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BACKGROUND: Clinical trials for retinitis pigmentosa (RP) likely require long follow-ups because of the slow progression of RP. Understanding patients’ attitudes toward participation in a long trial and their acceptability of strategies aimed at promoting retention/compliance is important for assessing feasibility and resource needs and optimizing trial design. METHODS: A crowdsourcing survey to adult RP patients was administered on social media in 2020 July-November. Patient enthusiasm level of study participation, acceptability of attending clinic visits every 4–5 months for 45-months, tele-visits with doctors, and of receiving text messages for medication reminders and for reporting missed dosages were surveyed. RESULTS: Among the 1473 respondents, over 95% use email or a mobile phone and receive text messages; 1157 (79%) respondents were very/somewhat enthusiastic about participation, among them, 80.6% were “very willing” to attend clinic visits every 4–5 months for 45 months; 90.3% were “very willing” to have tele-visits; 64.7% and 77.1% were willing to receive text reminders to take medication and messages surveying missed doses, respectively. The youngest age group (18–30) (22.1%) and oldest age group (70+) (26.1%) compared to the 41–50 years age group (14%) and women (23.5%) compared to men (14.2%) were statistically significantly more likely not to report high willingness to participate in clinical visits for 45 months. CONCLUSIONS: A trial requiring 4-years of commitment is feasible although retention can be challenging. Strategies including supplementing in-clinic visits with tele-visits and frequent communications may facilitate retention. This study also demonstrates a methodology useful for planning clinical trials for chronic diseases.

Mutations in GBA1, which encode for the protein glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease and dementia with Lewy bodies. In addition, growing evidence now suggests that the loss of GCase activity is also involved in onset of all forms of Parkinson's disease, dementia with Lewy bodies, and other dementias, such as progranulin-linked frontal temporal dementia. As a result, there is significant interest in developing GCase-targeted therapies that have the potential to stop or slow progression of these diseases. Despite this interest in GCase as a therapeutic target, there is significant inconsistency in the methodology for measuring GCase enzymatic activity in disease-modeling systems and patient populations, which could hinder progress in developing GCase therapies. In this review, we discuss the different strategies that have been developed to assess GCase activity and highlight the specific strengths and weaknesses of these approaches as well as the gaps that remain. We also discuss the current and potential role of these different methodologies in preclinical and clinical development of GCase-targeted therapies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Aims/hypothesis Slow progressors to type 1 diabetes are individuals positive for multiple pancreatic islet autoantibodies who have remained diabetes-free for at least 10 years; regulation of the autoimmune response is understudied in this group. Here, we profile CD4+ regulatory T cells (Tregs) in a small but well-characterised cohort of extreme slow progressors with a median age 43 (range 31–72 years), followed up for 18–32 years. Methods Peripheral blood samples were obtained from slow progressors (n = 8), age- and sex-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment and subsequently diagnosed with diabetes; this donor was individually evaluated in the analysis of the data. Peripheral blood mononuclear cells (PBMCs) were isolated, and to assess frequency, phenotype and function of Tregs in donors, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, using FlowSOM and CITRUS (cluster identification, characterization, and regression), was used to evaluate Treg phenotypes. Results Unsupervised clustering on memory CD4+ T cells from slow progressors showed an increased frequency of activated memory CD4+ Tregs, associated with increased expression of glucocorticoid-induced TNFR-related protein (GITR), compared with matched healthy donors. One participant with a raised HbA1c at the time of assessment had a different Treg profile compared with both slow progressors and matched controls. Functional assays demonstrated that Treg-mediated suppression of CD4+ effector T cells from slow progressors was significantly impaired, compared with healthy donors. However, effector CD4+ T cells from slow progressors were more responsive to Treg suppression compared with healthy donors, demonstrated by increased suppression of CD25 and CD134 expression on effector CD4+ T cells. Conclusions/interpretations We conclude that activated memory CD4+ Tregs from slow progressors are expanded and enriched for GITR expression, highlighting the need for further study of Treg heterogeneity in individuals at risk of developing type 1 diabetes. Graphical abstract

Anatomy is an early researched discipline of natural science. Ancient civilizations (e.g., Greece, Egypt, Mesopotamia, and China) made significant contributions to our current understanding of medicine, including human anatomy. However, in modern China (from 1912 to the present), some contemporary scholars prefer to overlook the fact that anatomy was studied before modern China. Therefore, the author chronologically lists typical hallmark events and publications related to human anatomy before modern China, summarizes the influences of anatomy on traditional Chinese medicine, and analyzes the reasons for the slow progression of anatomy before modern China. The purpose is to better understand the history and culture of anatomy before modern China, serving as the first step of anatomical education for medical students in mainland China.

Osteoma cutis (OC) is a group of rare skin ossification diseases, most of which are secondary to inflammation, scarring, trauma, or tumors, but a small portion are primary. Plate-like osteoma cutis is rare, especially after puberty. This report documents a case of a 30-year-old female, who presented with multiple stone-hard plates on the forehead and bilateral temples, with no relevant family history, or abnormalities in metabolism. These lesions showed slow progression over the last 11 years. The pathological diagnosis confirmed osteoma cutis. The forehead lesions were treated surgically due to aesthetic problems. In addition, long-term follow-up and observations are still needed to determine progression to deeper levels of tissue.

Author(s): Rodnoi, Pope; Le, Hai; Hiatt, Luke; Wick, Joseph; Barber, Joshua; Javidan, Yashar; Roberto, Rolando; Klineberg, Eric O | Abstract: ObjectiveTo investigate prevention of proximal junctional kyphosis (PJK) and failure (PJF) following adult spinal deformity (ASD) surgery utilizing a novel technique of posterior ligament augmentation with polyester fiber tether.MethodsThis study evaluated ASD adult patients who underwent posterior decompression and instrumented fusion from the thoracolumbar junction (T9-L1) to the pelvis from 2011-2017. Basic demographic data were obtained. Radiographic outcomes included proximal junctional angle (PJA), sagittal vertical axis, PJK, and PJF. The study population was divided into patients who had ASD surgery with and without ligamentous augmentation.ResultsA total of 43 subjects were evaluated, including 20 without and 23 with ligamentous augmentation. PJA increased over time for both groups. PJA was smaller for the augmented group, and rate of increase in PJA was slower in the augmented group (p l 0.0001). The rate of PJK was significantly higher in the nonaugmented group (p = 0.01). PJF was significantly less common in the augmented group (p = 0.003). Time to revision surgery was lower in the nonaugmented group (p = 0.003).ConclusionOur novel ligament augmentation technique utilizing polyethylene tape is an effective technique to slow progression of the PJA and lower the risk for proximal junctional disease in ASD surgery.

