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Background The natural course of a vortex vein varix, though not well understood, has been known to remain stable. However, here we report a novel case of a vortex vein varix that resolved after an extended period of monitoring. Case presentation An asymptomatic 96-year-old Caucasian man was found to have a vortex vein varix. At his previous examination 13 months prior, his fundus was normal. At 13 months of observation, his vortex vein varix become clinically undetectable. Further follow-up confirmed continued absence of the varix. Conclusion This case demonstrates the development then clinical resolution of a vortex vein varix with no clear identifiable factors for its evolution. This case is novel and offers new insight into the natural history of some vortex vein varices, implicating venous congestion as an instigator and venous collateralization as its alleviator, suggesting that vortex vein varices are likely more common than previously reported since some may be temporary and under-identified.

Background: Bietti crystalline dystrophy (BCD) is an autosomal recessive genetic disorder that causes progressive vision loss. Here, 12 patients were followed up for 1–5 years with fundus fluorescein angiography (FFA) to clarify BCD disease development and its classification. Methods: FFA images were collected for 12 patients with BCD who visited our clinic twice or more in 5 years. Peripheral venous blood was collected to identify a pathogenic gene related to the clinical phenotype.Results: FFA images identified two BCD types. Type 1 showed retinal pigment epithelium (RPE) atrophy at the macular area, followed by choriocapillaris atrophy, then RPE atrophy appeared at the peripheral retina. Type 2 showed RPE atrophy at the posterior pole and peripheral retina, followed by choriocapillaris atrophy around the macula and along the superior and inferior vascular arcades and optic disc nasal side. Then the posterior and peripheral lesions of type 1 and type 2 were extended to the mid-periphery; at last, all the RPE and choriocapillars atrophied, exposed choroid great vessels, but the macular RPE atrophy of type 2 can existed for a long time. Conclusions: The two different BCD development types provide a better understanding of the phenotype and the progression of the disease for a precise prognosis and prediction of pathogenesis.

Background Evidenced-based clinical guidelines for the treatment of low back pain (LBP) consistently suggest educating patients about their back pain, its natural course, and providing advice to keep active and continue working. Despite this evidence, clinicians routinely do not follow these recommendations resulting in ineffective and fragmented care. GLA:D® Back, a standardized care package, was originally developed in Denmark to assist clinicians in implementing evidence-based care. This study will evaluate the feasibility of implementing the English version of the Danish GLA:D® Back program in Alberta, Canada. Methods Thirty-five clinicians from nineteen clinics in Alberta, Canada, participated. Feasibility of program implementation, our primary objective, was evaluated within 3 months. Feasibility success was defined as 50% clinician/clinic adoption in addition to 66–88 enrolled participants registered in the database. Our secondary objectives included collecting data pertaining to clinician confidence, attitudes and behaviour of treating patients, perceived barriers and facilitators of program in addition to collecting patient-data regarding pain, function, general health and self-efficacy. Results The majority of the clinics (15/19, 79%) offered GLA:D® Back to their patients within the study period. Of the participating clinicians, GLA:D® Back was delivered by (25/35, 71%) of clinicians. In total, 78 patients were enrolled in the program and (69/78, 88%) participants attended the final assessment. Secondarily, clinicians demonstrated a biomedical and behavioural orientation along with high confidence when treating LBP patients while patient outcomes trended toward improvement. Conclusion The English translation of the Danish GLA:D Back program was feasible for Albertan clinicians to implement into practice in both urban and rural settings.

Purpose: To describe the natural history of acquired vitelliform lesions (AVLs) associated with different types of pigment epithelial detachments (PEDs) in dry age-related macular degeneration. Methods: A retrospective review of clinical examination and multimodal imaging data of patients with AVLs associated with PED(s) was performed. Results: This study included 25 eyes of 17 patients. The mean age of patients was 67.2 ± 9.7 (47–83) years. The mean follow-up time was 32.6 ± 16.2 (12–66) months, excluding four patients (five eyes) that were lost to follow-up. The mean logMAR BCVA was 0.21 ± 0.16 at baseline and 0.38 ± 0.28 at final visit ( p = 0.016). At the end of the follow-up period, PEDs enlarged in eight eyes (40%) and were unchanged in two eyes (10%). Spontaneous resolution of the central PED(s) with AVLs was seen in four (20%) eyes. Rupture of the PED(s) occurred in four eyes (20%), with two developing central foveolar atrophy afterwards. Overall, central foveolar atrophy was seen ultimately in four eyes (20%). Conclusion: It seems that high PED size may be a risk factor for PED rupture during follow-up. 1/3 of the eyes ended up with unfavorable anatomical outcome.

