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Background/objectives: There is scarce information about risk factors for exocrine pancreas insufficiency (EPI) in chronic pancreatitis (CP), and how it associates with other complications. The aim of the present study was to examine risk factors for EPI and associations to procedures and other CP related complications in a large, Northern European cohort.Patients and methods: We retrieved cross-sectional data on demographics, status on EPI, aetiological risk factors for CP, CP related complications as well as surgical and endoscopic treatment from the Scandinavian Baltic Pancreatic Club Database. Associations were assessed by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals.Results: We included 1869 patients with probable or definitive CP in the study. Exocrine pancreas insufficiency was present in 849 (45.4%) of patients. In multivariate analyses, EPI associated with smoking aetiology (OR 1.47 (1.20-1.79), p < 0.001), and nutritional/metabolic aetiology (OR 0.52 (0.31-0.87), p = 0.01) to CP. Pancreatic or common bile duct stenting procedure and pancreatic resection were both associated with EPI (ORs 1.44 (1.15-1.80), p = 0.002 and 1.54 (1.02-2.33), p = 0.04, respectively). The presence of diabetes mellitus (OR 2.45 (1.92-3.15), p < 0.001), bile duct stenosis (OR 1.48 (1.09-2.00), p = 0.02) and underweight (2.05 (OR 1.40-3.02), p < 0.001) were all associated with presence of EPI.Conclusions: Smoking, bile duct stenosis, previous stenting and resection procedures are all associated with EPI in patients with CP. Presence of EPI were also associated with malnutrition and diabetes mellitus. Hence, intensive nutritional surveillance is needed in these patients. (C) 2022 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC.

Aortic pathology is always a challenge for the clinician, and must be diagnosed and treated by a multidisciplinary team due to the technical and technological complexity of the resources used. Ongoing efforts to implement a systematic, protocolized approach involving "Aortic teams" made up of cardiologists, cardiac surgeons, vascular surgeons, anaesthesiologists and radiologists, among others are now leading to improved outcomes. The aim of this consensus document drawn up by the Aortic working groups of the Spanish Society of Anaesthesiology, Resuscitation and Pain Therapy (SEDAR) and the Spanish Society of Thoracic and Cardiovascular Surgery (SECTCV) is to disseminate a set of working protocols. The latest consensus document of the European Association for Cardio-Thoracic Surgery (EACTS) and the European Society for Vascular Surgery (ESVS) define the concept of "AORTIC TEAM"(1). The aortic team should be closely involved from diagnosis to treatment and finally follow-up, and should be formed of cardiac and vascular surgeons working together with anaesthesiologists, cardiologists, radiologists and geneticists. Treatment of aortic pathologies should be centralised in large centres, because this is the only way to effectively understand the natural course of the disease, provide the entire range of treatment options under one umbrella and treat potential complications. A streamlined emergent care pathway (24/7 availability), adequate transportation and transfer capabilities, as well as rapid activation of the multidisciplinary team must be available. In light of the complexity and constant evolution of therapeutic options, we present this first version of the Anaesthesiology and surgical guidelines for surgery of the ascending aorta and aortic arch. Some questions will no doubt remain unanswered, and future versions will include new techniques that, though implemented in some centres, are still not widely recommended.

As the number of individuals vaccinated against SARS-CoV-2 rises worldwide, population-level data regarding the vaccines' ability to reduce infection are being generated. Randomised trials have shown that these vaccines dramatically reduce symptomatic COVID-19; however, less is known about their effects on transmission between individuals. The natural course of infection with SARS-CoV-2 involves infection of the respiratory epithelia and replication within the mucosa to sufficient viral titres for transmission via aerosol particles and droplets. Here we discuss the available data on the existing, approved SARS-CoV-2 vaccines' capacity to reduce transmissibility by reducing primary infection, viral replication, capacity for transmission, and symptomaticity. The potential for mucosal-targeted SARS-CoV-2 vaccine strategies to more effectively limit transmission than intramuscular vaccines is considered with regard to known immunological mechanisms. Finally, we enumerate the population-level effects of approved vaccines on transmission through observational studies following clinical trials and vaccine distribution in real-world settings.

Chronic rotator cuff pathology is often complicated by fatty degeneration of the rotator cuff (FDRC) muscles, an insidious process associated with poor prognosis with or without surgical intervention. Currently there is no treatment for FDRC, and many studies have described a natural course for this disease almost always resulting in further degeneration and morbidity. Recapitulating FDRC using animal injury models, and using imaging-based studies of human FDRC, the pathophysiology of this disease continues to be further characterized. Researchers studying mesenchymal stem cell–derived progenitor cells and known fibrogenic and adipogenic signaling pathways implicated in FDRC seek to clarify the underlying processes driving these changes. While new cell- and molecular-based therapies are being developed, currently the strongest available avenue for improved management of FDRC is the use of novel imaging techniques which allow for more accurate and personalized staging of fatty degeneration. This narrative review summarizes the evidence on the molecular and pathophysiologic mechanisms of FDRC and provides a clinical update on the diagnosis and management of this condition based on the existing knowledge. We also sought to examine the role of newer biologic therapies in the management of RC fatty degeneration and to identify areas of future research.