The purpose is to characterize the clinical and laboratory parameters in children with different rates of congenital HIV infection progression and, based on the data obtained, to develop independent predictors of forecasting the course of the disease.Research methods. The comparison of clinical, immunological and virological parameters in 91 children with HIV infection with rapid (26%) and slow progression of the disease (74%) was carried out. The criterion for the rapid progression of HIV infection was considered the development of the AIDS clinic in the first two years of life.Results. Testing of clinical, immunological and virological parameters in a multivariate logistic regression model revealed independent predictors of rapid progression in children aged 6 months — HIV blood viral load more than 1 00 000 cop./ml (odds ratio OR 23.9; 95% confidence interval 95% CI 4.6—71.8; P < 0.001) and a decrease of blood CD4-lymphocytes less than 25% (OR 6.3; 95% CI 1.2—33.4; P = 0.029). The predictor «HIV blood viral load more than 100 000 cop./ml» was characterized by a higher sensitivity (91.3%), specificity (97.1 %) compared to the indicator «CD4 lymphocyte count less than 25%» (88.2% and 86.9%).Conclusion. In 26% of children with HIV infection, there is a rapid progression of the disease with the development of AIDS clinic during the first two years of life. The independent predictors of forecasting an unfavorable course of the disease are HIV blood viral load of more than 1 00 000 cop./ml and a decrease in CD4 lymphocytes in the blood of less than 25% at the age of 6 months. The level of viremia seems to be more preferable for predicting the course of HIV infection in children due to its high sensitivity and specificity.

The Ministry of Unification, for alleviation of tensions between the two Koreas, is planning cooperation in the health and medical fields such as COVID-19 quarantine and preparation against disaster. The relative priorities were determined for the areas for inter-Korean joint cooperation and the method. The results are as follows: First, experts suggested that the inter- Korean disaster safety cooperation is more important in Inter-Korean exchange area such as Mt. Kumgang and Kaesong Industrial Complex compared to in Area requiring joint response Second, they suggested that the inter-Korean disaster safety cooperation is more important in Recovery-centered type such as contingency and earthquake compared to in Slow progression or Strong-response types. Third, they recognized that the inter-Korean disaster cooperation is more important in the urgent response type than in the Permanent dispatch type. Fourth, they suggested that, although it is more difficult to reach an agreement between the two Koreas, the form of supporting using both equipment and personnel from is more necessary in inter-Korean cooperation in disaster safety.

Women currently represent nearly half of all medical school graduates and assistant professors at academic institutions. Despite the large pool of women in the academic medicine pipeline, relatively few ascend to top leadership positions and women remain grossly underrepresented among full professors, permanent department chairs, and highest-level deans/interim deans. Considerable evidence suggests that the gender imbalance observed at the top tiers of academic medicine is, in part, due to gender differences in promotional rates, with women being promoted more slowly than their male colleagues. The well-documented gender gaps in publications, grant support, recognition awards, speaker invitations, and leadership positions contribute to the slow progression of women in medicine, as promotions committees rely heavily upon these traditional measures of academic success to select candidates for career advancement. Additionally, implicit biases, which have been shown to favor men over women in science and leadership, influence decision-making processes relevant to the promotion of women in academia. With the large number of highly qualified women entering medicine, it is imperative that organizations, academic institutions, and leaders in the medical community address the systemic inequities that are preventing half the workforce from reaching its full potential.

Objetivo: discutir sobre o impacto do déficit de investimentos para o tratamento da Doença de Chagas no Brasil. Método: trata-se de uma revisão narrativa da literatura realizada nas seguintes bases de dados: SCIELO, LILACS, BIREME e MEDLINE. A amostra final foi composta por 27 artigos cientí­ficos publicados entre o perí­odo de 2000 a 2020. Resultados: o Brasil é um dos paí­ses com maior prevalência de pacientes portadores da doença, porém pouco se avançou em pesquisas nessa área, de modo a repercutir em um baixo incentivo e investimento dos governantes e da indústria farmacêutica para a Doença de Chagas, tendo em vista a doença ser de progressão lenta e o diagnóstico e o tratamento serem tardios. Conclusão: fica evidente a falta de investimento e polí­ticas públicas que possibilitem o diagnóstico e o tratamento precoce da doença tendo como conseqüência um déficit na qualidade de vida dos pacientes.

Introduction Brachial plexus lipomas are extremely rare benign tumors that may cause slow progression of neurological deficits leading to thoracic outlet syndrome. Up to now, surgery remains challenging. The aim of this study is to present our surgical treatment regime and long-term neurological outcome in three cases of giant brachial plexus lipomas and to show results of systematic review.Patients and Methods Retrospective analysis of our database “peripheral nerve lesion” to identify patients suffering from brachial plexus lipomas between January 1, 2012, and December 31, 2019. Systematic review was performed for literature published until March 31, 2020, analyzing PubMed, Google Scholar, Scopus, and the Cochrane Collaboration Library independently by two authors.Results Over the past years, three patients suffering from giant brachial plexus lipomas attended to our neurosurgical department. All patients underwent preoperative magnetic resonance imaging (MRI), ultrasound examinations, and electrophysiological testing. Tumors were removed microsurgically via anterior/posterior, supraclavicular/infraclavicular, and combined approaches. The patients were accessed postoperatively by MRI and clinical follow-up. Systematic review of the literature revealed 22 cases, which were analyzed in regard to demographics, surgical treatment, and neurological outcome.Conclusion Brachial plexus lipomas are an extremely rare cause for brachial plexus compression. Total microsurgical removal with intraoperative electrophysiological monitoring is the treatment of choice with excellent long-term MRI and clinical outcome.

Iron deficiency anemia (IDA) is probably the most ignored situation in the world of malnutrition-largely due to its slow progression. Multiple reasons can be attributed as the cause of IDA, which is not limited to any specific region or population; therefore, making it a matter of global concern. Despite the human body's ability to absorb and conserve iron stores, the gradual loss due to various physiological conditions leads to net deficiency of iron. Countless commercial iron supplements are available, but at given physiological conditions, almost all of these "Bio-not-available" iron forms quite often become ineffective. World Health Organization and other government bodies have jointly developed health advisories and tried to developed nutrition supplements several times in the last two decades. IDA, when combined with other disease conditions, becomes a life-threatening situation. At the same time, an overdose of iron could also be very harmful to the body. Therefore, it is important to deal with this situation with caution. This article covers iron metabolism, available options for iron supplementation, regulatory aspects and strategies to prevent IDA.

