Ingrid Eshun-Wilson and colleagues summarize gaps in primary HIV implementation research methods and reporting, and propose areas for future methodological development. With highly effective diagnostic, prevention, and treatment innovations available in HIV programs globally, the HIV field is increasingly turning to implementation and service delivery questions.Developing guidelines for implementation of interventions is markedly challenged by limitations in primary implementation research design and reporting, as well as difficulties in application of evidence synthesis and guideline development tools originally developed to appraise evidence for efficacy.Drawing on the processes of developing the WHO HIV service delivery guidelines for testing and treatment between 2018 and 2021, we present challenges and identify areas for future methodological development to improve the incorporation of implementation research across the full spectrum of the evidence generation continuum.We highlight gaps in design, measurement, and reporting of primary implementation research, as well as underreporting of relevant program data.We describe how routine application of current evidence synthesis tools may not sufficiently answer implementation questions and propose that methodological tools be optimized to identify high-quality non-randomized evidence and reduce penalization for heterogeneity in meta-analysis of implementation research.These findings serve as a blueprint for further methodological work to strengthen existing evidence synthesis and guideline development tools for HIV service delivery guidelines and for implementation research more broadly.Over the last 10 years, global technical guidance for the public health response to HIV—including but not limited to the World Health Organization (WHO)—has sought to make recommendations not only for clinical practice, but also how services should be implemented . While tThe increased focus on implementation questions has highlighted complexities in synthesizing and appraising research for development of scientific guidance on implementation practice . Many ofBetween 2018 and 2021, the LIVE project (a living database of HIV implementation science research) supported WHO guideline development for HIV through the conduct of systematic reviews and meta-analyses for the 2019 HIV self-testing guidelines and the 2021 HIV treatment service delivery guidelines . Review To supplement recognized evidence synthesis methods during the development of WHO guidelines for HIV service delivery, we applied implementation science tools to systematically characterize research findings. These included the Proctor and colleagues frameworks for characterizing implementation strategies and implementation outcomes and the PRECIS-2 framework for assessing real-world relevance in trials –14. We aDetailed specification and characterization of primary implementation strategies and co-strategies was not robust across studies included in reviews. As an example, in a review of re-engagement in care strategies—actors (those who conducted tracing efforts) and actions (tracing activities performed) were generally well specified; however, other implementation characteristics, such as the dose (frequency and intensity of contact attempts) and temporality (time when tracing was initiated in relation to last visit or appointment) and the action target (how a “lost” patient was defined and how the tracing sought to re-engage them) were less clear ,17. In aStudies rarely presented (in primary or ancillary publications) implementation outcomes. Among 8 studies included in a review of community ART initiation, 3 studies reported on cost of implementation and none reported on other implementation outcomes  . For guiHypothesized mechanisms by which implementation strategies were expected to exert effects were also rarely characterized. It was rare for protocols, primary or ancillary publications to include any explicit theory of program effectiveness and assumptions—or for studies to share revised mechanistic theories ex-post given new information during study implementation –21. CommA further challenge for synthesis was the limited reporting of contextual factors that influence the effectiveness of an implementation strategy—such as the historical and sociopolitical climate, social structures, organizational hierarchies, financing, governance, leadership, human resource capacity, and stigma ,28. UndeImplementation evidence generation and synthesis to date has infrequently incorporated extensive program implementation data ,33. RoutThe feasibility of implementing a given intervention within health system constraints is a core component of meaningful guidance for evidence-to-decision processes, yet there are no commonly used tools for assessing whether synthesized study findings are sufficiently pragmatic and relevant to real-world conditions. Thus, understanding to what degree the trial context and conditions mimic real-world conditions has implications for establishing guidance for scale up .To address this gap during guideline review processes, we applied the PRECIS-2 tool to evaluate the extent to which research findings could be applied to routine care  Table 2Table 2. 2 statistic, measuring statistical heterogeneity was greater than 90% in several meta-analyses, prompting evidence downgrading even in instances where the majority of effect estimates showed benefit (Synthesized effect estimates for implementation research frequently do not represent one true underlying effect (or a single distribution of effects). This was demonstrated by high levels of unexplained statistical heterogeneity in our guideline work: the I benefit . This heUnexplained differences in otherwise similarly named strategies, another form of heterogeneity, also complicates the use of network meta-analyses (NMA). NMAs offer a complementary methodology for comparing several implementation strategies through the use of common comparators. In theory, this approach is highly attractive for implementation research where the large number of potential strategies precludes head-to-head comparison of all possibilities. However, the application of this method to implementation research can by challenged by the need to meet the assumption of “transitivity.” In a systematic review of the effects HIVST delivery strategies marked differences in settings and population groups posed a threat to “transitivity” . TransitDuring the HIV service delivery guideline evidence synthesis process, discussion arose regarding what may be considered good evidence within the GRADE approach and what might be considered good evidence for implementation. GRADE offers a rigorous and standardized approach for assessing overall evidence certainty for a systematic review outcome  and determining the strength of a guideline recommendation. The application of such rating systems—that value high internal validity  and consistency across effect estimates—to implementation questions, however, means that implementation research can rarely attain a status of “high certainty” evidence, often leading to recommendations that are not strong and, thus, may not be adopted. While this may reflect an overall weak evidence base, another possibility worth interrogating is that the guidance for implementation demands data with different priorities (even if principles are shared).Non-randomized studies—a critical component of HIV implementation research—are initially an assigned low value within GRADE, and unless effect estimates are large or show a dose-response gradient, the inclusion of observational research results in immediate downgrading of evidence certainty . For queMethodological, clinical, and statistical heterogeneity are frequently present in syntheses of implementation research. This frequently results in low evidence quality ratings for implementation research, which limits the ability to make strong implementation guideline recommendations to inform policy. Implementation questions must, however, be tested across heterogeneous settings—the adaptability of the strategy to different settings is what tests its robustness for scalability—and heterogeneity is to be expected ,43. GuidStrengthening the guidelines for the GRADE evidence certainty domain of “indirectness”  could improve the application of this domain for implementation questions ,44. GuidQuasi-experimental designs are increasingly being used to explore HIV implementation questions. However, they have little recognition in evidence hierarchies and there are few tools to guide incorporation into evidence synthesis –49. For There are few detailed methodological guidelines for incorporating the implementation outcomes of acceptability, appropriateness, and adoption into guideline development processes. The incorporation of values and preferences is a cornerstone of the WHO evidence to decision framework; however, specific guidelines for assessments of acceptability, appropriateness, or adoption of strategies for those who are expected to enact or receive the intervention are less clearly defined ,53. The This reflection identified several critical areas for improvement in implementation research evidence generation, synthesis, and guideline development . FirstlyThe alignment of methods for the production, synthesis, and dissemination is critical for improving the utility and impact of implementation research for the HIV response. International guideline recommendations are routinely based on combinations of expert opinion and research evidence . If synthesized evidence does not adequately reflect the breadth and depth of implementation efforts, this limits the capacity for guidelines to actually inform translation and real-world implementation efforts. Adapting current evidence generation and synthesis methods to answer efficacy, effectiveness, and implementation questions can support the production of guidelines that provide more comprehensive recommendations on what to implement, how to do it, and under what conditions.


The question of how acute stress might affect memory has applied value because witnesses, victims, and perpetrators often report experiencing stress or associated emotions  during a crime. They might also experience acute stress when they are interviewed by the police. It is therefore important that legal professionals and memory scientists, particularly those acting as expert witnesses, can rely on evidence-based knowledge concerning the acute effects of stress on memory.Very high levels of stress impair the accuracy of eyewitness testimony.” However, in their study, only 61% of these experts deemed the statement reliable enough to present in court  enhances memory for that event,” only 32% of eyewitness experts did, highlighting the lack of consensus even amongst memory experts.In their article, Pezdek and Reisberg noted that they “focused on myths of which the contrary evidence seems particularly clear” (p. 144) and that the evidence they provided showed that “these widely held beliefs are (at least) without basis and, in many cases, flatly false” (p. 143). Although research on stress and memory has been ongoing over several decades, evidence or consensus on this topic is not as clear-cut as suggested. In a recent survey of 73 memory experts, Marr et al.  showed tPezdek and Reisberg acknowledged the complexity of the stress-memory relationship by referring to a meta-analysis . Researchers should strive to ensure that stress is properly induced and verified by using objective measures wherever possible, alongside self-report measures (cf. Shields et al., To provide evidence against Myth #2, Pezdek and Reisberg cited findings from the eyewitness memory field suggesting that encoding stress impairs memory. However, this past work suffers from serious methodological limitations (Sauerland et al., Pezdek and Reisberg  also disor discounted without examining the surrounding context and keeping the findings from both the eyewitness and fundamental memory fields in mind.We conclude that the empirical research base to date does not allow for any strong conclusions about the effect of encoding stress on memory. Rather, whether acute stress impairs, enhances, or does not reliably affect memory performance is dependent on many moderators, most of which still need to be more thoroughly investigated in future research (Marr et al., Future research on this topic will provide a clearer understanding of the factors that critically contribute to the relationship between stress and memory and the direction of that relationship. In the meantime, however, it is important to acknowledge the existing shades of gray when discussing stress effects on memory, particularly in applied legal settings. That being said, certain sub-topics relevant to the stress-memory relationship in eyewitness settings do show greater expert consensus than others (e.g., those related to stress severity and detail type; Marr et al., CM drafted the commentary. All other authors provided critical feedback and contributed to the development and finalization of the commentary.