Frozen Shoulder (FS) by many specialists is still considered a benign, self-limiting condition, which usually resolves without intervention. This concept originated in the 70’, stating that FS will proceed from “the freezing” phase, with the predominance of inflammation and pain to “the frozen” phase with marked stiffness in the joint and “the thawing” phase, with a progressive return to the normal Range Of Motion (ROM) and function. Nevertheless, numerous authors have recently challenged this concept, arguing that most patients with FS will never fully recover, and suffer from residual pain and loss of function. Lack of early intervention, when a patient does not improve with conservative treatment, might lead to disability. We have discussed the recent concepts in the natural course of the disease and discussed both noninvasive and surgical methods in the treatment of FS.

Background One hundred seventy-eight dogs with cutaneous and renal glomerular vasculopathy (CRGV) were evaluated to further the understanding of the natural course of CRGV. CRGV, a form of thrombotic microangiopathy, can cause skin lesions and potentially acute kidney injury (AKI) with a high mortality rate. Methods Cases were submitted from multiple practices from 2012 until June 2019. Clinical histories and laboratory data were reviewed to describe the features of CRGV. Results Most cases (91%) occurred between November and May. Fifteen dogs (8.4%) with CRGV were in contact with another dog that developed skin lesions +/- AKI. Limb lesions were present on 144 dogs (80.9%) at presentation. Median time from appearance of a lesion to AKI was 3 days (range -4-45 days). Neurological signs occurred in 33 dogs (18.6%) including at presentation in 2 (1.1%). Systemic signs were present in 13 dogs prior to a skin lesion (7.3%). Non-steroidal anti-inflammatory drugs were prescribed prior to AKI identification in 92 of 170 dogs (54.1%). Thrombocytopenia was present in 115 of 137 (83.9%) of dogs. Conclusion The timeframe over which AKI may develop is longer than previously reported, neurological signs can be identified at presentation or during hospitalisation, and thrombocytopenia is even more common than previously reported.

Objective: Natural course and clinical outcomes of chronic hepatitis B virus (HBV) infection is closely releated to immun responses of host and viral factors. Studies have suggested that there is strongly correlation between the level of IL-17 and especially of advanced liver damages associated with HBV. Role of IL-17 on natural course of chronic hepatitis B disease is yet to be fully clarified. This study aimed to evaluate the correlation between serum IL-17 levels with histological, virological, serological and biochemical data of chronic hepatitis B patients. Material and Method: Simultaneous liver biopsy and blood samples were obtained from 88 with chronic HBV enfection. Ishak modified histological activity index system was used for histological evaluation.The patients were divided into three groups taking into account by scoring as none/mild (F0-1), moderate / severe (F2-4) and cirrhosis (F5-6) according to the stages of fibrosis (F). It was analyzed using enzyme-linked immunosorbent assay (ELISA) to IL-17 levels in serum samples. Results: A total of 88 CHB patients were evaluated, with an average age of 41.77±13.39, 43 male and 45 female. Fibrosis stage of 64 (72.7%) of the patients included in the study was determined as F2-4. There were no statistically significant correlation between serum IL-17 levels with histological, virological, serological and biochemical data of patients. Conclusion: These data indicate that the immunopathological role of IL-17 on HBV-related especially low and moderate liver injuries are limited.