Alzheimer's disease (AD) is a neuronal disorder with insidious onset and slow progression, leading to growing global concern with huge implications for individuals and society. The occurrence of AD has been increased and has become an important health issue throughout the world. In recent years, the care of more than 35 million patients with AD costs over $ 600 billion per year, it is approximately 1 percent of the global Gross Domestic Product. Currently, the therapeutic approach is not effective for neurological deficits especially after the development of these major neurological disorders. The discovery of the technique called cell-based therapy has shown promising results and made important conclusions beyond AD using the stem cells approach. Here we review recent progress on stem cell-based therapy in the context of AD.

Proper glycaemic control can slow progression of diabetes complications. One of the main causes of poor glycaemic control is delayed initiation of insulin therapy.To explain the reasons for delayed insulin initiation based on a behavioural model using patients' innate psychological needs.We enrolled 151 patients with type 2 diabetes who had indications for insulin therapy. Thirty general practitioners (GPs) were included as care providers. Patients were studied by questionnaires evaluating components of self determination theory, such as competency, relatedness and autonomy. We also evaluated patients' attitudes towards insulin therapy using the Insulin Treatment Appraisal Scale questionnaire. GPs' attitudes towards insulin therapy were assessed with a different questionnaire.Competency of patients was scored as acceptable (14.44/20). Relatedness score was low at around 15.63/30. The findings suggested that the patients' intrinsic motivation was less than their extrinsic motivation (8.41/15 vs 15.03/20). The main barrier to insulin therapy on the patients' side was rejection of severity of illness (67.5%). According to GPs, low compliance (96.7%) was the main cause of delayed insulin prescription.We observed that patients do not have a proper understanding about their illness. Due to the low score of relatedness as a representative of patients and care providers' relationship, we highlight the importance of educating both about insulin therapy and how they can have the most effective relationship in this process.العوائق التي تَُول دون بدء العلاج بالأنسولين لداء السُّكَّري من النمط الثاني الذي لا يمكن ضبطه جيداً استناداً إلى نظرية تقرير المصير.أرمين رجب، بيجا خالو، صغرى رابي زاده، حميد العليمي، سالومي صالحي، رضا مجدزاده، حسين ميرميرانبور، أسد الله رجب، علي رضا إستغاماتي، منوچهر نخجواني.يمكن أن يؤدي ضبط سكر الدم على نحوٍ صحيح إلى إبطاء تفاقم مضاعفات السُّكَّري. ويُعد تأخر بدء العلاج بالأنسولين أحد الأسباب الرئيسية التي تحول دون الضبط الجيد لسكر الدم.هدفت هذه الدراسة إلى شرح أسباب تأخُّر بدء العلاج بالأنسولين بِناءً على نموذج سلوكي يستند إلى احتياجات المرضى النفسية الفطرية.شملت هذه الدراسة 151 مريضاً بالسُّكَّري من النمط الثاني تستدعي حالاتهم العلاج بالأنسولين. وشملت ثلاثين ممارساً عاماً يضطلعون بدور مُقدِّمي خدمات الرعاية. وخضع المرضى للدراسة عن طريق استبيانات لتقييم مكوِّنات نظرية تقرير المصير، مثل الكفاءة والارتباط والاستقلالية. كما أجرينا تقييماً لمواقف المرضى تجاه العلاج بالأنسولين باستخدام استبيان مقياس تقييم العلاج بالأنسولين. وقُيّمَت مواقف الممارسين العامِّين تجاه العلاج بالأنسولين باستخدام استبيان مختلف.حصلت كفاءة المرضى على درجة مقبولة (14.44 / 20)، فيما حصل الارتباط على درجة منخفضة تُقدَّر بنحو 15.63 / 30. وأشارت النتائج إلى أن الدافع الذاتي للمرضى كان أقلَّ من دوافعهم الخارجية (8.41 / 15 مقابل 15.03 / 20). وتَثَّل العائق الرئيسي الذي يحُول دون إقدام المرضى على العلاج بالأنسولين في عدم الاعتراف بشدة المرض (67.5٪). ووَفْقاً للممارسين العامِّين، كان انخفاض الامتثال (96.7٪) السبب الرئيسي لتأخُّر وصف الأنسولين.لاحظنا أن المرضى لا يتمتعون بفهمٍ صحيحٍ لمرضهم. ونظراً لانخفاض درجة الارتباط كممثل للعلاقة بين المرضى ومُقدِّمي خدمات الرعاية، فإننا نُسلّط الضوءَ على أهمية تثقيف كلٍ منهما بشأن العلاج بالأنسولين، وكيف يمكن الوصول إلى أفضل علاقة فعّالة بين الطرفين في إطار هذه العملية.Obstacles face à la mise en place de l’insulinothérapie dans le diabète de type 2 mal contrôlé selon la théorie de l’autodétermination.Un contrôle adéquat de la glycémie permet de ralentir la progression des complications du diabète. Le retard dans la mise en place de l’insulinothérapie constitue l’une des principales causes d’un mauvais contrôle de la glycémie.Expliquer les raisons du retard de la mise en place du traitement par insuline sur la base d’un modèle comportemental fondé sur les besoins psychologiques innés des patients.Nous avons recruté 151 patients atteints de diabète de type 2 pour lesquels l’insulinothérapie était indiquée. Une trentaine de médecins généralistes ont été inclus en qualité de prestataires de soins. L’étude a été menée au moyen de questionnaires évaluant des composantes de la théorie de l’autodétermination, telles que la compétence, l’affiliation et l’autonomie. Nous avons également évalué les attitudes des patients vis-à-vis de l’insulinothérapie à l’aide du questionnaire de l’échelle d’évaluation de l’insulinothérapie (Insulin Treatment Appraisal Scale). Les attitudes des médecins généralistes vis-à-vis de l’insulinothérapie ont été évaluées au moyen d’un questionnaire différent.La compétence des patients a été jugée acceptable (14,44/20). Le score se rapportant à l’affiliation était faible, à environ 15,63/30. Les résultats suggèrent que la motivation intrinsèque des patients était inférieure à leur motivation extrinsèque (8,41/15 contre 15,03/20). Du côté des patients, le rejet de la gravité de la maladie (67,5 %) constituait le principal obstacle à la mise en place de l’insulinothérapie. Selon les médecins généralistes, une faible observance (96,7 %) était la principale cause de retard dans la prescription d’insuline.Nous avons observé que les patients ont une mauvaise compréhension de leur maladie. En raison de la faiblesse du score concernant l’affiliation, en tant qu’élément représentant la relation entre les patients et les prestataires de soins, nous soulignons l’importance d’une meilleure sensibilisation des malades et soignants à l’insulinothérapie et de la manière de mettre en place une relation efficace.