Sarcoidosis is a systemic inflammatory disease that can cause granulomatous infiltration of almost all organs and tissues which allows for a wide variety of presentations that may overlap with other disease processes. Renal sarcoidosis is a much rarer site of extrapulmonary involvement and may present as hypercalcemia, tubular or glomerular dysfunction, and/or granulomatous interstitial nephritis. Prompt diagnosis of sarcoidosis is crucial for initiating appropriate treatment and avoiding organ dysfunction.Herein, we describe a case of an armed forces service member who developed extrapulmonary sarcoidosis and renal sarcoidosis with acute complications refractory to glucocorticoids requiring adalimumab. The case highlights and emphasizes a rare manifestation of extrapulmonary sarcoidosis, the importance of avoiding premature closure of the differential diagnosis to avoid diagnostic delay and treatment imitation, and the unique clinical reasoning that occurs in active-duty personnel where diagnoses and subsequent treatments can have career implications and affect the ability of the service member to maintain the ability to deploy worldwide. Sarcoidosis is a chronic, systemic inflammatory disease of unknown etiology characterized by the abnormal development of noncaseating granulomas within organs and tissues . AfricanAny organ can be affected in sarcoidosis, and approximately 30%-50% of patients have extrapulmonary involvement . The pulImportantly, when systemic diseases such as sarcoidosis develop in an active-duty service member, it may have implications on the individual’s future military career and worldwide deployability which is essential to maintaining a medically ready and able force. Specific diagnoses and anticipated treatment courses may inhibit a service member from having full operational capabilities and maintaining military-based competencies, and thus, require medical separation from service. The case presented herein highlights the heterogenetic presentation of sarcoidosis as well as stresses the importance of avoiding premature closure of the differential diagnosis to avoid diagnostic delay. This case also gives insight into military medicine decision-making, as it is critical for meeting the overall military’s mission that service members are fully medically ready and capable of executing orders around the globe.A previously healthy 29-year-old African-American active-duty male presented to his primary care physician with the chief complaint of concern for high blood pressure as previous outpatient readings had been elevated. He denied experiencing headaches, visual changes, shortness of breath, chest pain, or lower extremity swelling and described eating a well-balanced nutritional diet and regularly participating in exercise. He reported an intentional weight loss of five pounds over the last six months and denied fatigue or decreased endurance. His past medical history was significant for sickle cell trait and right wrist pain secondary to a right scaphoid wrist nonunion fracture that occurred six months prior without an inciting event or trauma that was associated with significant intramedullary cystic changes, a large radiocarpal joint effusion, and loss of bony architecture on radiographs and magnetic resonance imaging (MRI) with and without contrast. He had undergone an anterior and posterior interosseous neurectomy with distal pole excision for this issue and was engaged in occupational therapy. His family history was significant for hypertension in his mother and maternal grandmother but denied any other family history. He denied alcohol use but reported daily e-cigarette/vaping use with nicotine. On physical examination, his vitals were within normal limits besides his blood pressure, which was 153/101 mmHg. He was in no acute distress with a regular heart rate and regular rhythm and his lungs were clear to auscultation. The rest of his examination was unremarkable. His initial laboratory evaluations ordered by the outpatient provider are listed in Table The patient was notified immediately of the critical lab values and was referred to the Emergency Department (ED) for further care. He had pancytopenia with mild neutropenia, hyponatremia, and hyperkalemia, renal injury of undetermined chronicity, hypercalcemia, a protein gap, elevated liver-associated enzymes (LAEs), and an elevated lactate dehydrogenase (LDH). In the ED, a computed tomography (CT) chest, abdomen, and pelvis without contrast was performed and showed multiple nodules throughout the lungs with more confluent opacities within the right middle and lower lobes as well as splenomegaly Figure . The patIn the context of his elevated ACE level, hypercalcemia, and renal injury with nephrotic-range proteinuria, there was a suspicion of an infiltrative process such as sarcoidosis. He then underwent a CT-guided lung core biopsy with pathology revealing non-caseating granulomatous inflammation with numerous multinucleated giant cells in a background of fibrosis consistent with sarcoidosis. Stains were negative for atypical mycobacteria and fungal infections. These results were supportive of a diagnosis of presumed sarcoidosis with lung involvement and apparent renal sarcoidosis that could explain the patient’s symptoms and laboratory findings. Given the patient’s nephrotic-range proteinuria, he was placed on an angiotensin II receptor blocker (ARB).Pneumocystis jirovecii pneumonia (PJP) prophylaxis with atovaquone and a proton pump inhibitor. He had follow-up appointments with Pulmonology, Rheumatology, and Nephrology. In his follow-up with Rheumatology, the patient was eventually placed on adalimumab subcutaneously due to intolerable side effects from corticosteroids  as well as lack of improvement with corticosteroids. Ultimately, the patient’s diagnoses and the requirement for long-term injectable medications classified him as indefinitely non-worldwide deployable, and he was ultimately medically separated from the military.Upon discharge, his calcium levels had improved, and serum creatinine improved to 2.6 mg/dL although the patient was still pancytopenic. The patient’s discharge labs are shown in Table Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomatous infiltration of tissues, and almost any organ can be affected . The vasThe case described herein is a rarer initial manifestation of sarcoidosis as the patient’s extrapulmonary manifestations were primarily renal and hematologic, rather than the more common manifestations of skin lesions, lymphadenopathy, arthritis, and uveitis. Hematologic abnormalities in sarcoidosis may be secondary to hypersplenism, bone marrow suppression, or destruction via autoimmune mechanisms . Renal sRecognizing and diagnosing sarcoidosis is difficult in the context of its wide range of clinical manifestations and ability to affect many organ systems. However, early recognition and prompt diagnosis allow for earlier treatment which may help prevent irreversible organ dysfunction and life-threatening complications. In our case, the clinical suspicion of a plasma cell dyscrasia or hematologic malignancy and the overlap of presentations led to an asynchronous evaluation, premature closure of the differential diagnosis, and ultimately a possible delay of diagnosis and treatment initiation for several days. For example, the patient may have received a CT-guided lung biopsy days earlier rather than waiting for the bone marrow biopsy to result. When a patient presents with an acute illness necessitating inpatient care and causing organ damage , it’s important to combat the clinical inertia of anchoring bias and to ensure the execution of clinical reasoning and a synchronous evaluation to prioritize differential diagnoses and to avoid diagnostic inaccuracies and delay of treatment. One could postulate that in the case described, a tissue or lung biopsy may have been considered earlier in the hospitalization course prompting glucocorticoid initiation, improvement of symptoms and organ dysfunction, and an earlier hospital discharge.Specific to military medicine, systemic diseases such as sarcoidosis and their respective treatments in an active-duty service member may have implications on the service member’s ability to execute the worldwide deployability required of a military member. For example, active-duty service members can be deployed to very remote, austere environments worldwide which cannot support the proper storage or administration of certain medications or may increase the risk of complications and death given the lack of easily accessible medical capabilities. This is critical to know as a civilian physician, as many of our service members receive their care in the civilian sector, as it may change education and counseling performed to the patient on occupational expectations and could change treatment options. Frequently this comes into play for individuals who require intravenously administered or injectable medications, as austere environments cannot reliably administer or store these medications. For example, our patient required adalimumab which was not compatible with the ability to deploy on a moment’s notice. As such, certain disease processes and required treatments thereafter may require medical separation from the military of a service member to maintain a worldwide deployable force and to avoid an increased risk to service members based on occupational requirements.In conclusion, this case report highlights unique and rare manifestations of sarcoidosis and the importance of avoiding anchoring bias and prematurely closing the differential diagnosis to avoid diagnostic error and to expedite the correct management in a patient. Sarcoidosis presentations may overlap with many other disease processes and should be kept on the differential until definitively ruled out. Additionally, this case provides insight into the clinical decision-making in military medicine in evaluating a patient for continued service in the armed forces in the context of their specific disease process and treatments required to maintain a medically ready and worldwide deployable force.