Background & aims Bacterial infections (BI) affect the natural course of cirrhosis and were suggested to be a landmark event marking the transition to the decompensated stage. Our specific aim was to evaluate the impact of BI on the natural history of compensated cirrhosis. Methods We analyzed 858 patients with cirrhosis, evaluated for the INCA trial (EudraCT 2013-001626-26) in 2 academic medical centers between February 2014 and May 2019. Only patients with previously compensated disease were included. They were divided into 4 groups: compensated without BI, compensated with BI, 1st decompensation without BI, and 1st decompensation with BI. Results About 425 patients (median 61 [53-69] years) were included in the final prospective analysis. At baseline, 257 patients were compensated (12 [4.7%] with BI), whereas 168 patients presented with their 1st decompensation (42 [25.0%] with BI). In patients who remained compensated MELD scores were similar in those with and without BI. Patients with their first decompensation and BI had higher MELD scores than those without BI. Amongst patients who remained compensated, BI had no influence on transplant-free survival, whereas patients with their 1st decompensation and concurrent BI had significantly reduced transplant-free survival as compared with those without BI. The development of BI or decompensation during follow-up had a greater impact on survival than each of these complications at baseline. Conclusions In compensated patients with cirrhosis, the 1st decompensation associated to BI has worse survival than decompensation without BI. By contrast, BI without decompensation does not negatively impact survival of patients with compensated cirrhosis.

Objective: The SSADHD Natural History Study was initiated in 2019 to define the natural course and identify biomarkers correlating with severity. Methods: The study is conducted by 4 institutions: BCH (US clinical), WSU (bioanalytical core), USF (biostatistical core), and Heidelberg (iNTD), with support from the family advocacy group (SSADH Association). Recruitment goals were to study 20 patients on-site at BCH, 10 with iNTD, and 25 as a standard-of care cohort. Results: At this half-way point of this longitudinal study, 28 subjects have been recruited (57% female, mean 9 years, range 18 months–40 years). Epilepsy is present in half and increases in incidence and severity, as do psychiatric symptoms, in adolescence and adulthood. The average Full Scale IQ (FSIQ) was 53 (Verbal score of 56, Non Verbal score of 49), and half scored as having ASD. Although there was no correlation between gene variant and phenotypic severity, there were extreme cases of lowest functioning in one individual and highest in another that may have genotype-phenotype correlation. The most common EEG finding was mild background slowing with rare epileptiform activity, whereas high-density EEG and magnetoencephalography showed reduction in the gamma frequency band consistent with GABAergic dysfunction. MR spectroscopy showed elevations in the GABA/NAA ratio in all regions studied with no crossover between subjects and controls. Conclusions: The SSADH Natural History Study is providing a unique opportunity to study the complex pathophysiology longitudinally and derive electrophysiologic, neuroimaging, and laboratory data for correlation and to serve as biomarkers for clinical trials and prognostic assessments in this ultra-rare inherited disorder of GABA metabolism.

Simple Summary Over the last decade the incidence of enchondroma and atypical cartilaginous bone tumors (ACTs) increased enormously. Management of these tumors in the long bones is shifting towards active surveillance, as negative side effects of surgical treatment seem to outweigh the potential benefits. To support development of evidence-based guidelines for active surveillance, we studied the natural course of enchondroma and ACTs in the long bones. In this study, MRI analysis of 128 cases was performed with a minimum interval of 24 months between baseline and last MRI. Our data showed that the majority of the cartilaginous tumors (87%) remained stable or showed regression on MRI. Only 13% showed some progression on MRI, although none of the tumors developed characteristics of high-grade chondrosarcoma. Based on our results, active surveillance is considered safe for enchondroma and ACTs of the long bones, and follow-up schemes should be tailored on natural course. Abstract Management of atypical cartilaginous tumors (ACTs) in the long bones is shifting towards active surveillance to avoid unnecessary surgeries. The frequency and duration of active surveillance for these tumors is unclear as there is little knowledge of its biological behavior. In this retrospective study, we examined the natural course of enchondroma and ACTs through active surveillance. A total of 128 central cartilaginous tumors, located in the long bones, with a minimum interval of 24 months between baseline and last MRI were included. MRI characteristics (e.g., size, scalloping, fat entrapment) were scored and tumors were classified according to the changes between MRIs. Mean follow-up of this study was 50 months, range = 25–138 months. The majority of the cartilaginous tumors (87%) remained stable (n = 65) or showed regression (n = 46) on MRI. A total of 87% of the cases that developed tumor regression presented with entrapped fat at diagnosis. Only 13% (n = 17) showed some progression on MRI, although none of the tumors developed characteristics of high-grade chondrosarcoma. Based on our results, active surveillance is considered safe for enchondroma and ACTs of the long bones. We propose active surveillance for all asymptomatic enchondroma or ACTs in the long bones irrespective of tumor size, and follow-up schemes should be tailored on natural course.