Colorectal cancer (CRC) is the second leading cause of cancer death in men and women in the United States. The opportunity for nurse practitioners (NPs) to initiate preventive measures to guide early detection of CRC is great given its slow progression. We present a collaborative project between a state NP association and colleagues from the Medical Affairs Division of a pharmaceutical company to develop an electronic survey to assess NP knowledge, beliefs, and practice patterns for CRC screening. Survey data identified that NP knowledge of CRC screening guidelines is variable and may contribute to low screening rates.

Flame retardants are widely used in electronic equipment, construction materials, and furniture to prevent fires from starting and to slow progression. Environmental monitoring studies show their presence in house dust, biomonitoring studies occasionally detect the chemicals in biological samples, and animal toxicology studies show high-dose effects. Yet laboratory studies and real-world fire statistics confirm that flame retardants have benefits that need to be weighed against possible risks to human health. Tetrabromobisphenol A (TBBPA), is used to make brominated epoxy printed wiring boards, and to a lesser extent, flame retarded acrylonitrile butadiene styrene (ABS) plastic is often used to make electronic casings. Evaluating available toxicology data and using conservative exposure assumptions, the risks of using TBBPA in these applications is exceedingly low. Given the benefits of TBBPA and flame retardants, it is essential that carefully conducted, chemical- and use-specific risk assessment be used to inform regulatory action which could possibly undermine public fire protection.

Background and Purpose: We aimed to delineate the determinants of the initial speed of infarct progression and the association of speed of infarct progression (SIP) with procedural and functional outcomes. Methods: From a prospectively maintained stroke center registry, consecutive anterior circulation ischemic stroke patients with large artery occlusion, National Institutes of Health Stroke Scale score ≥4, and multimodal vessel, ischemic core, and tissue-at-risk imaging within 24 hours of onset were included. Initial SIP was calculated as ischemic core volume at first imaging divided by the time from stroke onset to imaging. Results: Among the 88 patients, SIP was median 2.2 cc/h (interquartile range, 0–8.7), ranging most widely within the first 6 hours after onset. Faster SIP was positively independently associated with a low collateral score (odds ratio [OR], 3.30 [95% CI, 1.25–10.49]) and arrival by emergency medical services (OR, 3.34 [95% CI, 1.06–10.49]) and negatively associated with prior ischemic stroke (OR, 0.12 [95% CI, 0.03–0.50]) and coronary artery disease (OR, 0.32 [95% CI, 0.10–1.00]). Among the 67 patients who underwent endovascular thrombectomy, slower SIP was associated with a shift to reduced levels of disability at discharge (OR, 3.26 [95% CI, 1.02–10.45]), increased substantial reperfusion by thrombectomy (OR, 8.30 [95% CI, 0.97–70.87]), and reduced radiological hemorrhagic transformation (OR, 0.34 [95% CI, 0.12–0.94]). Conclusions: Slower SIP is associated with a high collateral score, prior ischemic stroke, and coronary artery disease, supporting roles for both collateral robustness and ischemic preconditioning in fostering tissue resilience to ischemia. Among patients undergoing endovascular thrombectomy, the speed of infarct progression is a major determinant of clinical outcome.

Mucopolysaccharidosis type I mild forms include Scheie syndrome and Hurler-Scheie syndrome that are characterized by slow progression, intact intelligence, and primarily effect on visual organ, musculoskeletal and cardiovascular systems. Early diagnostics, multidisciplinary approach to examination and monitoring, timely management are crucial in maintenance of patients' quality of life, preventing complications development and early disability. The article provides the overview of published data and description of 3 clinical cases with mild course of mucopolysaccharidosis type I.

The world is experiencing a cataclysmically increasing burden from chronic illnesses. Chronic diseases are on the advance worldwide and treatment strategies to counter this development are dominated by symptom control and polypharmacy. Thus, chronic conditions are often considered irreversible, implying a slow progression of disease that can only be hampered but not stopped. The current plant-based movement is attempting to alter this way of thinking. Applying a nutrition-first approach, the ultimate goal is either disease remission or reversal. Hereby, ethical questions arise as to whether physicians' current understanding of chronic illness is outdated and morally reprehensible. In this case, physicians may need to recommend plant-based diets to every patient suffering from chronic conditions, while determining what other socioecological factors and environmental aspects play a role in the chronic disease process. This article provides insights to aspects of diet and chronic illness and discusses how the plant-based movement could redefine current understanding of chronic disease. The ethical justifications for recommending of a plant-based diet are analyzed. The article concludes that not advocating for plant-based nutrition is unethical and harms the planet and patients alike.

Summary Lafora disease (LD) is a fatal childhood dementia characterized by progressive myoclonic epilepsy manifesting in the teenage years, rapid neurological decline, and death typically within ten years of onset. Mutations in either EPM2A, encoding the glycogen phosphatase laforin, or EPM2B, encoding the E3 ligase malin, cause LD. Whole exome sequencing has revealed many EPM2A variants associated with late-onset or slower disease progression. We established an empirical pipeline for characterizing the functional consequences of laforin missense mutations in vitro using complementary biochemical approaches. Analysis of 26 mutations revealed distinct functional classes associated with different outcomes that were supported by clinical cases. For example, F321C and G279C mutations have attenuated functional defects and are associated with slow progression. This pipeline enabled rapid characterization and classification of newly identified EPM2A mutations, providing clinicians and researchers genetic information to guide treatment of LD patients., Graphical abstract, Highlights • Lafora disease (LD) patients present with varying clinical progression • LD missense mutations differentially affect laforin function • An empirical in vitro pipeline is used to classify laforin missense mutations • Patient progression can be predicted based on mutation class, Disease; Biochemistry; Structural biology; Biophysics