MLH1, MSH2, PMS2, MSH6) or the EPCAM gene. It is estimated to affect 1 in 300 individuals and confers a lifetime risk of cancer of 10-90%, depending on the specific variant and type of cancer. Lynch syndrome is the most common cause of inherited colorectal cancer, but for women, endometrial cancer is more likely to be the sentinel cancer. There is also evidence that certain PVs causing Lynch syndrome confer an increased risk of ovarian cancer, while the risk of ovarian cancer in others is not well defined. Given this, it is essential for the practicing gynecologist and gynecologic oncologist to remain up to date on the latest techniques in identification and diagnosis of individuals with Lynch syndrome as well as evidence-based screening and risk reduction recommendations for those impacted. Furthermore, as the landscape of gynecologic cancer treatment shifts towards treatment based on molecular classification of tumors, knowledge of targeted therapies well-suited for mismatch repair deficient Lynch tumors will be crucial. The objective of this review is to highlight recent updates in the literature regarding identification and management of individuals with Lynch syndrome as it pertains to endometrial and ovarian cancers to allow gynecologic providers the opportunity to both prevent and identify Lynch-associated cancers earlier, thereby reducing the morbidity and mortality of the syndrome.Lynch syndrome is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants (PVs) in DNA mismatch repair genes ( The lifetime risk of developing cancer among those with Lynch syndrome is highly variable, ranging from 10-90%, and is now understood to be related to the specific pathogenic variant (PV) causing the disorder in an individual or family  having 3 relatives with any Lynch-associated cancer with 1 being the first degree relative of the other 2, 2) there are 2 successive generations are affected, and 3) 1 is diagnosed before the age of 50 . The senClinical prediction models were developed to improve the detection of individuals with Lynch syndrome compared to methods based primarily on family history such as the Amsterdam II Criteria and Revised Bethesda Criteria. Their strength is that they screen for Lynch syndrome prior to a person being diagnosed with cancer. Several models have been created, such as MMRpredict, MMRpro, and PREMM5 –28. EachMLH1 hypermethylation testing depending on the pattern of loss of expression visualized to determine whether the loss of expression is sporadic or a result of a germline PV. An adjunct or lesser alternative to IHC staining is tumor-based MSI testing  . IHC sta testing . MSI tes testing . MSI-H tBRCA mutations and other molecular features that may influence treatment decisions  recommends single gene testing if there is a known PV within a person’s family and if they are clinically low-risk for other PVs . MultigeInterpretation of genetic testing results is key to counselingTable 3 Once an individual is diagnosed with Lynch syndrome, they should be counseled regarding both their personal risk of cancer and also their family’s potential risk. This should include a conversation regarding cascade testing, which involves genetic testing of a known carrier’s relatives to determine whether these family members are affected, and thus also at increased risk. Cascade testing is recommended to begin with first-degree relatives, as these individuals have a 50% chance of having the same Lynch syndrome PV, and if positive, expand cascade testing to their first-degree relatives .in vitro fertilization (IVF), and involves testing an embryo in the lab for a specific PV to reduce the risk of passing this PV on to future children. For Lynch syndrome, this would mean testing the embryos of a Lynch syndrome carrier and their partner for the specific MMR PV the carrier is known to have. Identifying which embryos carry this PV allows the REI specialist to inform the parents undergoing IVF and selectively transfer embryos that are not carriers, thus preventing a future child from being affected by Lynch syndrome. It is important to address the timing of IVF if the Lynch syndrome carrier is female, as it may be affected by the recommended timing of risk-reducing hysterectomy to prevent endometrial cancer or risk-reducing oophorectomy to prevent ovarian cancer, as is discussed in the next section  specialist to discuss preimplantation genetic testing (PGT). This diagnostic test is used in conjunction with  section .3Once a diagnosis of Lynch syndrome is established, it is recommended to begin the process of screening for early development of Lynch-associated cancers and in some instances undergo risk-reducing procedures or initiate chemoprevention under the care of physicians with expertise in the management of high-risk carriers. While screening and risk reduction methods exist for other Lynch-associated cancers, colonoscopy screening for colorectal cancer being at the forefront, this review will focus on those measures targeted towards the screening and prevention of endometrial and ovarian cancers in those with Lynch syndrome.3.1Multiple approaches to screening for endometrial cancer in asymptomatic women diagnosed with Lynch syndrome have been proposed, including endometrial biopsy and transvaginal ultrasound (TVUS). Importantly, none of these methods have been shown to reduce the morbidity and mortality of women with Lynch syndrome –56. ThisTVUS is less invasive than endometrial biopsy, however, it offers lower detection rates and it is not recommended in premenopausal females since endometrial thickness varies greatly throughout a menstrual cycle , 54. A fvia pap smear for endometrial and ovarian cancer patients in comparison to cancer-free controls found a specificity of 99%, though it was limited by modest sensitivity   –66. EachFor women diagnosed with Lynch syndrome who present with symptoms, including but not limited to abnormal bleeding, pelvic mass or pain, abnormal discharge, or weight loss, women’s health providers should have high suspicion for endometrial cancer and investigation in the form of endometrial biopsy and/or transvaginal ultrasound should be performed.Risk reduction of endometrial cancer is another aspect of management of which providers and women with Lynch syndrome need to be aware Table 4.Lifestyle and medical chemoprevention options should also be discussed with individuals with Lynch syndrome. In accordance with general population recommendations, those with Lynch syndrome should be counselled to maintain or attain a normal body weight given the well-defined association of obesity with the development of endometrial cancer. They should also be counselled to engage in 30 minutes of exercise daily or 150-300 minutes of moderate intensity exercise weekly exercise per American Cancer Society (ACS) guidelines .As for medical chemoprevention, there is evidence that daily aspirin may be associated with a reduction in all Lynch-associated cancer diagnoses in those with Lynch syndrome . The CAPHormonal therapies, including combined oral contraceptive pills (OCPS), oral progestins, or progesterone containing intrauterine devices (IUDs), are an alternative form of risk-reduction for those with Lynch syndrome prior to completion of childbearing and risk-reducing hysterectomy. Data for endometrial cancer prevention with hormonal therapies in the Lynch population specifically are limited and the majority of evidence is extrapolated from studies in the general population –73. Popu3.2As with endometrial cancer, multiple screening methods for the early detection of ovarian cancer have been proposed for asymptomatic women with Lynch syndrome, though no evidence exists supporting an improvement in morbidity or mortality for any method , 56. AnnAny female with Lynch syndrome presenting with bloating, a palpable mass, abdominal pain, weight gain or loss, early satiety, or other concerning symptoms should undergo imaging to determine if ovarian cancer is present.MSH6 and PMS2, where there is no strong recommendation for oophorectomy based on current available evidence. It should be noted throughout the discussion that regardless of the recommendation for bilateral oophorectomy, bilateral salpingectomy is recommended at the time of risk reducing hysterectomy  is an option for women with Lynch syndrome, though again, there are no studies in the Lynch syndrome population. Studies in the general or BRCA populations do suggest a benefit in ovarian cancer prevention with the use of COCPs, but again, Lynch-associated ovarian cancer is fundamentally different than BRCA-associated ovarian cancer, thus it is not clear whether a true benefit exists in the Lynch syndrome population , 94–97. An exciting intervention that may be on the horizon for cancer prevention in carriers of Lynch syndrome is that of cancer vaccines. These investigational vaccines are developed against neoantigens produced by frameshift mutations in those with MSI-H tumors and Lynch syndrome . There a4via PD-1 blockade than tumors without these features, there is now evidence that patients with Lynch-associated tumors may benefit from alternative treatment plans (All treatment options that are available to those with sporadic endometrial and ovarian cancers are also available to those with Lynch-associated endometrial and ovarian cancers, and prior to molecular analysis of tumors, treatment recommendations were the same regardless of Lynch status. Since the relatively recent discovery that MMR deficient and MSI-H tumors, the key characteristics of Lynch tumors, may be more susceptible to immunotherapy that functions nt plans . It is wnt plans .Whether initial adjuvant therapy for endometrial cancer should be dictated by MMR deficiency is controversial based on available evidence. A retrospective study comparing outcomes between MMR deficient endometrial tumors and MMR proficient endometrial tumors following adjuvant therapy with either radiation or chemotherapy revealed a trend toward lower recurrence rates among patients with MMR deficiency, but on multivariate analysis, there was no association with progression-free or overall survival . HoweverRegarding radiation therapy in those with Lynch-associated endometrial cancer, one should also consider the possibility of second primary malignancies after radiation treatment. While evidence is unavailable for an increased risk of second primaries attributable to radiation treatment for endometrial cancer specifically in a Lynch population, there is some evidence of increased risk for second primary malignancies after radiation for endometrial cancer in the general population . Other sin vitro studies that called into question whether platinum resistance is associated with MMR deficiency (Evidence regarding initial adjuvant therapy in MMR-deficient ovarian cancers is also conflicting. One retrospective study found similar survival rates between MMR-deficient and MMR-proficient ovarian cancers, thus recommended treating them similarly . Some stficiency , 113. AtWhile studies are inconclusive regarding MMR deficiency and its influence on upfront therapy, recent evidence in favor of immunotherapy for recurrent or progressive MMR-deficient endometrial and ovarian cancers has emerged. The theory behind immunotherapy is to utilize the body’s own immune system to attack tumor cells, and this branch of treatment has been shown to be effective in multiple types of cancer. In fact, pembrolizumab, a monoclonal antibody that inhibits T-cell apoptosis by blocking the PD-1 receptor on these immune cells, is FDA approved for all non-colorectal, MSI-H and MMR deficient tumors, regardless of tumor site, and it the first therapy to receive accelerated approval for a tumor-agnostic indication . In gyneWhether immunotherapy will be of use for upfront treatment of Lynch-associated endometrial or ovarian cancers is under investigation. Not only will the MMRd-GREEN Trial shed light on this, there is also the IMHOTEP trial, which is currently underway investigating pembrolizumab as neoadjuvant therapy prior to surgical resection of MSI-H and MMR-deficient tumors of multiple sites . The use5While much has been discovered about our understanding of cancer risk and our ability to reduce risk for those with Lynch syndrome, there remains a great deal to be discovered to diminish its associated morbidity and mortality. Improvements in technology are needed to increase identification of individuals at high risk for Lynch syndrome, not only by utilizing high quality screening tests, but also for increased patient access to these tools and for reduction in costs to allow more universal testing. The same is true for screening for Lynch-associated cancers in patients diagnosed with Lynch syndrome, especially given that endometrial cancer and ovarian cancer screening has not yet been shown to have a mortality benefit. Identifying barriers and improving access to risk reduction measures is another future direction in the study of Lynch syndrome, and perhaps the greatest frontier is determining whether Lynch-associated endometrial and ovarian tumors should be treated differently than sporadic endometrial and ovarian tumors. Dedication to these efforts will bring about the implementation of important practice changes and hopefully afford us the mortality benefit in the management of Lynch-associated endometrial and ovarian cancers we have been seeking.KU was involved in concept development, writing, and editing. KR was involved in concept development, writing, and editing. All authors contributed to the article and approved the submitted version.