Background Following the broad application of new analytical methods, more and more pathophysiological processes in previously unknown diseases have been elucidated. The spectrum of clinical presentation of rare inherited metabolic diseases (IMDs) is broad and ranges from single organ involvement to multisystemic diseases. With the aim of overcoming the limited knowledge about the natural course, current diagnostic and therapeutic approaches, the project has established the first unified patient registry for IMDs that fully meets the requirements of the European Infrastructure for Rare Diseases (ERDRI). Results In collaboration with the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), the Unified European registry for Inherited Metabolic Diseases (U-IMD) was established to collect patient data as an observational, non-interventional natural history study. Following the recommendations of the ERDRI the U-IMD registry uses common data elements to define the IMDs, report the clinical phenotype, describe the biochemical markers and to capture the drug treatment. Until today, more than 1100 IMD patients have been registered. Conclusion The U-IMD registry is the first observational, non-interventional patient registry that encompasses all known IMDs. Full semantic interoperability for other registries has been achieved, as demonstrated by the use of a minimum common core data set for equivalent description of metabolic patients in U-IMD and in the patient registry of the European Rare Kidney Disease Reference Network (ERKNet). In conclusion, the U-IMD registry will contribute to a better understanding of the long-term course of IMDs and improved patients care by understanding the natural disease course and by enabling an optimization of diagnostic and therapeutic strategies.

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Although incidental brain meningiomas are becoming an increasingly common radiological finding, as yet their optimal management is still a major unknown. Numerous studies have been published on the natural course of such tumours in an attempt to understand their potential growth rate, but the choice of management strategy—whether to wait and see, or to opt for surgery or radiosurgery—must also take into account several other factors, namely the position, size and radiological appearance of the tumour; the age of the patient; and any undiscovered symptoms. From a radiological point of view, more than 63% of asymptomatic meningiomas will not grow in size. The radiological features associated with a low rate of tumour growth are the existence of calcifications and the absence of signs of surrounding oedema. However, because of their location and/or the risk of producing neurological deficits, some meningiomas, even small ones, need to be treated.

This chapter explores cytotoxic therapies and various dermatologic adverse effects (DAEs) from their use. Medications featured here provide an overview of indications for each drug class as well as profiles of their potential mucocutaneous reactions. For each anticancer agent, a clinical summary is provided, offering an a overview of incidence, natural course, clinical features, and management of its dermatologic adverse effects. This chapter is designed to assist practitioners in anticipating the dermatologic manifestations of these anticancer therapies and managing any complications should they arise.

Our understanding of fatty liver syndromes and their relationship with the metabolic syndrome has improved over recent decades and, paralleling this, we are now at the dawn of the NAFLD (nonalcoholic fatty liver disease) to MAFLD (metabolic-associated fatty liver disease) transition. The pitfalls of NAFLD diagnosis, together with disappointing results in therapeutic trials, and the inconsistencies and risks inherent in a “negative” definition (such as “nonalcoholic”) as opposed to a “positive” one (i.e., “metabolic”) are predicted to facilitate the proposed renaming of NAFLD to MAFLD. However, a premature change of terminology would not necessarily address major unmet needs in this area, and may even become counterproductive. As an aid to selecting more homogeneous cohorts of patients, I propose the LDE (Liver, Determinants, Extra-hepatic) classification system which, in principle, may help to assess the natural course of disease as well as the efficacy of novel drugs in patients with NAFLD/MAFLD.

Targeted and immunotherapies comprise two of the most promising and expanding classes of agents in oncology. This chapter reviews clinical indications for targeted and immunotherapies, and describes their corresponding associated dermatologic adverse effects (DAEs) in these settings. For each medication discussed, a clinical synopsis is provided which showcases incidence, natural course, clinical features, and management of potential mucocutaneous reactions. This chapter is designed to assist clinicians in anticipating, recognizing, and managing the dermatologic manifestations of these increasingly utilitzed therapies.