Simple Summary Colorectal cancer (CRC) is a significant public health problem, being a major cause of cancer death worldwide. Hence, the identification of biomarkers able to support CRC detection is crucial. This work analyses a panel of six biomarkers, namely interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), matrix metalloproteinase (MMP)-2, MMP-9, haemoglobin (Hb) and M2-pyruvate kinase (M2-PK), in stool samples from patients with CRC, advanced adenomas, other lesions and healthy individuals. Our results indicate that the levels of Hb and M2-PK were increased in CRC patients in comparison to the controls. Moreover, the combination of these biomarkers increased the specificity or sensitivity for CRC detection and thus present potential for diagnosis of CRC. Abstract Background: Colorectal cancer (CRC) is a major cause of cancer-related death worldwide. Cancer progression, including invasion and metastasis, is a major cause of death among CRC patients. Current methods for CRC screening commonly consist of a combination of faecal immunochemical test (FIT) for stool occult blood detection and invasive procedures such as colonoscopy. Considering the slow progression of CRC, and that symptoms usually emerge at advanced stages, its early diagnostic can limit cancer’s spread and provide a successful treatment. Biomarkers have a high potential for the diagnosis of CRC in either blood or stool samples. Methods: In this study, we analysed the diagnostic value of six different biomarkers in stool samples of patients with CRC, advanced adenomas, other lesions and healthy individuals. We have also assessed the overall performance of the combination of these biomarkers for CRC detection. Results: The results indicate that haemoglobin (Hb) and M2-pyruvate kinase (M2-PK) levels were increased in CRC patients in comparison to the controls. Conversely, the concentrations of matrix metalloproteinase (MMP)-2, MMP-9, and tumour necrosis factor-alpha (TNF-α) were not significantly different between the tested groups. Conclusion: The combination of FIT-Hb with the M2-PK levels increased the specificity or sensitivity for CRC detection and thus present potential as faecal diagnostic biomarkers for CRC.

Since the advent of thin-film composite polyamide membranes brought forth a breakthrough in desalination and water purification membranes nearly half a century ago, recent years have only witnessed marginal improvements in the water-salt selectivity of these membranes. The slow progression is partly attributable to limited understanding of membrane synthesis–structure–performance relationships. A centralized archive of reverse osmosis membrane (RO) characterization data may lead to a shared understanding of features that maximize RO performance and unify research efforts. The Open Membrane Database (OMD), which can be found at www.openmembranedatabase.org , is a growing database of over 600 water purification and desalination membranes that are sourced from peer-reviewed journals, patents, and commercial product data. Here, we outline the detailed functionality of the database, the transport theory underlying the membrane performance calculations, and best practices for membrane performance testing and reporting. The user-sourced, open-access database may be used to benchmark novel RO membranes against the state of the art, conduct meta-analyses, and develop synthesis–structure–performance relationships, each of which will be critical to advancing membrane development.

This clinical trial (ChiCTR1800019185) is designed to be an open‐label, prospective, single‐center, single arm exploratory research study. The study will recruit non‐small cell lung cancer patients (NSCLC) with slow progression after first‐line treatment with EGFR‐TKI drugs. Slow progression will be confirmed by the presence of serum carcinoembryonic antigen or imaging evaluation. The primary aim is to assess progression‐free survival after EGFR‐TKIs treatment combined with apatinib 250 mg once daily. The secondary objectives are to evaluate objective efficacy, disease control rates, quality of life, overall survival, and safety. From September 2018 to September 2020, under specific entry and discharge standards, we plan to enroll 38 eligible patients until the end of the study. We hope that our study will help to explore a new way of combining the small molecular inhibitors of antiangiogenesis with EGFR‐TKIs to overcome acquired drug resistance.

Adenoic cystic carcinoma (SACC, ACC) in the head and neck area, occurring in small and large salivary glands are relatively rare tumors, usually undergoing slow progression. ACC is characterized by a different clinical course compared to other cancers, with a long latency period, a tendency to form late, initially asymptomatic metastases and a small percentage of responses to systemic treatment. This article presents current recommendations for diagnostic procedures and treatment possibilities.

Gorham–Stout disease (GSD) is a rare form of osteolysis, the aetiology and pathogenesis of which remains controversial to this date. Although more than 200 cases of GSD have been reported so far, this disease continues to go undiagnosed in the initial stages owing to its varied clinical presentations and rarity. Through this case report of GSD in a 3-year-old boy, we discuss the slow progression of the disease over a period of 13 years. The literature review is also done with an emphasis on the role of an oral and maxillofacial radiologist in understanding the disease at its incipient stage.

AIMS Due to their rarity, the natural history and imaging of myxoid meningiomas are not completely characterized. We analyzed clinical, imaging, and pathologic features of myxoid meningioma seen neurosurgically or in consultation between 1999 and 2018. MATERIALS AND METHODS Archival material was searched for meningiomas designated "myxoid meningioma" at Vanderbilt University School of Medicine (1997 - 2004) and the University of Rochester School of Medicine and Dentistry (1994 - 2018). RESULTS Our cases were predominantly in females and presented with a slow progression of symptoms. Each tumor was in the hemispheres. Magnetic resonance imaging (MRI) found most were hyperintense on T2-weighted images. Each meningioma had foci of limited meningothelial amongst extensive myxoid histology with Alcian-blue-staining stroma and EMA-immunoreactive cells. CONCLUSION Myxoid meningiomas present with atypical imaging and histologic characteristics but are not truly metaplastic, i.e., are not differentiated to a different cell type.

Background Treatments affect both relapse-related disability and short-term disability change, but measurements of their impact on long-term outcomes remain a challenge. Objective To ascertain the contribution of relapse-associated disability to overall disability in relapse-onset multiple sclerosis (RMS) using long-term data collected in our clinic. Materials and methods Retrospective study of a cohort of newly diagnosed patients with RMS, (n = 176) was undertaken, measuring all confirmed changes in disability up to 15 years after onset. Worsening was assessed yearly and in 5-year epochs and was attributed to either relapse (RW) or slow progression (PW). Results At data lock, 139/176 (81%) of patients were still actively followed, with Expanded Disability Status Scale (EDSS) available for 10 years post-onset in 145/176 (82%) patients and 15 years post-onset EDSS in 83 patients (mean follow-up entire group 12.7 years post-onset). RW accounted for a large amount of worsening seen in the first 15 years of RMS. RW was less frequent over time, but accounted for most EDSS changes in the first decade of MS (167/267, 63% of EDSS changes), and remained important even in years 11-15 (17/50, 34% of EDSS changes). Median change in disability due to RW vs PW was similar over the entire 15 years. Conclusions Worsening of treated MS was associated with relapses in many RMS patients throughout the first 15 years after onset, suggesting an opportunity for long-term benefit through relapse reduction.