Idiopathic inflammatory myopathies (IIMs) are a group of acquired muscle diseases with muscle inflammation, weakness, and other extra-muscular manifestations. IIMs can significantly impact the quality of life, and management of IIMs often requires a multi-disciplinary approach. Imaging biomarkers have become an integral part of the management of IIMs. Magnetic resonance imaging (MRI), muscle ultrasound, electrical impedance myography (EIM), and positron emission tomography (PET) are the most widely used imaging technologies in IIMs. They can help make the diagnosis and assess the burden of muscle damage and treatment response. MRI is the most widely used imaging biomarker of IIMs and can assess a large volume of muscle tissue but is limited by availability and cost. Muscle ultrasound and EIM are easy to administer and can even be performed in the clinical setting, but they need further validation. These technologies may complement muscle strength testing and laboratory studies and provide an objective assessment of muscle health in IIMs. Furthermore, this is a rapidly progressing field, and new advances are going to equip care providers with a better objective assessment of IIMS and eventually improve patient management. This review discusses the current state and future direction of imaging biomarkers in IIMs. Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of acquired muscle diseases characterized by muscle inflammation, weakness, and other extra-muscular manifestations –4. ClassDisease severity of IIMs can vary, and patient quality of life can be significantly impaired , 2. The A PubMed search was done for the terms “myositis and biomarkers,” “MRI and myositis,” “electrical impedance myography and myositis,” and “ultrasound and myositis” for all English language literature until 14 February 2023. Overall, this resulted in a total of 2,672 results which were then screened by AZ for applicability to this topic. This resulted in 199 publications that were reviewed for this study .Magnetic resonance imaging (MRI) has been used to assess muscle involvement in myositis for over three decades , and it Normal, healthy muscle generates an intermediate signal intensity, slightly higher than water and much lower than fat using T1 weighted image sequences. On the contrary, T2-weighted sequences generate a much lower signal for healthy muscle in comparison to fat and water , 12. WitMRI captures a wide area of muscle and provides more detailed information than computed tomography and muscle ultrasound. Moreover, it can identify changes in the deep muscles which can be particularly challenging with muscle ultrasound and electromyography. Thus, MRI is particularly helpful for the identification of muscle involvement patterns that can be used to distinguish between IIMs and myopathies in general.In myositis, there is muscle edema in the early stage of active muscle disease and muscle atrophy and fatty replacement in the later stages of muscle damage which alters the normal MRI signal of muscles. However, in some cases, both can co-exist , 17. TheThe pattern of muscle involvement can be helpful to distinguish between IIMs –27. In PPatients with IMNM often have severe lower limb muscle edema with fatty replacement and atrophy, and pelvic muscles and adductors are usually more affected than patients with DM . PatientApart from the standard T1 and T2 (or STIR), other MRI sequences also can provide valuable information on muscle health in myositis. Diffusion-weighted imaging (DWI) measures the mobility of free water in the living tissue; areas of increased free water content result in increased diffusivity, and apparent diffusion coefficient (ADC), an index of diffusivity, is higher in these regions and can identify muscle edema that is comparable to STIR . ApparenMuscle edema and fat deposition are not unique to IIM and can be seen in denervation changes (including disorders of the motor neurons), neoplasm, infection, and muscle injury , 39–44. Diffusion tensor imaging (DTI) evaluates the anisotropic diffusion of water molecules which can help characterize physiological and microstructural properties of skeletal muscles and architectural organization –49. DM pThe problem of long scanning times is not limited to DTI imaging but also applies to traditional MRI T2 sequences which can take up to 30 min per thigh , 53. A nQualitative assessment of muscles can identify a specific pattern and can help in diagnosis but is subjected to individual biases and may not accurately represent disease progression and treatment response. There has been an unmet need for a more objective measure of muscle damage in IIMs , 59.Semi-quantitative methods use visual assessment by an evaluator who assigns a numerical grade on an ordinal scale. The Mercuri scale, a commonly used semi-quantitative grading score scale, grades muscle images between 0 and 4  and was created to mitigate this problem to some extent –62. ThisQuantitative MRI has the potential to be a useful biomarker in clinical practice and in the context of clinical trials . They alComputer-based analysis of pixel intensity values is a commonly employed quantitative muscle MRI technique . QuantitA 3-Point-Dixon MRI fat-water imaging quantifies tissue fat content on a 0%−100% fat-fraction (FF) scale and has been previously used in neuromuscular diseases  64–67).–67.64–67T2 relaxation time has been referenced as a more objective marker to assess muscle disease. T2 relaxation is sensitive to changes in water distribution and lipid content, and it is an objective marker of muscle health. However, fat replacement in advanced IIM can confound the interpretation of muscle T2 values and published T2 values for fat vary significantly –76. CombQuantification of muscle metabolism by measuring pH and high-energy phosphate metabolites  by phosphorus-31 magnetic resonance spectroscopy (P-MRS) can identify metabolic abnormalities in DM, juvenile dermatomyositis (JDM), and also treatment response , 80, 81.Magnetic resonance elastography (MRE) can provide an assessment of muscle stiffness based on the propagation of shear waves , 86. In Whole-body MRI is useful to capture distal and patchy disease activity that was not appreciated clinically and would have been missed by dedicated regional imaging . It is bOnly limited classification criteria have incorporated MRI as a variable in the classification of IIM . AdditioWhile MRI is a very useful imaging biomarker of IIM, it has some limitations . First, Ultrasound imaging of the muscle tissue is becoming an important tool in neuromuscular medicine given its non-invasive nature, ease of use, and improved resolution for soft tissue structures –107. UltDifferent IIMs have typical but non-specific ultrasound features , 117. InIBM has been studied with quantitative muscle ultrasound. Affected muscles show an increased echogenicity on the ultrasound image which indicates the replacement of muscle with fat and fibrosis –123. IBMUltrasound has also been used to assess diaphragm thickness in myositis and allows for the assessment of anatomy and function . RespiraMusculoskeletal power Doppler ultrasonography (PDUS) has been used to diagnose and measure vascularity in inflammatory disorders. PDUS allows simultaneous assessment of disease activity at more sites than contrast-enhanced MRI . A PDUS Shear wave elastography (SWE) is an ultrasound-based technique that has been studied in tendinopathy, muscle spasticity, and Duchenne muscular dystrophy –135. SWEMachine learning has been studied on ultrasound in patients with myositis; one study showed that the deep learning approach performed better than conventional machine learning and required no user intervention . Newer mOne additional utility is the use of ultrasound to conduct guided biopsies. Ultrasound can provide images in real time as well as identify abnormal muscle morphology, making it well-suited to target muscle biopsies with improved tissue diagnostic yield. A disadvantage of using ultrasound-guided needle muscle biopsy can be under-sampling when compared to an open biopsy resulting in an inadequate amount of specimens or non-diagnostic tissues.The are several advantages to muscle ultrasound. It can be performed quickly at the patient bedside and does not require prolonged maintenance of a posture. It is less expensive than muscle MRI. However, despite its convenience and portability, it cannot replace MRI in assessing disease activity in the IIMs at the present state. Part of the issue with ultrasound is that it is limited in its ability to identify edema in comparison to other modalities , 141 Ta.Electrical impedance myography (EIM) is a non-invasive technique that uses subthreshold electrical current to measure the obstruction to current flow . It invoAn animal study of intra-muscular EIM to assess muscle inflammation showed that changes in low-frequency EIM parameters are sensitive to the presence of inflammatory infiltrates and have the potential to serve as a simple means of quantifying the presence and extent of inflammation without the need for biopsy . In faciEIM provides information on muscle health but does not provide information on patient's function and statistical significance does not always clearly translate to clinical significance. EIM has not been used as the sole primary outcome measure in clinical trials but has been used as an exploratory outcome measure in a natural history study of SMA , 155. EI18F)-labeled fluorodeoxyglucose positron emission tomography (FDG PET) is generally used for detecting malignancies; however, FDG also accumulates in inflammatory lesions where glucose-consuming inflammatory cells infiltrate. There have been a few studies looking into the utility of FDG PET in myositis (Fluorine-18 (myositis . A studymyositis . Anothermyositis . A follomyositis .11C]PIB) and [18F] florbetapir. Lilleker et al.  has been investigated as a diagnostic tool for IBM and differentiates it from other IIMs such as PM –162. Ther et al.  performe studies , 162.In patients with DM, FDG PET is also used to screen for malignancy . Thus, iOver the course of the last few years, there have been significant imaging advances which have allowed improved diagnosis as well as better monitoring of treatment response in IIMs. These imaging techniques complement currently available outcome measures and may play a critically important role in future clinical trials.MRI is the most studied imaging technology in IIMs. It may be used to support a clinically suspected diagnosis when other standard measures are not helpful. Once validated, it can possibly be used longitudinally to assess disease activity and muscle damage more rigorously. While initially only the T1 and T2 weighted sequences were used for assessment, more recent advances have allowed for the development of newer sequences that provide additional information, and there is potential to capture the early stages of myositis prior to the development of lab abnormalities. MRI is sensitive in showing muscle edema and active myositis , 17, 28.Arguments against the use of MR imaging include the fact that it is expensive, may take a long time to complete, and requires prolonged immobility in potentially uncomfortable positions. Over the past few decades, the cost of obtaining MR imaging has decreased significantly, and the availability of MR is more widespread. Additionally, new techniques are offering faster imaging while preserving quality. However, at the present state, MRI may not be sufficient enough to make a diagnosis of IIM. While MRI captures muscle pathology, particularly muscle edema and fat infiltration, as mentioned earlier, none of these changes are specific for muscle inflammation, and similar findings can also be seen in some muscular dystrophies and hereditary myopathies such as Pompe disease –167. TodAnother tool that is becoming an important part of the myositis specialist arsenal is muscle ultrasound . NeuromuMany other technologies, including EIM and PET, have shown promise in the imaging of muscle tissues, and studies are ongoing. Eventually, some of these new technologies will be integrated into the management and tracking of patients with IIMs after further validation as disease biomarkers. We believe that these imaging modalities may result in a paradigm shift in future in the diagnosis and management of the IIMs. Optimized imaging technologies may add another dimension to the tracking of treatment response during the treatment of IIMs. The use of these new technologies may lead to the design of more efficient screening clinical trials with smaller sample sizes and shorter duration which will be invaluable for the treatment of rare diseases like the IIMs.MRI is the most widely studied imaging technology in IIM, and despite its limitation, it has major advantages over US or EIM . Only liThere have been significant advances in imaging technologies in the past two decades that have impacted the clinical practice and management of patients with IIMs. These evolving technologies have the potential to provide an objective assessment of muscle health once their utility is confirmed in large-scale prospective studies. Eventually, we anticipate that these technologies will be incorporated into a validated paraclinical assessment system that allows for more sensitive tracking of disease activity and treatment response to therapeutic interventions both in the clinic and in the context of therapeutic clinical studies.AZ reviewed all the abstracts from the initial search results and identified the articles. SS provided some of the imaging used in these manuscripts and contributed to the MRI section of the manuscript writing. MD critically reviewed this manuscript and also updated several sections of the manuscript and developed the table used in this manuscript. BR designed and developed the original draft along with AZ. PM critically reviewed the manuscript and added some sections on MRI imaging and updated the manuscript as needed. All authors contributed to the article and approved the submitted version.