Abdominal aortic aneurysm (AAA) is life-threatening, its natural course is progressively sac expansion and rupture. Elegant studies have been conducted to investigate the molecular markers associated with AAA growth and expansion, this topic however, still needs to be further elucidated. This study aimed to identify potential genes for AAA growth and expansion based on comprehensive bioinformatics approaches. Firstly, 29 up-regulated genes were identified through DEGs analysis between large AAA and small AAA in GSE57691. Secondly, signed WGCNA analysis was conducted based on GSE57691 and the green module was found to exhibit the topmost correlation with large AAA as well as AAA, 133 WGCNA hub genes were further identified. Merged gene set including 29 up-regulated DEGs and 858 green module genes was subjected to constructing a PPI network where 195 PPI hub genes were identified. Subsequently, 4 crucial genes including POU2AF1, FCRLA, CD79B, HLA-DOB were recognized by Venn plot. In addition, by using GSE7084 and GSE98278 for verification, POU2AF1 showed potential diagnostic value between AAA and normal groups, and exhibited a significant higher expression level in large AAA samples compared with small AAA samples. Furthermore, immunohistochemistry results indicated up-regulation of POU2AF1 in large AAA samples than small AAA samples, which implies POU2AF1 may be a key regulator in AAA enlargement and growth. In summary, this study indicates that POU2AF1 has great predictive value for the expansion of AAA, and may contribute to the further exploration of pathogenesis and progression of AAA.

Background Congenital cytomegalovirus-associated hearing loss (cCMV-associated HL) is a common cause of congenital or early-onset deafness. Although cCMV infection has been reported to lead to various types of HL, the natural course of cCMV-associated HL over a long period is not yet known. Objectives To investigate the clinical phenotype of cCMV-associated HL in the largest study to date. Methods Thirty-one CMV-positive children, diagnosed by examining CMV DNA extracted from their dried umbilical cords retrospectively, were divided into unilateral and bilateral HL groups, and their hearing ability was evaluated using pure-tone audiometry and auditory steady-state response over time. Results Thirteen patients (41.9%) had unilateral HL and 18 (58.1%) had bilateral HL. In most cases of unilateral cCMV-associated HL, the ear with better hearing maintained a normal hearing threshold. Notably, in most cases of both unilateral and bilateral HL, the ear with worse hearing ultimately showed severe to profound HL. Conclusion Our findings revealed that the natural course of cCMV-associated HL was different between the cases of unilateral and bilateral HL, as well as between the ears with better or worse hearing in all cases. These findings indicate that accurate diagnosis could enable proper follow-up and management of cCMV-associated HL in children.

The aim of the article was to analyze the purposes in life of young Brazilians. A total of 560 students, aged 15-19 years, from the five geopolitical regions of Brazil, answered an open questionnaire developed by the Stanford Center on Adolescence and adapted to the specificities of the research. The data were analyzed using the Theory of Organizing Models of Thinking, which enabled us to identify six models of purposes. Most young people expressed their life purposes as a natural course of life or as an idealized dream; most of them also presented a self-centered view of their purposes, focused on their own accomplishments. The results reveal an association between life purposes and identity of young Brazilians in the interaction with collective values, particularly regarding the overcoming of economic difficulties and financial achievements. Resumo O artigo tem como objetivo analisar os projetos de vida de jovens brasileiros. Quinhentos e sessenta estudantes, com idade entre 15 e 19 anos, representantes das cinco regiões geopolíticas do Brasil responderam um questionário aberto formulado pelo Stanford Center on Adolescence e adaptado aos propósitos do trabalho. Os dados foram analisados por meio da Teoria dos Modelos Organizadores do Pensamento e permitiram a identificação de seis formas de projetar o futuro. Observou-se que a maioria dos jovens entende seus projetos de vida como um curso natural da vida ou como um sonho ou idealização, assim como apresentam uma visão de futuro altamente centrada no eu e em suas próprias conquistas. Os resultados evidenciam a articulação da construção dos projetos de vida dos jovens brasileiros à formação de suas identidades na interação com os valores coletivos, em especial em relação à superação de dificuldades econômicas e a conquistas financeiras.