ObjectiveThe rate of progression of the ischemic lesion is variable in patients with stroke. We tested the hypothesis that the tissue saving effect of mechanical thrombectomy (MT) is greater in fast progressors.MethodsA single-center cohort of consecutive patients (n=242) with occlusions of the terminal internal carotid or M1 segment of the middle cerebral artery treated with MT (n=195) or best medical treatment (n=47), known time from onset, and full imaging (baseline CT perfusion and follow-up MRI) available was studied. The estimated infarct progression rate (eIPR) was calculated at baseline and patients were categorized as fast/slow progressors according to the median eIPR of 4.8 mL/hour. The primary outcome measure was the interaction between eIPR category and MT on infarct growth. The secondary outcomes assessed the effect of MT on final infarct volume and functional status in relation to the eIPR category. The safety outcomes were mortality and symptomatic intracranial hemorrhage.ResultsThe eIPR category had a modifying effect (Pi=0.017) of MT on infarct growth that was significantly reduced with MT only in fast progressors (median (IQR) 3.8 mL (−11–55) vs 41 mL (11–107) with medical treatment; p=0.009, adjusted p=0.045). There was also a significant interaction on final infarct volume (Pi=0.005), with a greater reduction after MT in fast progressors. The functional status improved with MT both in fast and slow progressors, with no significant modifying effect of eIPR category (Pi=0.201). There were also no significant interactions on safety outcomes.ConclusionMT in stroke patients with large vessel occlusion limits infarct growth more significantly in fast progressors.

Rheumatoid arthritis (RA) is an inflammatory disease that is prevalent worldwide and seriously threatens human health. Though traditional drug therapy can alleviate RA symptoms and slow progression, high dosage and frequent administration would cause unfavorable side effects. Phototherapy including photodynamic therapy (PDT) and photothermal therapy (PTT) has demonstrated distinctive potential in RA treatment. Under light irradiation, phototherapy can convert light into heat, or generate ROS, to promote necrosis or apoptosis of RA inflammatory cells, thus reducing the concentration of related inflammatory factors and relieving the symptoms of RA. In this review, we will summarize the development in the application of phototherapy in the treatment of rheumatoid arthritis.

Background: Necrotizing Soft Tissue Infections (NSTIs) are uncommon rapidly spreading infection of the soft tissues for which prompt surgical treatment is vital for survival. Currently, even with sufficient awareness and facilities available, ambiguous symptoms frequently result in treatment delay.Objectives: To illustrate the heterogeneity in presentation of NSTIs and the pitfalls entailing from this heterogeneity.Discussion: NSTI symptoms appear on a spectrum with on one side the typical critically ill patient with fast onset and progression of symptoms combined with severe systemic toxicity resulting in severe physical derangement and sepsis. In these cases, the suspicion of a NSTI rises quickly. On the other far side of the spectrum is the less evident type of presentation of the patient with gradual but slow progression of non-specific symptoms over the past couple of days without clear signs of sepsis initially. This side of the spectrum is under represented in current literature and some physicians involved in the care for NSTI patients are still unaware of this heterogeneity in presentation.Conclusion: The presentation of a critically ill patient with evident pain out of proportion, erythema, necrotic skin and bullae is the classical presentation of NSTIs. On the other hand, non-specific symptoms without systemic toxicity at presentation frequently result in a battery of diagnostics tests and imaging before the treatment strategy is determined. This may result in a delay in presentation, delay in diagnosis and delay in definitive treatment. This failure to perform an adequate exploration expeditiously can result in a preventable mortality.

The World Health Organization describes the chronic disease as “disease of long duration and generally slow progression” and the chronic conditions as “health problems requiring continuous management for years or even decades”. The aim of this research was to explore the correlation of physical activity and quality of life relating to health (QoLrH), in groups of patients with chronic diseases, with mellitus diabetes, with B-thalasaimia and with renal failure. Α tool consisted of: a) short form of the international physical activity questionnaire (IPAQ) and b) short form of the quality of life questionnaire (SF-36) during the period 2010-2011,was filled in by 133 patients from the Renal Dialysis Unit in 4 general hospitals of the Health District of Peloponnese. 51.1% of the participants were women, 33.8% were graduates from Colleges/ Universities, and 59.4% are married. 53.0% of them were working for 6-8 hours daily and 68.9% consider their income to be insufficient for their living and personal needs. Furthermore, some seem to be affected from various other organic disorders, comorbidities. Apart from the body disorders known from the bibliography, we statistically remark a significant negative influence of all levels – dimensions of the quality of life in all three groups of patients. In particular: (52.6%)had low physical activity. Men had considerably higher marks in the synoptic scale of physical health a fact that indicates better physical health in comparison to women. Additionally, there was a significant difference in the marks of the participants at the synoptic scale of physical health in accordance with their level of education, both of the high school graduates and the graduates of Universities. Moreover, the participants that used to work 6-8 hours daily had considerably higher marks in the synoptic scale of physical health from other participants. Women got considerably higher marks in the synoptic scale of mental health. From the results’ analysis it arose that for all three groups of patients there was significant correlation between all the dimensions of quality of life. Therefore, the higher it gets the quality of life regarding one dimension, the better it becomes regarding all the others too.

Background Opening-wedge high tibial osteotomy produces opening gaps; however, there is little consensus on bone graft necessity and the material that would produce a superior union. The purposes of the present study were (1) to compare the serial union patterns associated with various bone-void fillers, (2) to determine whether bone-void filler is necessary to achieve bone union of the opening gap, and (3) to determine whether bone union is different according to the correction degree during opening-wedge high tibial osteotomy. Methods In this retrospective study, 97 knees were randomly assigned to treatment with hydroxyapatite chip bone (Group A), allogenic chip bone (Group B), or no bone graft (Group C) and were analyzed after a minimum 1-year follow-up. To compare the bone union pattern, the area of callus filling located at the most medial side on an anteroposterior radiograph of the knee was recorded, and a modified van Hemert scoring system was used in the mediolaterally divided 5 zones. The correlations between the correction degree and bone union scores were evaluated. Results There were no significant differences in the extent of mediolateral bone-healing at 6 weeks or 3 months postoperatively (p = 0.172 and p = 0.228). However, Group C showed more prominent progression of the gap filling to the medial side compared with Groups A and B at 6 months postoperatively (p = 0.002). Group C showed slow progression of bone union up to 6 weeks but surpassed the other groups at 6 months. The union pattern was not different between Groups A and B, and the correction degree was not correlated with bone union beyond 3 months postoperatively. Conclusions Despite the different gap-healing patterns, opening-wedge high tibial osteotomy without bone graft achieved bone union comparable with allogenic and synthetic graft materials. Group C (no bone graft) showed slower progression of bone union but surpassed the other groups at around 6 months. Based on the union pattern, there was no difference depending on the correction degree and the use of bone-void fillers. Level of evidence Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