Editorial on the Research TopicControversies in neonatal hypoglycemiaThe conundrum of how to manage neonatal hypoglycemia continues to be plagued by multiple controversies, including its definition, whether current screening guidelines fulfill the criteria for being good screening tests, what tools should be used to measure and monitor glucose concentrations, and whether early feeding or milk composition influences glucose homeostasis. Moreover the conflation of data from a huge diversity of infants from healthy term newborns to those with variable risk factors makes interpretation of data into useful guidance for clinical practice challenging.Robust evidence that asymptomatic transitional neonatal hypoglycemia negatively impacts neurodevelopment and whether its treatment improves outcomes is lacking. Based on these concerns, international organizations provided “eminence-based” recommendations regarding screening and management, but because of perceived too liberal or conservative treatment thresholds recommended, many institutions have developed their own guidelines. Thus, since the 1950–60s when clinical manifestations were first clearly associated with severe neonatal hypoglycemia    and Pedics (AAP)  based thIbrahim et al. developed a risk scoring algorithm to determine whether intravenous dextrose was required for resolution of hypoglycemia in hypoglycemic infants of gestational diabetic mothers. This retrospective single center study identified a hypoglycemic risk score at 1 h of age. They found that a high risk score significantly predicted the need for parenteral dextrose, and concluded that early identification of newborns who do and do not require intravenous dextrose for resolution of hypoglycemia will be helpful in triaging them to either remain with their mothers or to be transferred to units with higher levels of care.Risk scoring algorithms are used in clinical medicine to assess the likelihood of developing a particular outcome, such as death, need for hospitalization, or a disease, using demographic variables, signs and symptoms, and other clinically relevant factors. intermittent blood glucose sampling. But is its use currently “ready for prime time” in the clinical care of newborns at risk of hypoglycemia? Kalogeropoulou et al. reviewed continuous glucose monitoring use in premature and term newborns, and highlighted its potential advantages, but also noted important shortcomings that limit its use at the bedside. It was not designed nor has it been approved for use in newborns, and lacks accuracy at the lower glucose concentrations common in hypoglycemic newborns. It detects clinically silent neonatal hypoglycemia, however, in follow-up studies, silent hypoglycemia has not been linked with adverse academic performance (Continuous glucose monitoring is a promising technology that may eventually supplant formance . While cHarris et al. from GLOW Study participants (The relationship between feeding and changes in glucose concentrations was evaluated by icipants . Contraricipants  regardinStanley et al. This review makes a robust case that most forms of neonatal hypoglycemia, including transitional hypoglycemia, are due to hyperinsulinism. They show that rat newborn pancreatic beta-cell islets have lower glucose-stimulated insulin secretion than older infants and children, which is due to delayed trafficking of KATP channels from the cytosol to the cell membrane, or to genetic abnormalities in the channel itself, thereby leading to unremitting insulin secretion and hypoglycemia. Finally, they recommend screening for pathological hypoglycemia by measuring both glucose and ketone concentrations to identify infants with persistent hyperinsulinemic hypoglycemia before brain injury occurs.New approaches to screening and management of neonatal hypoglycemia based on improved understanding of molecular mechanisms of hypoglycemia was published by This collection of manuscripts highlights some of the persisting controversies surrounding neonatal hypoglycemia, including that school age academic performance and long-term neurodevelopment is not different between transiently asymptomatic hypoglycemic newborns and non-hypoglycemic at-risk newborns , and tre


Great efforts are focused on the development of safe nano-carriers for the treatment of cancer in order to overcome some of the typical limitations of conventional therapies. The present Special Issue collects various interesting contributions addressing the use of active nanoparticles. The biocompatibility, low toxicity and high therapeutic efficiency of hydroxyapatite (HAp) and carbonate apatite have justified their use as nano-carriers for drug delivery. A good example is the evaluation of goose bone ash (GBA) as a pH-responsive carrier for the delivery of doxorubicin (DOX) into breast cancer cells . A prompSome new therapies are based on the fact that cancer cells are strongly anabolic and require a great amount of energy to survive and proliferate. Thus, molecules able to interfere with mitochondrial biogenesis appear especially interesting. The inhibitory effect of antibiotics against bacteria can also lead to negative effects on mitochondrial protein synthesis . This feCockle-shell-derived aragonite calcium carbonate nanoparticles (ACNP) have also been evaluated as promising targeting carriers against cancer cells . pH-sensThe efficacy of targeted drugs is impaired by their difficulty to penetrate deep into tumour tissues . Thus, cThe pharmacological activity of nanocomposites can be improved through a deep knowledge of the cellular uptake and particle localization. The use of fluorescein isothiocyanate (FITC)-conjugated nanocomposites is interesting to identify the accumulation of particles in the cells using TEM since the success of a given treatment can be visualized. Specifically, graphene oxide–polyethylene glycol nanocarriers were loaded with protocatechuic acid as an anticancer drug, tagged with folic acid for cancer cells targeting and finally conjugated with FITC . DiagnosNanoparticles can be efficiently designed to provide hyperthermia and local tumour ablation with the help of a controllable heat mediator that minimizes the adverse effects on surrounding healthy tissues . Novel t3O4 has superparamagnetic properties which can be beneficial in the use of targeted therapies. Specifically, nanoparticles incorporating magnetic Fe3O4 can be directed to tumours using a magnetic field. Therefore, efforts are focused on improving the performance of such particles. A recent example is the green preparation of systems based on a montmorillonite matrix loaded with Fe3O4 nanoparticles. Carrageenan and protocatechuic acid were also incorporated acid as stabilizer and anticancer drug, respectively [Feectively . This naAlthough research on the development and clinical applications of magnetic nanoparticles mainly concerns particles with a spherical shape, it must be considered that both magnetic behaviour and biological activity can be improved by using anisotropic nanoparticles. Magnetic drug delivery, hyperthermia and resonance imaging, among other properties, are thus dependent on the particle shape, as recently been reviewed . The unique properties of carbon nanotubes can be considered to produce nanocarriers for both drug delivery  and cancPolymeric micelles have received great attention as drug delivery systems due to their biocompatibility and structural stability. Nevertheless, low drug entrapment efficiency is a great challenge. Some efforts have been focused on obtaining supramolecular micelles with hydrogen bonding motifs that are able to promote a fast self-assembly of polymeric chains to increase the affinity for selected drugs . For exaStatins are cholesterol-reducing agents, which, among other effects, seem to reduce the risk of liver cancer ,24. A prThe highly branched architecture of dendrimers appears appropriate to develop nanocarriers due to the high number of terminal groups on their surface. Thus, they appear appropriate to bind metals with anti-cancer properties . RutheniThe high resistance of cancer stem cells to conventional therapies impedes the eradication of cancer. Novel therapies are being developed to obtain a more effective reduction of metastasis and cancer recurrence . Gold naCisplatin (Cispt) is probably the most active agent against bladder cancer, since is able to form DNA adducts that lead to cell apoptosis . AdvantaA personalized cancer treatment requires the use of ultrasensitive techniques to perform an early diagnosis. Techniques based on the use of plasmonic nanoparticles offers some advantages as a real alternative or complement to the most conventional techniques. Thus, biomarkers like specific peptides and proteins, microRNA, circulating tumour DNA and cells and exosomes can be well detected and quantified. The potential and versatility of plasmonics are revealed through the use of multiple analysis techniques like Raman scattering spectroscopy, surface plasmon spectroscopy, mass spectroscopy, dynamic light scattering spectroscopy, colorimetry and fluorescence microscopy, as has recently been reviewed .


