sutures in a continuous or interrupted fashion. Sharaiha et al. reported the results from a large multicenter study for comprising of 122 patients who underwent endoscopic suturing to anchor stents ( 68 days .The vacuum-assisted closure (VAC) device is another promising option to be considered. In this technique, a vacuum-sealed sponge connected to a constant suction is inserted into the wound cavity. This helps in the removal of fluid and debris, promoting granulation tissue. Wedemeyer et al. successfully treated 8 patients with postesophagectomy leaks with VAC. The leak got healed in 7 out of 8 patients (88%) with a mean duration of 23 days .One of the major issues in the postsurgical leak healing process is the epithelialization of the defect and subsequent tract formation which results in the formation of chronic draining fistulas. This usually slows down the healing process and limits the use of other endoscopic therapies. Therefore, de-epithelialization of the leak edges is vital in these cases and can be achieved by Argon Plasma coagulation (APC) as one of the preferred methods , 14. ThePostsurgical anastomotic leaks have serious complications with significant morbidity and mortality. As mentioned, there are several endoscopic techniques which have shown efficacy and promising outcomes with no single standard technique to manage individual defects, rather a combination of techniques, complementary to each other. The choice of the endoscopic technique depends on several factors including the site, size, duration of the leak, and operator experience with these techniques. In our patient, we used APC to de-epithelize or denude the luminal surface of the involved intestinal tract and later used hemostatic clips. The hemostatic clip was used since the size of the defect was small. Our case emphasizes the use of endoscopic techniques to treat postsurgical anastomotic leaks and fistulas early on in suitable patients as a successful alternative option to conventional therapies; however, future large case series or prospective studies are required to validate the efficacy and safety of endoscopic therapies.


Cancer identification and classification from histopathological images of the breast depends greatly on experts, and computer-aided diagnosis can play an important role in disagreement of experts. This automatic process has increased the accuracy of the classification at a reduced cost. The advancement in Convolution Neural Network (CNN) structure has outperformed the traditional approaches in biomedical imaging applications. One of the limiting factors of CNN is it uses spatial image features only for classification. The spectral features from the transform domain have equivalent importance in the complex image classification algorithm. This paper proposes a new CNN structure to classify the histopathological cancer images based on integrating the spectral features obtained using a multi-resolution wavelet transform with the spatial features of CNN. In addition, batch normalization process is used after every layer in the convolution network to improve the poor convergence problem of CNN and the deep layers of CNN are trained with spectral–spatial features. The proposed structure is tested on malignant histology images of the breast for both binary and multi-class classification of tissue using the BreaKHis Dataset and the Breast Cancer Classification Challenge 2015 Datasest. Experimental results show that the combination of spectral–spatial features improves classification accuracy of the CNN network and requires less training parameters in comparison with the well known models . The proposed structure achieves an average accuracy of 97.58% and 97.45% with 7.6 million training parameters on both datasets, respectively. Breast cancer is reported as one of the most leading cause in deaths of women by the International Agency for Research on Cancer (IARC) ,2,3. TheClassification of signals or images categorize the image into one of the predefined classes . This prSince last decade, supervised machine learning algorithms have gained immense popularity and all researchers are extensively using them for computer vision applications . SupportA CNN model is proposed utilizing both spectral and spatial information based on a concatenation of multiresolution spectral information obtained from the wavelet transform at the various deep layer of CNN.Utilization of average pooling instead of max pooling operation and batch normalization after each convolution operation is introduced to solve the poor convergence problem.Performance comparison of the proposed model with various CNN models is presented on two datasets, namely, Breast Cancer Classification Challenge 2015 and BreaKHis.The deep architecture of CNN learns hierarchy of features like pixel, edge, pattern, region from the set of training images . CNN basThe rest of this paper is organized as follows. A binary classification model using a residual learning CNN approach was proposed to learn discriminative features from histopathological images . The algIn the same context, Xie et al.  used theA similar approach based on the restricted Boltzmann machine in DNN was introduced in . The conIn , the autIn , image-wThe main idea of the proposed method is to fuse the spectral information obtained from the multi-resolution wavelet transform with spatial information