To assess the effect of clinical factors on the development and progression of atrophy and fibrosis in patients with neovascular age-related macular degeneration (nAMD) receiving long-term treatment in the real world.An ambispective 36-month multicentre study, involving 359 nAMD patients from 17 Spanish hospitals treated according to the Spanish Vitreoretinal Society guidelines, was designed. The influence of demographic and clinical factors, including the presence and location of retinal fluid, on best-corrected visual acuity (BCVA) and progression to atrophy and/or fibrosis were analysed.After 36 months of follow-up and an average of 13.8 anti-VEGF intravitreal injections, the average BCVA gain was +1.5 letters, and atrophy and/or fibrosis were present in 54.8% of nAMD patients (OR = 8.54, 95% CI = 5.85-12.47, compared to baseline). Atrophy was associated with basal intraretinal fluid (IRF) (OR = 1.87, 95% CI = 1.09-3.20), whereas basal subretinal fluid (SRF) was associated with a lower rate of atrophy (OR = 0.40, 95% CI = 0.23-0.71) and its progression (OR = 0.44, 95% CI = 0.26-0.75), leading to a slow progression rate (OR = 0.34, 95% CI = 0.14-0.83). Fibrosis development and progression were related to IRF at any visit (p 0.001). In contrast, 36-month SRF was related to a lower rate of fibrosis (OR = 0.49, 95% CI = 0.29-0.81) and its progression (OR = 0.50, 95% CI = 0.31-0.81).Atrophy and/or fibrosis were present in 1 of 2 nAMD patients treated for 3 years. Both, especially fibrosis, lead to vision loss. Subretinal fluid (SRF) was associated with good visual outcomes and lower rates of atrophy and fibrosis, whereas IRF yields worse visual results and a higher risk of atrophy and especially fibrosis in routine clinical practice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Most patients die of respiratory failure within 3 years of onset. In this study, we reported a female Chinese ALS patient with SOD1 c.404G C, p.S135T mutation. The missense mutation was identified as "Likely pathogenic" according to the ACMG/AMP 2015 guideline. The patient presented with weakness and atrophy of lower limbs with slow progression. We reviewed two other reports on patients with the same SOD1 p.S135T mutation. These patients had lower extremity onset, negative Babinski sign, slow disease progression, and prolonged survival. This report indicates that specific phenotype-genotype correlations of SOD1 p.S135T mutation in ALS.

We report two cases from the frontotemporal lobar degeneration (FTLD) spectrum with a remarkably slow progression. The first case demonstrated insidious-onset behavioral symptoms and personality changes resembling behavioral variant of frontotemporal dementia, followed by a benign course of over 26 years, and his brain autopsy revealed the diffuse form of argyrophilic grain disease. The second case presented with slowly progressive cognitive and motor deficits, reminiscent of the corticobasal syndrome, deteriorated very slowly over 22 years and his brain autopsy revealed FTLD-TDP with C9ORF72 pathology. These two cases confirm the notion of slowly progressive frontotemporal lobar degeneration caused by an underlying FTLD pathology, rather than a phenocopy.

Seborrheic keratosis (SK) is a common epidermal tumor, consisting of a benign proliferation of immature keratinocytes. The natural history of SK is a slow progression over time and complete remission is not expected. The article presents the first case of a complete resolution of a large (2.5 cm diameter) SK lesion after hyperbaric oxygen therapy (HBOT). In addition to the case presentation, the pathophysiology of SK and the potential beneficial physiological effects of HBOT are reviewed and discussed.

The habit of chewing arecanut leads to fibrosis in the oral tissues, which can lead to cancer. Despite high mortality, fibrosis has limited clinical success owing to organ-specific variations, genetic predispositions, and slow progression. Fibrosis is a progressive condition that is unresponsive to medications in the severe phase. To understand underlying macromolecular changes we studied the extracellular matrix's (ECM) key molecular modifications in the early and late phase of arecanut-induced fibrosis in skin. To study the fibrosis, we topically applied arecanut extract on the mice skin. We observed that the matrix changes observe early and late phases based on ECM characteristics including the matrix proteins and the glycans. A spike in the levels of proteoglycans and β-sheet structures are noted in the early phase. A significant drop in the proteoglycans and strengthening of amide covalent interactions is observed in the late phase. Although, almost no physical changes are noticeable only in the early phase; the late phase observes thick collagen bundling and a 4-fold stiffening of the skin tissue. The study indicates that the temporal interplay of proteins and glycans determine the matrix's severity state while opening avenues to research directed towards the phase-specific clinical discovery.

International audience; Neuromuscular disorders are rare diseases for which few therapeutic strategies currently exist. Assessment of therapeutic strategies efficiency is limited by the lack of biomarkers sensitive to the slow progression of neuromuscular diseases (NMD). Magnetic resonance imaging (MRI) has emerged as a tool of choice for the development of qualitative scores for the study of NMD. The recent emergence of quantitative MRI has enabled to provide quantitative biomarkers more sensitive to the evaluation of pathological changes in muscle tissue. However, in order to extract these biomarkers from specific regions of interest, muscle segmentation is mandatory. The time-consuming aspect of manual segmentation has limited the evaluation of these biomarkers on large cohorts. In recent years, several methods have been proposed to make the segmentation step automatic or semi-automatic. The purpose of this study was to review these methods and discuss their reliability, reproducibility, and limitations in the context of NMD. A particular attention has been paid to recent deep learning methods, as they have emerged as an effective method of image segmentation in many other clinical contexts.

The course of multiple sclerosis begins with a relapsing-remitting phase, which evolves into a secondarily progressive form over an extremely variable period, depending on many factors, each with a subtle influence. To date, no prognostic factors or risk score have been validated to predict disease course in single individuals. This is increasingly frustrating, since several treatments can prevent relapses and slow progression, even for a long time, although the possible adverse effects are relevant, in particular for the more effective drugs. An early prediction of disease course would allow differentiation of the treatment based on the expected aggressiveness of the disease, reserving high-impact therapies for patients at greater risk. To increase prognostic capacity, approaches based on machine learning (ML) algorithms are being attempted, given the failure of other approaches. Here we review recent studies that have used clinical data, alone or with other types of data, to derive prognostic models. Several algorithms that have been used and compared are described. Although no study has proposed a clinically usable model, knowledge is building up and in the future strong tools are likely to emerge.