Background There is an incomplete understanding of the natural course of mild to moderate aortic stenosis (AS). We aimed to evaluate the natural course of patients with mild to moderate AS and its association with coronary artery disease (CAD). Methods We retrospectively analyzed 787 patients diagnosed with mild to moderate AS using echocardiography between 2004 and 2010. Cardiac death and aortic valve replacement (AVR) for AS were assessed. Results A median follow-up period was 92 months. Compared to the general population, patients with mild to moderate AS had a higher risk of cardiac death (hazard ratio [HR], 17.16; 95% confidence interval [CI], 13.65–21.59; P < 0.001). Established CAD was detected in 22.4% and associated with a significantly higher risk of cardiac mortality (adjusted HR, 1.62; 95% CI, 1.04–2.53; P = 0.033). The risk of cardiac death was lower when patients were taking statin (adjusted HR, 0.64; 95% CI, 0.41–0.98; P = 0.041), which was clear only after 7 years. Both patients with CAD and on statin tended to undergo more AVR, but the difference was not statistically significant (the presence of established CAD; adjusted HR, 1.63; 95% CI, 0.51–3.51; P = 0.214 and the use of statin; adjusted HR, 1.86; 95% CI, 0.76–4.58; P = 0.177). Conclusion Mild to moderate AS does not have a benign course. The presence of CAD and statin use may affect the long-term prognosis of patients with mild to moderate AS., Graphical Abstract

BACKGROUND Infantile hemangiomas (IH) represent the most common type of benign tumors of infancy. Vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (bFGF) have a central role in the pathogenesis of infantile hemangiomas. METHODS In this prospective study, we aimed to investigate the relationship between serum VEGF and bFGF levels and clinical characteristics and the serological changes in VEGF and bFGF levels associated with propranolol treatment in infants diagnosed with IH. Blood samples were taken from 34 patients with IH and 10 controls. Serum VEGF and bFGF levels were studied by ELISA. RESULTS At initial diagnosis, median serum bFGF levels were 11.1 ng/ml (4.8-16.6) in patients with IH (n=34) and 2.6 ng/ml (1.7-4.7) in controls (p < 0.001), and, median serum VEGF levels for same groups were 58.5 ng/ml (25.3-190.2) and 11.4 ng/ml (8.2-19.8) (p < 0.001), respectively. Serum VEGF and bFGF levels were not correlated. In 18 infants who were treated with propranolol with serial measurements, median serum bFGF levels were 10.7 ng/ml, 9.8 ng/ml and 10.5 ng/ml (p= 0.8), and median serum VEGF levels were 68.6 ng/ml, 63.5 ng/ml and 45.1 ng/ml (p < 0.001) at initial diagnosis, at first and third months, respectively. Median regression rates of the hemangiomas at the first and third months were -%47.3 and -%58.3 (p < 0.001), respectively. CONCLUSIONS Serum bFGF levels didn`t change in time. Serum VEGF levels seemed to follow the natural course of IH and might be a marker for follow-up. The contribution of propranolol treatment should also be considered.

The latest statistics regarding human mortality on our planet show that of the 56.9 million deaths that occurred worldwide in 2016, more than half (54%) were related to ten diseases, which, in their natural course, cause suffering in all dimensions—physical, emotional, family, social, and spiritual—despite all available treatments. These diseases have remained the principal causes of global death for the last 15 years, and it is worth mentioning that they account for an announced statistic of death; that is, these people were diagnosed with diseases that threaten the continuity of life, and they would therefore have been candidates to receive palliative care. The suffering of the health professionals who took care of these people is not recognized, or legitimized, or even allowed in our culture of health care (or, rather, illness). The whole process of self-care should convey to the health professional that their life is as important and valuable as all of the lives they are dedicated to caring for. Therefore, it should receive the same attention to—and care for—its own human dimensions: physical, emotional, family, social, and spiritual. With this care, we can then dedicate ourselves in a more conscious way and become more capable of achieving the results that we long for in our work.