obtained using CNN layers. Wavelet transform allows decomposition of an image at various resolution levels providing powerful insight information at frequency level. It helps to scrutinize the local discriminative characteristics in histopathological images . One of This can be extended for two-dimensional image analysis, i.e., two-dimensional scaling function and separable decomposition of the wavelets can be expressed as followThe discrete wavelet transform of an image Thus, Haar wavelet transform decomposes the image by convolving it with low pass and high pass filter generating coefficients at low-frequency values (approximate coefficients) and high frequency values . The further decomposition of low-frequency values generates next level coefficients at another resolution level. This hierarchical structure of the wavelet transform is shown in Kausar et al.  preproceI is the input image, P is the average filter and Performance of wavelet level decomposition at level 6 is better than others irrespective of decomposition type . After dTherefore, wavelet transform can be represented equivalent to pooling operation asInstead of using a fixed average filter in the average pooling operation, the wavelet transform uses four filters with stride 2. This down-samples the size of the features by 2. To get the advantage of both spectral as well as spatial information the concatenation of wavelet features and spatial features obtained from the convolution layer is carried out.In this work, the histopathological images are augmented and then the model is trained using this augmented dataset. The performance of the model is evaluated on two publically available datasets, namely BreaKHis dataset  and BreaThe network is likely to overfit with a small dataset. Therefore, training images have been increased using data augmentation, where, the images have been divided into number of patches and rotation. Then, mirroring and shifting operations on patches are used to augment dataset. Image patching and augmentation have been used well on histological images classification . RotatioTo quantify and validate the performance of the proposed method, well-known metrics, namely, classification accuracy, area under the curve, sensitivity and specificity are used. For classification problem, a predicted output can be classified into four states. (a) True Positive (TP) suggest that image is classified as benign correctly, i.e., both label and classification are benign type (b) False Positive (FP) suggest that image is wrongly classified as benign type. That is the label is not benign and classification is benign type (c) True Negative (TN) suggest that both label and classification are not benign (d) False negative (FN) suggest wrong classification, which means image label is benign and classified as malignant. Using these parameters, sensitivity ) is defined as ability of the algorithm to correctly identify images with diseases and Specificity defines the ability of the algorithm to correctly classify image without diseases. Mathematical formulation of these metrics are as follows:The tradeoff between the specificity and sensitivity can be evaluated using receiver operating characteristic (ROC). Thus increment in the sensitivity values causes decrements in the specificity. The the area under the ROC (AUC) depicts the balance between these two attributes. The large AUC indicates the better separability between the classes by the algorithm. The following subsections represent the performance analysis of proposed algorithm for both binary classification and multi-class classification using these attributes.The dataset is arbitrarily divided into 70% training dataset and 30% testing dataset. All images patches are resized to The experimental results for the BCC2015 dataset are conducted for multi-class classification, where images are classified between the four class . The same model with same parameters has been used in the experiment. Images are augmented as previous described. The training and testing accuracy for this dataset are shown in the Comparison with state-of-art methods is also reported in In this paper, we proposed a method for histopathological cancer image classification based on a modified CNN model. The weakness of the traditional CNN model is that its classification depends on the spatial features only that can be obtained from the training dataset. However, the spectral features play an equivalent role to the spatial features in the classification. Hence, the CNN model is modified and Haar wavelet-based spectral features are fused with spatial features to enhance the performance of the classifiers. Two databases, breaKHis dataset and BCC2015, are used in the experiments with different criteria of magnification factor, augmented patches, binary classification, and multi-class classification. The proposed model achieved an average accuracy of 97.58% and 97.45% on the breaKHis dataset and BCC2015 dataset, respectively, which is higher than most of the state-of-art methods. It is also observed that it requires only 7.6 million learning parameters, which proposes a design of a lightweight CNN algorithm with inclusion of spatial and spectral information. Future research will focus on testing other wavelet families, such as Daubechies, Biorthogonal, Coiflet, which may have good capability in structure discrimination.