We apply a pattern-based classification method to identify clinical and genomic features associated with the progression of Chronic Kidney disease (CKD). We analyze the African-American Study of Chronic Kidney disease with Hypertension dataset and construct a decision-tree classification model, consisting 15 combinatorial patterns of clinical features and single nucleotide polymorphisms (SNPs), seven of which are associated with slow progression and eight with rapid progression of renal disease among African-American Study of Chronic Kidney patients. We identify four clinical features and two SNPs that can accurately predict CKD progression. Clinical and genomic features identified in our experiments may be used in a future study to develop new therapeutic interventions for CKD patients.

Pulmonary alveolar microlithiasis is a rare autosomal recessive condition that is characterized by the formation of excessive calcium phosphate microliths in the alveoli. Most patients are diagnosed in adulthood due to the slow progression of the disease. Children with this disease are asymptomatic, and changes in the lung parenchyma are usually discovered incidentally. The diagnosis is made by the combination of a positive chest imaging and histological examination. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by chronic seropositive symmetrical inflammatory polyarthritis with numerous extra-articular manifestations. It targets the lining of the synovial membranes, frequently affects females more than males, and is treated with the disease-modifying antirheumatic drugs (DMARDs). If left untreated, it leads to increased morbidity, mortality, and socioeconomic burdens. In this case, we report a 19-year-old young man who presented with clinical and radiographic features of PAM associated with RA.

Annual screening of urinary parameters, ongoing clinical vigilance, and proper medical therapy can help to keep declining renal function at bay.

Acromegaly is a rare disorder of chronic growth hormone (GH) hypersecretion, frequently caused by a pituitary adenoma, resulting in excessive generation of insulin-like growth factor-I (IGF-I), the mediator of most of the GH effects. Clinical manifestations of acromegaly may be subtle or severe, and characterized by somatic overgrowth, multiple comorbidities, physical disfigurement, and increased mortality. Gigantism develops when GH hypersecretion occurs in young patients before epiphyseal bone closure occurs. There is an equal gender predisposition in acromegaly and the average age at diagnosis ranges between 40 and 50 years, while a minority of cases (up to 5%) are diagnosed before the age of 20. Due to its insidious clinical onset, slow progression, and variable clinical spectrum, diagnosis is often delayed. Furthermore, there are some patients with physical features that resemble acromegaly but with normal GH/IGF-I axis (termed “pseudoacromegaly”); in these patients, the correct diagnosis can be challenging due to the rarity and significant overlap of physical features. Otherwise, diagnosing acromegaly in most cases is usually straightforward based on the identification of clinical symptoms and signs, biochemical confirmation by measuring serum IGF-I levels and assessing nadir serum GH levels during an oral glucose tolerance test, and by performing pituitary magnetic resonance imaging. In recent years, clinicopathological studies of pituitary tumors have demonstrated that each tumor type has a distinct pathophysiology resulting in varying clinical manifestations that may require different therapeutic approaches. Because of the association of excess comorbidities and mortality with acromegaly, it is thus important to detect and optimally treat patients early to reduce the risks of long-term morbidity and premature death.

The slow progression of early age-related macular degeneration (AMD) stages to advanced AMD requires the use of surrogate end points in clinical trials. The use of combined end points may allow for shorter and smaller trials due to increased precision. We performed a literature search for the use of composite end points as primary outcome measures in clinical studies of early AMD stages. PubMed was searched for composite end points used in early/intermediate AMD studies published during the last 10 years. A total of 673 articles of interest were identified. After reviewing abstracts and applicable full-text articles, 33 articles were eligible and thus included in the qualitative synthesis. The main composite end point categories were: combined structural and functional end points, combined structural end points, combined functional end points and combined multicategorical end points. The majority of the studies included binary composite end points. There was a lack of sensitivity analyses of different end points against accepted outcomes (i.e., progression) in the literature. Various composite outcome measures have been used but there is a lack of standardization. To date no agreement on the optimal approach to implement combined end points in clinical studies of early stages of AMD exists, and no surrogate end points have been accepted for AMD progression.

Background Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytosis with slow progression over the years that is particularly difficult to diagnose. Cases Here we report three cases of ECD without BRAF mutation presenting with a renal mass, hairy kidney appearance, and a rather benign course, for which the diagnosis of ECD was delayed, characterized by multiple investigations and unsuccessful treatments attempts. In two cases the distinction from IgG4-related disease required multiple investigations and reevaluation of the clinical, radiological, histological, and immunological characteristics. Conclusion A correct diagnosis of ECD may take several years and often requires revisiting previous hypotheses. Reassessment of histological slides and more modern complementary exams such as PET-CT or BRAF and MAPK-ERK mutation analysis can help to confirm the diagnosis of ECD and to select effective therapy.

Peptides can offer the versatility needed for a successful oncology drug discovery approach. Peptide-drug conjugates (PDCs) are an emerging targeted therapeutic that present increased tumour penetration and selectivity. Despite these advantages, there are still limitations for the use of peptides as therapeutics exemplified through their slow progression to get into the clinic and limited oral bioavailability. New approaches to address these problems have been studied and successfully implemented to enhance the stability of peptides and their constructs. There is great promise for the future of PDCs with two molecules already on the market and many variations currently undergoing clinical trials, such as bicycle-toxin conjugates and peptide-dendrimer conjugates. This review summarises the entire process needed for the design and successful development of an oncology PDC including chemical and nanomaterial strategies to enhance peptide stability within circulation, the function of each component of a PDC construct, and current examples in clinical trials.

Aim: To develop clinical algorithms for the assessment and management of slow progress of labour. Population: Low-risk singleton, term, pregnant women in labour. Setting: Institutional births in low- and middle-income countries. Search Strategy: We systematically reviewed the literature on normal labour progression, and guidance on clinical management of abnormally slow progression from 1 December 2015 to 1 December 2020. Case scenarios: We developed two clinical algorithms: one for abnormally slow labour progression and arrest during first and one for second stage. Conclusions: Identifying abnormal progress of labour is often challenging. These algorithms may help to reduce misdiagnosis.