Introduction: There are limited reports on the natural history of hen’s egg (HE) allergy (HEA) in children Methods: Using the database in our hospital, a total of 137 patients diagnosed with a definitive immediate-type reaction to HE when they turned 6 years were enrolled, and the natural course of HEA was prospectively examined until patients turned 12 years. Tolerance was defined as being able to pass an oral food challenge to consume a half or whole heated HE or consume heated HE freely without symptoms. Thirty patients (21.9%) who were enrolled for oral immunotherapy and 21 (15.3%) who discontinued follow-up were considered dropouts. Kaplan-Meier estimation was used to evaluate the rate of tolerance. Results: Fifty-five of the 137 patients (40.1%) had a previous HE anaphylaxis history; 61 (44.5%) patients had acquired tolerance to HE by age 12 years; and 25 (18.2%) continued total or partial HE elimination. The estimated acquired tolerance rates by ages 7, 9, and 12 years were 14.6%, 40.8%, and 60.5%, respectively. A previous history of HE anaphylaxis before 6 years of age, reacting to small amounts of heated HE by 6 years of age, and higher ovomucoid-specific immunoglobulin E values at the same age were associated with persistent HEA. Conclusion: This study provides important insights into the natural course of HEA beyond early childhood, with the acquisition of HE tolerance continuing throughout the duration of the study.

Pain burn-out during the course of chronic pancreatitis (CP), proposed in the 1980s, remains controversial, and has clinical implications. We aimed to describe the natural course of pain in a well-characterized cohort.We constructed the clinical course of 279 C P patients enrolled from 2000 to 2014 in the North American Pancreatitis Studies from UPMC by retrospectively reviewing their medical records (median observation period, 12.4 years). We assessed abdominal pain at different time points, characterized pain pattern (Type A [short-lived pain episodes] or B [persistent pain and/or clusters of recurrent severe pain]) and recorded information on relevant covariates.Pain at any time, at the end of follow-up, Type A pain pattern or B pain pattern was reported by 89.6%, 46.6%, 34% and 66% patients, respectively. In multivariable analyses, disease duration (time from first diagnosis of pancreatitis to end of observation) did not associate with pain - at last clinical contact (OR, 1.0, 95% CI 0.96-1.03), at NAPS2 enrollment (OR 1.02, 95% CI 0.96-1.07) or Type B pain pattern (OR 1.01, 95% CI 0.97-1.04). Patients needing endoscopic or surgical therapy (97.8 vs. 75.2%, p 0.001) and those with alcohol etiology (94.7 vs. 84.9%, p = 0.007) had a higher prevalence of pain. In multivariable analyses, invasive therapy associated with Type B pain and pain at last clinical contact.Only a subset of CP patients achieve durable pain relief. There is urgent need to develop new strategies to evaluate and manage pain, and to identify predictors of response to pain therapies for CP.

Diagnostic and therapeutic innovations have changed the way we now approach liver tumours in children and adolescents. Novel imaging tools, increasing awareness, and surveillance has led to early diagnosis of benign and malignant liver tumours. Multidisciplinary interventions have favourably altered the natural course in some liver tumours. The role of liver transplantation is expanding and has become fully integrated into today's therapeutic algorithms. Transarterial locoregional and ablation therapies have been successful in adults and are being explored in children to facilitate resectability and improve outcome. For the first time, North American, Japanese, and European experts have designed a global trial to optimize management of malignant liver tumours and aim to find signature molecular profiles that will translate to individualised treatment strategies.This article aims to offer an overview of recent advances in our understanding of liver tumours in children. It focuses on the paediatric hepatologist's view and their role in the multidisciplinary management of benign and malignant liver tumours.