The water deficit experienced by crops is a function of atmospheric water demand (vapor pressure deficit) and soil water supply over the whole crop cycle. We summarize typical transpiration response patterns to soil and atmospheric drying and the sensitivity to plant hydraulic traits. We explain the transpiration response patterns using a soil–plant hydraulic framework. In both cases of drying, stomatal closure is triggered by limitations in soil–plant hydraulic conductance. However, traits impacting the transpiration response differ between the two drying processes and act at different time scales. A low plant hydraulic conductance triggers an earlier restriction in transpiration during increasing vapor pressure deficit. During soil drying, the impact of the plant hydraulic conductance is less obvious. It is rather a decrease in the belowground hydraulic conductance (related to soil hydraulic properties and root length density) that is involved in transpiration down-regulation. The transpiration response to increasing vapor pressure deficit has a daily time scale. In the case of soil drying, it acts on a seasonal scale. Varieties that are conservative in water use on a daily scale may not be conservative over longer time scales (e.g. during soil drying). This potential independence of strategies needs to be considered in environment-specific breeding for yield-based drought tolerance. A review explaining the link between soil–plant hydraulics and water use regulation during soil and atmospheric drying. The resIn combination with more variable rainfall patterns and depending on soil hydraulic properties, the enhanced atmospheric water demand may further lead to more frequent and severe limitations in soil water availability, which is the second main driver of plant water deficit.From a plant’s perspective, water deficit occurs when water availability cannot match plant water demand for growth and transpiration at a particular time . In ligh−1) is driven by VPD relative to atmospheric pressure  and depends on leaf area . Additionally, on a short time scale, transpiration regulation is related to the stomatal conductance to water vapor  of the leaves and can be expressed as . The flow is proportional to the differences in water potentials and the hydraulic conductance of the components of the SPAC , 1972. RTwo main groups of mechanisms have been demonstrated to be involved in stomatal regulation: firstly, metabolic mechanisms that operate through the production of hormones, including abscisic acid ABA; . Such phSecondly, a passive mechanism of stomatal closure induced by the hydraulic connection between epidermal cells and guard cells was demonstrated (Ksp (mg s−1 kPa−1) is the soil–plant hydraulic conductance, Tr (mg s−1) is the transpiration rate, and ψsoil (kPa) and ψleaf (kPa) are the soil matric and leaf water potential, respectively. The physiological mechanism by which plants can sense a change in hydraulic conductance, and not simply a change in water status , is not clear. Ksp and stomatal conductance  that limiting Tr at high VPD may, on the one hand, lead to a yield increase in drought-prone environments, potentially due to soil water conservation early in the growing period  as a function of the water supply and demand under varying environmental conditions. We use a quantitative hydraulic framework that can theoretically simulate the transpiration rate response to both environmental drivers of drought by linking the observation that stomatal closure is associated with a decrease in leaf water potential to soil–plant hydraulics, in order to explain the observed data. The goal of this review is to identify plant hydraulic traits that impact water use regulation, in the context of improving yield in water limited environments for varying atmospheric and edaphic conditions, rather than to discuss physiological mechanisms of stomatal closure.BP, kPa, blue curves, BP can vary considerably between genotypes (BP. Less responsive genotypes transpire linearly until comparatively dry atmospheric conditions (high or no VPDBP within the tested range of VPD).A large number of studies characterizing the diversity of the transpiration rate response to increasing VPD have been reported in many crop species . Typicalenotypes . VPD-sensoil or hsoil, hPa or cm). Alternatively, the soil moisture level is expressed as the fraction of transpirable soil water (FTSW), defined as the percentage of the range of max. and min. soil/pot water holding capacity  is the pot weight of each day over the experimental period, PWfinal (g) is the pot weight by the end of the dry-down experiment, typically when the normalized transpiration ratio  reaches 0.1, and PWinitial (g) is the pot weight at the beginning of the experiment when the soil is expected to be at maximum water holding capacity. The advantage of this expression is that it enables the comparison of plants grown in various soil textures with differing max. and min. soil moisture ranges.where FTSWTn, g) firstly, by dividing it by the daily average transpiration rate of the control pots per genotype in well-watered conditions :Similarly, the transpiration rate is usually normalized to minimize the interference of day-to-day variations in environmental conditions  and to be able to compare different-sized plants. This is done either by normalizing the transpiration rate by leaf area (e.g. n) by the initial average transpiration ratio  for each pot over the time when the respective pot was still in well-watered conditions (and secondly by dividing the resulting daily transpiration ratio (TRBP), upon which the transpiration rate decreases almost linearly during further soil drying. Significant intra-specific variability exists in this value  Merr), they found that a comparatively low plant hydraulic conductance was associated with a restricted transpiration rate. They proposed the limiting hydraulic conductance to be located between the xylem and the guard cells, specifically in the symplastic water pathway, potentially involving transmembrane water channels  and maize (Zea mays L. saccharata), respectively. and roots in maize (Zea mays L.). Similarly, Triticum aestivum L.). They used different AQP inhibitors that were fed to de-rooted and intact plants. De-rooted plants did not show differences in VPD response or variations in transpiration sensitivity to AQP inhibitors between genotypes, contrary to intact plants. Moreover, genotypes differed in root hydraulic conductance when pressurizing the whole root system. Triticum durum Desf.), by Pennisetum glaucum (L.) R.Br.), and by Cicer arietinum L.), for example. The suggested link between metaxylem vessel size and VPD responsiveness is in line with the results of Kplant, cm3 s−1 MPa−1). The model calculates the leaf water potentials based on transpiration rate, soil matric potential, and the hydraulic conductances of the components of the SPAC  to leaf water potential ratio. The simulation predicts that plants with a lower Kplant are more sensitive to increasing VPD  hydraulic conductance causes a more negative leaf water potential to sustain a given transpiration rate and it triggers stomatal closure.Hence, experimental evidence suggests that differences between genotypes in the transpiration rate response to increasing VPD are controlled by plant hydraulic conductance . We usedTaken together, growing experimental evidence concordantly indicates that plant traits and ecophysiological mechanisms that potentially modify the plant hydraulic conductance impact the transpiration rate response to increasing VPD. Such mechanisms include the abundance and activity of AQP in leaves ; leaf arCompared with the transpiration rate response to increasing VPD, much less is known about the underlying mechanisms and plant hydraulic properties impacting the transpiration rate response to progressive soil drying. Evidence from To understand the transpiration rate response to soil drying, relating transpiration rate to soil matric potential is as important as relating transpiration rate to volumes of water because volumetric water contents do not evenly translate into water accessibility to plants . For coaBuilding on soil, hPa) for two plants exhibiting differential active root length . The rationale is that the size of the root system actively taking up water is a critical determinant for the water fluxes and soil matric potential gradients at the soil–root interface during soil drying because a bigger active root length means that the transpiration rate-induced fluxes are distributed over a larger surface, which results in lower fluxes (cm s−1) in the soil. A more extensive root system would attenuate soil matric potential gradients at the soil–root interface and thereby slow down the water flux in the soil  genotypes that decreased transpiration rate at higher FTSW (i.e. less negative ψsoil) are expressing a comparatively higher plant conductance  will determine how susceptible a plant is to a change in total conductance. For plants with low hydraulic resistance (i.e. a high hydraulic conductance), the soil hydraulic resistance will become a limiting factor for the overall resistance sooner in such a system in series, and plants will sense it earlier. Plants with a high conductance are therefore expected to be more sensitive in their transpiration rate response to an increase in matric potential gradients around roots in drying soils. Note that this concept implies that plants, especially stomata, respond to a change in soil–plant hydraulic conductance rather than to an absolute leaf water potential.While it is accepted that the transpiration rate response to soil drying is linked to a decrease in soil  hydraulic conductivity, how plant hydraulic properties impact this response still needs to be resolved. Currently, two contradictory concepts have been identified. The first concept posits that genotypes decreasing transpiration rate in comparatively wetter soil conditions are characterized by a low plant/root hydraulic conductance  during soil drying. These include processes that modify the root surface area that actively takes up water, which depends on root architectural traits , mechanisoil), the transpiration rate can be sustained until comparatively high VPD (soil) stomata close at relatively low VPD  or the soil (e.g. Lroot) to identify traits relevant in different environments. During atmospheric drying, the transpiration rate response to increasing VPD is associated with hydraulic limitations within the plant tissues. Therefore, the sensitivity of the transpiration rate to increasing VPD is high for traits that impact the hydraulic conductance of the plant  independently. However, to some extent, they might be positively correlated (BP) and the transpiration responsiveness to soil drying (indicated by FTSWBP) for crops. There seem to be three patterns. Firstly, within certain species, some genotypes appear to be either overall conservative (low VPDBP and high FTSWBP) or consumptive (high VPDBP and low FTSWBP) in their water use  or in their seasonal response to decreasing soil moisture, and vice versa .The first pattern, where genotypes within certain species exhibit a range of water usage from conservative to consumptive on both daily or seasonally , stomata may close at relatively low VPD during atmospheric drying . An increasing number of studies show that the consistent identification of VPD responsiveness is difficult as it interacts with the environmental conditions during the growth period. The exposure to a comparatively high average VPD over the growth period was shown to lead to a shift in the transpiration rate restriction to occur at higher VPD or even to the loss of the transpiration rate sensitivity to VPD (max/Kplant)≥0.5 MPa, where Trmax is the transpiration rate at the highest VPD. It was hypothesized that this transpiration rate behavior is especially beneficial in well-watered environments as it enables a plant to exploit the full carbon assimilation potential when there is no apparent risk of water deficit  do not show any restriction in transpiration rate when VPD increases  is determined by the dynamics of the interaction between water demand (VPD) and supply (soil moisture availability) during the crop cycle, which determine the transpiration sensitivity to key hydraulic traits. Our species comparison suggests that species have different water use strategies and traits controlling their water use when exposed to atmospheric and soil drying, indicating different sources of hydraulic limitations and varying sensitivities to adjustments of traits.Experimental investigations of the transpiration rate response to increasing VPD and soil drying are often carried out independently to identify the hydraulic and physiological bottlenecks. When the atmosphere dries, water potential gradients within the plant are expected to limit water flow. Under soil drying, the development of water potential gradients in the soil and at the soil–root interface will trigger water flow limitations. Therefore, traits and physiological mechanisms involved in the transpiration rate response to atmospheric drying differ from the ones impacting soil drying. Hence, although the underlying mechanisms of transpiration regulation are similar , plant transpiration sensitivity to hydraulic traits can differ, resulting in different water use strategies daily and on seasonal time scales. This variability in plant water use strategies and their effects on crop productivity in water-limited regions have not yet been fully explored. That would require experiments exploring the interaction between rising VPD and soil drying. Moreover, investigating the effect of atmospheric drying and soil drying on plant transpiration at the field scale is still pending.


Extraocular muscles that are entrapped in orbital fracture sites require emergent surgical treatment. Muscle entrapment can present with subtle findings or mimic other conditions, contributing to delays in diagnosis. Here, we present two cases of extraocular muscle entrapment that were not immediately identified. By discussing the diagnostic challenge in these cases, we aim to increase the comfort of all physicians in identifying muscle entrapment in the emergency department. Orbital fractures are a common injury in patients presenting to emergency departments in the United States, with an estimated 350,379 emergency department visits in the US and a cost burden of more than 2 billion dollars between 2006 and 2017 [Assessing for extraocular muscle entrapment can fall outside the comfort zone of many physicians involved in emergency care, including ED physicians and radiologists. This article aims to bring awareness to some of the challenges in the diagnosis by sharing the clinical course of two patients in whom the diagnosis of entrapment was initially missed. We aim to increase physician confidence in diagnosing extraocular muscle entrapment in the emergency setting, thus optimizing the quality of care for patients.Case 1 A healthy 12-year-old male with no past ocular history presented to the emergency department after a physical assault in which he suffered blunt trauma to the face. The patient denied vision changes. The physical examination in the emergency department noted edematous left upper and lower eyelids but otherwise normal eye exam with total extraocular motility. The patient's heart rate was found to be 43 beats per minute. A non-contrast computed tomography (CT) scan of the head was performed , the trapdoor fracture with entrapment was misinterpreted as a mucous retention cyst, bradycardia was not identified as a potential sign of entrapment, and the clinically limited eye movements were not noted until outpatient follow-up. In the second case (case #2), the CT scan was interpreted as an orbital floor fracture with tissue herniation. However, the external exam did not show significant edema or ecchymosis, which led to an inappropriately low clinical suspicion of entrapment. In this case, the patient's eye movements were erroneously judged as complete until outpatient follow-up. Both cases highlight the importance of careful eye examinations in patients with orbital fractures and the necessity for clinical correlation with radiographic imaging. Thankfully, both patients underwent prompt treatment after entrapment diagnosis and fully recovered extraocular muscle function. However, not all patients have a prompt or reliable follow-up with specialists after their initial care. Missing the diagnosis of entrapment in the emergency room could expose the patient to undue risk of permanent disability or even death.Orbital fractures - Etiology Bones of the orbit are vulnerable to fracturing on experiencing significant direct force. Orbital fractures are commonly associated with assault, falls, traffic accidents, or sports injuries and are more common in younger and male patients ,4. The oMuscle and soft tissue entrapment happen when a fractured bone displaced by the fracturing force moves back towards its normal non-displaced position, trapping tissue into the fracture site. This so-called trapdoor style fracture is more common in pediatric patients due to the more malleable nature of younger bone -9, but iOphthalmic examination of patients with an orbital fracture is often significant for periorbital edema and ecchymosis. However, it is important to recognize a phenomenon known as white eye blowout fractures, as illustrated in case #2. These fractures are characterized by a benign external appearance with underlying entrapped tissues [Sequelae of extraocular muscle entrapment - Why do we care?Entrapped soft tissue not surgically released promptly can become ischemic, leading to contracture and compromised muscle function even after surgical release. The resultant asymmetry in extraocular muscle function can lead to persistent diplopia, which profoundly affects the quality of life  and may As the early intervention is associated with better postoperative function, it is generally recommended that entrapped fractures be repaired within 48 hrs of the insult ,15. If tEven before ischemic damage occurs, a potentially life-threatening consequence of extraocular muscle entrapment is bradycardia or asystole caused by the oculocardiac reflex, also known as the Dagnini-Aschner phenomenon . A triadExtraocular muscle assessments - How to assess?Extraocular movements (EOM) may be hard to assess in children, in uncooperative patients, in those with significant facial soft tissue edema or lacerations, or in those with significant chemosis ,8. UtiliInterpreting the EOM exam can be difficult. Though new ocular misalignment after trauma (noted in any direction of gaze) should raise suspicion for muscle entrapment, preexisting comorbidities, and periocular edema can muddle the clinical picture. It is, therefore, valid for the clinician to remember specific signs that further raise suspicion for entrapment. For example, diplopia on gaze directed away from an orbital fracture site or diplopia both towards and away from the fracture site, dubbed "double diplopia," are both commonly associated with entrapment. Pain or an increase in the intraocular pressure of greater than 4 mm when attempting to look in the diplopia field are other phenomena that raise suspicion for entrapment over other potential causes of EOM restriction .To assess for the oculocardiac reflex, the patient should be connected to a heart monitor. The baseline heart rate should be noted on the primary gaze/ with eyes at rest. The reflex is considered positive if the heart rate decreases by at least 20% within the first 5 seconds of attempting an extreme gaze . The refImaging - Potential challengesSuboptimal imaging can make the identification of orbital fractures challenging. A computerized tomography head scan, typically ordered for trauma cases involving the head, may not encompass the orbits and is taken in slices too thick to identify small orbital fractures . OrbitalTrapdoor fractures  are especially challenging to identify as radiographic evidence of a closed fracture may be minimal, even with optimal imaging protocols . This leOur cases illustrate typical challenges in diagnosing muscle entrapment in orbital fractures. Effectively identifying restrictions in eye movements, clinically correlating radiographic findings, and assessing for an oculocardiac reflex can help prevent delays in diagnosis. Delays in treatment can lead to lifelong consequences. Thankfully, both patients described in this paper were diagnosed on follow-up and successfully treated.