ObjectivesReport predictors and the natural course of paravalvular leak (PVL) following implantation of the ACURATE neo transcatheter heart valve (THV).BackgroundUnderstanding the mechanisms of PVL may help to improve patient selection, patient outcomes and the design of next-generation THVs.MethodsA total of 30 patients (mean age 81±5 years, 47% women) undergoing transcatheter aortic valve replacement with the ACURATE neo were enrolled in the PREDICT PVL study. The effective regurgitant orifice area (EROA, in mm2) of PVL was assessed by transthoracic and transoesophageal echocardiography before discharge and at 6 months follow-up.ResultsPVL was none/trace in 10 (33%), mild in 18 (60%) and moderate in 2 (7%) patients and occurred in distinct locations with largest EROAs in the area of the left coronary cusp and its adjacent commissures. Independent predictors for EROA were implantation depth (r coefficient −1.9 mm2 per mm implantation depth, p=0.01), leaflet calcification (6.2 mm2 per calcification grade, p=0.03) and THV size L (7.6 mm2 more than size S or M, p=0.01). At 6 months follow-up, EROA decreased by 29% from 13.7±9.7 mm2 to 9.5±7.9 mm2 (pConclusionsPVL occurred predominantly in the region of the left coronary cusp and decreased by 29% during 6 months of follow-up. Our results underscore the importance of adequate patient selection and optimal implantation depth.

Background: Accurate information on the natural course of giant paraesophageal hernia is scarce, challenging therapeutic decisions whether or not to operate. Objective: We aimed to investigate the long-term outcomes, including hernia-related deaths and complications (e.g. volvulus, gastrointestinal bleeding, strangulation) of patients with giant paraesophageal hernia that were conservatively managed, and to determine factors associated with clinical outcome. Methods: We retrospectively analysed charts of patients diagnosed with giant paraesophageal hernia between January 1990 and August 2019, collected from a university hospital in The Netherlands. Included patients were subdivided into three groups based on primary therapeutic decision at diagnosis. Radiological, clinical and surgical characteristics, along with long-term outcomes at most recent follow-up, were collected. Results: We included 293 patients (91 men, mean age 70.3 ± 12.4 years) with a mean duration of follow-up of 64.0 ± 58.8 months. Of the 186 patients that were conservatively treated, a total hernia-related mortality of 1.6% was observed. Hernia-related complications, varying from uncomplicated volvulus to strangulation, occurred in 8.1% of patients. Only 1.1% of patients included in this study required emergency surgery. Logistic regression analysis revealed the presence of symptoms (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.8–20.6), in particular obstructive symptoms (vomiting, OR 15.7, 95% CI 4.6–53.6; epigastric pain, OR 4.4, 95% CI 1.2–15.8 and chest pain, OR 6.1, 95% CI 1.8–20.6) to be associated with the occurrence of hernia-related complications. Conclusions: Hernia-related death and morbidity is low in conservatively managed patients. The presence of obstructive symptoms was found to be associated with the occurrence of complications during follow-up. Conservative therapy is an appropriate therapeutic strategy for asymptomatic patients.

Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a precancerous lesion of cholangiocarcinoma, for which surgical resection is the most effective treatment. We evaluated the predictors of malignancy in IPNB according to anatomical location and the prognosis without surgery. Methods: A total of 196 IPNB patients who underwent pathologic confirmation by surgical resection or endoscopic retrograde cholangiography or percutaneous transhepatic cholangioscopic biopsy were included. Clinicopathological findings of IPNB with invasive carcinoma or mucosal dysplasia were analyzed according to anatomical location. Results: Of the 116 patients with intrahepatic IPNB (I-IPNB) and 80 patients with extrahepatic IPNB (E-IPNB), 62 (53.4%) and 61 (76.3%) were diagnosed with invasive carcinoma, respectively. Multivariate analysis revealed that mural nodule > 12 mm (p = 0.043) in I-IPNB and enhancement of mural nodule (p = 0.044) in E-IPNB were predictive factors for malignancy. For pathologic discrepancy before and after surgery, IPNB has a 71.2% sensitivity and 82.3% specificity. In the non-surgical IPNB group, composed of nine I-IPNB and seven E-IPNB patients, 43.7% progressed to IPNB with invasive carcinoma within 876 days. Conclusions: E-IPNB has a higher rate of malignancy than I-IPNB. The predictive factor for malignancy is mural nodule > 12 mm in I-IPNB and mural nodule enhancement in E-IPNB.

Multiple sclerosis is a relatively common, immune-mediated neurologic disease of the central nervous system that can cause significant disability and lead to reduced quality of life. There are several currently approved disease-modifying therapies, and more in the pipeline being developed and tested. As the field learns more about the pathophysiology and natural course of the disease, the treatment approaches are also being investigated. This article reviews data on available treatments along with a discussion of future treatment targets under investigation.