Retinal remodeling refers to a series of progressive pathological changes in the retina that are caused by photoreceptor degeneration . By examining the synaptic architecture of the primary visual cortex, they showed that RP significantly decreased the density of dendritic spines and altered their distribution. The most notable changes in the visual cortex occurred after a prolonged period of retinal degeneration, by affecting the presynaptic thalamocortical VGLUT2-immunoreactive terminals and postsynaptic dendritic spines of layer V pyramidal cells. This study shows, for the first time, morphological changes in the visual cortices of RP rodents, involving an excellent preclinical resource to understand how retinal degeneration impacts on the visual cortex and whether it can be alleviated through different therapeutic strategies.Ziółkowska and Lewczuk examine the mRNA expression profiles of rhodopsin, melanopsin, c-Fos, and Birc5 in the retinas of albino rats under exposure to white and monochromatic light. The results showed that the photoreceptor inner and outer segment measurements were significantly decreased, accompanied by reduced expression of Rho and Opn4 mRNA expression after exposure to blue and green light. However, increased Birc5 and c-fos mRNA expression was observed after exposure to these types of light. These authors conclude that the increased expression of the anti-apoptotic gene Birc5 may be an early response that helps to reduce light-induced retinal damage.ex vivo model of spontaneous neuroretinal degeneration in pig eyes. Puertas-Neyra et al. described the longitudinal changes associated with key molecular pathways that control cellular death. Concomitant with neuroretinal degeneration and astroglial cell stress, they identified an upregulation of major effectors involved in apoptosis  and necroptosis . Interestingly, such molecular changes are associated with dysregulation of the autophagy machinery, which is critical for neuroretinal homeostasis and is impaired in a plethora of ocular conditions  is associated with inner retinal neuronal deterioration, particularly to the loss of bipolar and amacrine cell populations from rod- and cone-driven visual pathways. This study strengthens the paradigm that safeguarding Müller glial function is pivotal for neuroprotective strategies aimed at protecting vision in photoreceptor degenerations.Finally, We hope that this Research Topic has helped to clarify certain aspects of retinal remodeling that occur as a secondary consequence of photoreceptor death, thereby facilitating a better understanding of this phenomenon to help maximize interventions by optimizing the most promising therapeutic strategies.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Identity construction is an integral developmental task for adolescents and young adults (AYA). The intersection of deaf identity and disabling hearing loss (DHL) adds a layer to the complex process of identity construction.This literature review highlights the self-ascribed deaf identities of AYA and seeks to understand how AYA with DHL forge these identities. Knowledge areas for prospective research and practice are uncovered.A traditional literature review of qualitative empirical evidence on AYA’s accounts of their deaf identity construction was conducted on seminal literature and peer-reviewed journals in psychology, disability studies and deaf studies.The emerging self-ascribed deaf identities of AYA are diverse. The identities include Deaf, hearing, hard-of-hearing (HOH), bicultural HOH, identities that detach from disability, bicultural DeaF, unresolved and fluid identities. Complex trade-offs exist where the construction of certain identities forgoes certain reasonable accommodations, interventions or relations that are critical for personal development and wellbeing.Current literature orients deaf identity formation around hearing status and Deaf-hearing communal dynamics. In-depth research comprising facets of AYA’s personal, enacted and relational identities is required to conscientise rehabilitation professionals about the nuances of deaf identity issues and how to develop interventions that are supportive and responsive to the clinical and psychosocial challenges of AYA with DHL.This paper deviates from the d/Deaf identity dichotomy, revealing a spectrum of deaf identities that AYA forge. The rationales of AYA’s deaf identities, underlying processes and possible vulnerable identities are unpacked. Recommendations for prospective research pertaining to identity construction among deaf AYA are made. The World Health Organization WHO :40 categIn hearing healthcare, AYA are becoming the focal point for audiological interventions as the prevalence and risk of acquiring DHL in this population are on the rise. Globally, HL is the third leading condition that accounts for years lived with disability (Global Burden of Disease 2019 Hearing Loss Collaborators Evidently, DHL affects psychosocial wellbeing, implicating identity construction among other processes. The purpose of audiological rehabilitation is to improve communication function and psychosocial wellbeing. As modern-day audiological rehabilitation shifts from traditional medical models to more person-centred approaches, psychosocial aspects such as understanding who the person receiving care is in the context of DHL are critical. Although underexplored, research shows that identity issues relating to DHL can disrupt the provision and uptake of audiological interventions (Clark et al. Throughout adolescence and young adulthood, individuals actively consolidate ideations about themselves and their surroundings (Kemmery & Compton Together, these identity formation theories capture the essence of audiological rehabilitation, which lies in improving psychosocial and communication function for persons with DHL. Thus, they lay a foundational framework through which to understand deaf identity construction among AYA with DHL. Through their background as developmental psychologists, Erikson and Marcia’s theories speak to psychosocial aspects and highlight exploration as a key process in identity construction. Marcia’s theory further edifies Erikson’s theory by providing a means to classify one’s identity status and any associated challenges. As communication scientists, Hetch and colleagues’ Communication Theory of Identity depicts the layered nature of identity and frames anew the understanding of communication function by emphasising communication as a means to identity construction.Erikson  theoriseAs an expansion on Erikson’s theory, Marcia deduced four identity statuses, namely identity achievement, moratorium, foreclose and identity diffusion Marcia :557. EacIt can be argued that the ability to communicate facilitates exploration. In fact, one theory posits that through communication identity is constructed, and the communication itself is identity (Jung & Hecht Personal identity is constructed at an individual level as an outcome of one’s self-perception (Pang & Hutchinson This literature review lies at the intersection of three concepts, identity construction, disability and HL among AYA. Little is known about how these concepts converge during adolescence and young adulthood. It seeks to highlight and understand the self-ascribed deaf identities that AYA with DHL construct. Notably, understanding identity construction is a good starting point for contextualising audiological rehabilitation interventions to the periods of adolescence and young adulthood to support identity construction as a critical psychosocial task. Therefore, this review will outline existing knowledge around deaf identity construction among AYA with DHL. Existing knowledge gaps, the implications for audiological practice and opportunities for further research will be highlighted.This literature review explored existing literature on deaf identity construction in the context of DHL among AYA. Database searches on PubMed, PsycINFO, Google Scholar and hand searches on seminal literature and key peer-reviewed journals in psychology, deaf studies and disability studies were perused to review qualitative research articles. Searches considered literature from 2002 to 2022 and key search terms included ‘identity construction’, ‘deaf identity’ and ‘deaf ‘adolescents’. As this was a traditional literature review that was exploratory in nature, searches were not confined to prescribed protocols. The studies selected for review were not contextualised to any geographical setting to broaden the scope of the review and were qualitative in nature consisting mainly of ethnographic and phenomenological studies as these explored elaborate accounts from AYA themselves, of their self-ascribed deaf identities.Traditionally, persons with HL are thought to assume one of two identities, Deaf or deaf (McIlroy & Storbeck Researchers in psychology that sought to illustrate diversity came up with a model consisting of four developmental stages for deaf identities on the basis of people’s relation with Deaf culture (Glickman & Carey More recently, a Bicultural DeaF identity was coined by a Bicultural DeaF researcher in disability studies for embracing identity formation in both hearing and Deaf spaces McIlroy . A partiThe experience of identity construction among AYA with DHL is a unique one. Research has shown that in comparison to their hearing peers, AYA with DHL typically embark on their deaf identity development journey earlier Kunnen :505. TheThe construction of Deaf identities seems to be characterised by an early onset and sense of pride in Deaf culture. In a 5-year longitudinal study of the identity development of seven Deaf adolescents in a Netherlands school for the Deaf, researchers found that as early as 14 years, the students had the strongest commitment in the identity domain of being Deaf compared to the other identity domains such as life philosophy, friends, parents, studies and self Kunnen :505. ThiVarying experiences have been found among AYA who identify as HOH. In a phenomenological study, a participant stated that he identified as HOH and perceived himself as having a dual identity, hearing and deaf (Kemmery & Compton Moreover, a young adult in an ethnographic South African study identified as HOH, stating that he felt he was part of both hearing and deaf worlds; however, did not completely belong to either (McIlroy & Storbeck Research has shown that some AYA will construct a hearing identity despite their HL. One adolescent in Jerusalem with a cochlear implant felt she could hear well and integrated into the hearing community (Rich et al. On the other side, some AYA show an identity crisis. Adolescents and young adults who experience an identity crisis are often isolated and expressed denial and grief regarding their HL (Brunnberg Furthermore, some AYA construct identities that disregard HL-related disability as a central factor in their identity construction. One study exploring the identity issues of 52 HOH adolescents in New Zealand found that most of them did not perceive themselves as having any hearing disability despite being medically and audiologically diagnosed with some level of DHL Kent :231. In This is exemplary of how self-constructed identities can vary greatly with externally ascribed identities and all their connotations. For instance, the diagnosis of DHL is a form of labelling that attaches the externally ascribed identity of disability, one that carries stigma, with society often perceiving disability as a liability Murugami . Given tThe fluidity of deaf identity is also expressed in the experiences of AYA with DHL. In a phenomenological study, HOH adolescents in the United States expressed that their identity varied depending on context (Kemmery & Compton The literature shows the variability and diversity of deaf identity. Could some identities be more vulnerable than others? Complex trade-offs seem to exist for some identities that AYA with DHL construct. As seen in the current literature, despite having a DHL, constructing hearing identities and identities that detach from disability may cause AYA to forgo reasonable accommodations because of non-disclosure or non-uptake of interventions to aid them, putting them in a vulnerable position (Bell et al. A synthesis of the literature on identity construction reveals that identity formation is not dichotomous or homogenous. Identity formation is intricate. Contrary to traditional deaf identity beliefs, AYA construct a spectrum of identities, which are driven by varying rationales. Even so, the depiction of deaf identity mainly fixates on hearing status or the cultural dynamics of hearing and Deaf communities, reinforcing a rigid view of deaf identity. Notably, exploring identity construction within the bounds of hearing status or Deaf and hearing cultural dynamics is restrictive and does not address the wider scope of identity and the psychosocial needs of AYA with DHL. Evidently, deaf identity is constructed through self-perception, engaging with disability, building relationships, adopting social roles and assimilating into communities (Bell et al. Contemporary discourse on deaf identity is changing, emphasising a need for portraying deaf identity in a manner that is broader and all-encompassing (Morgan & Kaneko The topic of identity construction is still widely under-researched from a healthcare stance and more specifically in relation to audiological practice. Identity issues are said to affect audiological outcomes and health behaviours and should be paid attention to in the care of AYA (Clark et al. Therefore, in-depth qualitative research exploring identity construction among deaf AYA is necessary. The processes underlying deaf identity formation that encompass personal, enacted and relational identities need to be highlighted. This will make for a conceptualisation of deaf identity that is inclusive and conscious of other significant identity domains of the person. Certainly, knowing AYA’s self-ascribed identities alone is insufficient. It is also necessary to understand the inherent compromises and challenges that these identities pose and how best to mitigate them through adequate support. Further research pertaining to identity construction is pertinent in the fields exploring disability and rehabilitation where there is a constant striving to provide person-centred and holistic care that acknowledges and supports individuals in the diverse functions that they assume.