Purpose Mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma are rare autosomal recessive lysosomal storage disorders. Data on the natural course of the diseases are scarce. These data are important for counseling, therapies development, and improvement of outcome. The aim of this study is to gain knowledge on the natural history of ML by obtaining data on survival, symptom onset, presenting symptoms, diagnosis, and pathogenic variants associated with the MLII or MLIII phenotype. Methods A systematic review on all published MLII and MLIII cases between 1968 and August 2019 was performed. Results Three hundred one articles provided data on 843 patients. Median age at diagnosis: 0.7 for MLII and 9.0 years for MLIII. Median survival: 5.0 for MLII and 62.0 years for MLIIIII. Median age of death: 1.8 for MLII and 33.0 years for MLIII. Most frequent causes of death in all ML were pulmonary and/or cardiac complications. Pathogenic variants were described in 388 patients (GNPTAB: 571, GNPTG 179). Conclusion This review provides unique insights into the natural history of MLII and MLIII, with a clear genotype–phenotype correlation with the most frequent pathogenic variant c.3503_3504del in MLII and in MLIII alpha/beta c.22A>G for GNPTAB. All pathogenic GNPTG variants resulted in MLIII gamma.

Background: Given the strong relationship between depression and anxiety, there is an urge to investigate their shared and specific long-term course determinants. The current study aimed to identify and compare the main determinants of the 9-year trajectories of combined and pure depression and anxiety symptom severity. Methods: Respondents with a 6-month depression and/or anxiety diagnosis (n=1,701) provided baseline data on 152 sociodemographic, clinical and biological variables. Depression and anxiety symptom severity assessed at baseline, 2-, 4-, 6- and 9-year follow-up, were used to identify data-driven course-trajectory subgroups for general psychological distress, pure depression, and pure anxiety severity scores. For each outcome (class-probability), a Superlearner (SL) algorithm identified an optimally weighted (minimum mean squared error) combination of machine-learning prediction algorithms. For each outcome, the top determinants in the SL were identified by determining variable-importance and correlations between each SL-predicted and observed outcome ( ρ p r e d ) were calculated. Results: Low to high prediction correlations ( ρ p r e d : 0.41-0.91, median=0.73) were found. In the SL, important determinants of psychological distress were age, young age of onset, respiratory rate, participation disability, somatic disease, low income, minor depressive disorder and mastery score. For course of pure depression and anxiety symptom severity, similar determinants were found. Specific determinants of pure depression included several types of healthcare-use, and of pure-anxiety course included somatic arousal and psychological distress. Limitations: Limited sample size for machine learning. Conclusions: The determinants of depression- and anxiety-severity course are mostly shared. Domain-specific exceptions are healthcare use for depression and somatic arousal and distress for anxiety-severity course.

Background This study aimed to assess the baseline levels of D-dimer, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) and monitor the natural course of these serum markers after uneventful primary total joint arthroplasty. Methods This prospective study enrolled 81 patients undergoing primary total knee arthroplasty or total hip arthroplasty. The level of serum D-dimer, CRP, and ESR was measured preoperatively and on postoperative days 1, 3, 5, 15, and 45. Mean peak values, peak times, and distribution were compared between D-Dimer, CRP, and ESR. Results The mean preoperative serum D-dimer, CRP, and ESR level was 412 ± 260 (range 200-980) ng/mL, 2.93 ± 2.1 (range 1-18) mg/L, and 22.88 ± 17.5 (range 3-102) mm/h, respectively. The highest mean peak for D-dimer, CRP, and ESR was at postoperative day 1, 3, and 5, respectively. Conclusion D-dimer levels reached peak levels on postoperative day 1 and then declined rapidly to a plateau level by postoperative day 3. A second, albeit small, peak in the level of D-dimer occurred on postoperative day 15. The level of CRP and ESR remained elevated for much longer with CRP returning to baseline on postoperative day 45 and the level of ESR had not returned back to normal on postoperative day 45.

Background The value of the single-breath diffusing capacity of the lungs for carbon monoxide (D lco ) relates to outcomes for patients with COPD. However, little is known about the natural course of D lco over time, intersubject variability, and factors that may influence D lco progression. Research Question What is the natural course of D lco in patients with COPD over time, and which other factors, including sex differences, could influence this progression? Study Design and Methods We phenotyped 602 smokers (women, 33%), of whom 506 (84%) had COPD and 96 (16%) had no airflow limitation. Lung function, including D lco, was monitored annually over 5 years. A random coefficients model was used to evaluate D lco changes over time. Results The mean (± SE) yearly decline in D lco % in patients with COPD was 1.34% ± 0.015%/y. This was steeper compared with non-COPD control subjects (0.04% ± 0.032%/y; P = .004). Sixteen percent of the patients with COPD, vs 4.3% of the control subjects, had a statistically significant D lco % slope annual decline (4.14%/y). At baseline, women with COPD had lower D lco values (11.37% ± 2.27%; P lco annual decline of 0.89% ± 0.42%/y (P = .039). Interpretation Patients with COPD have an accelerated decline in D lco compared with smokers without the disease. However, the decline is slow, and a testing interval of 3 to 4 years may be clinically informative. The lower and more rapid decline in D lco values in women, compared with men, suggests a differential impact of sex in gas exchange function. Trial Registry ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.gov

Connective tissue disorders are common in women of reproductive age, and hence are seen frequently in maternal medicine clinics. The disorders, and their treatments, may have significant adverse effects on fertility, the developing fetus, and on pregnancy outcomes. In turn pregnancy may affect the natural course of the illness. Pre-pregnancy planning and multidisciplinary management are vital to optimise maternal and fetal outcomes. This review will cover a general approach and specific management points of common autoimmune and genetic conditions. Alterations in the maternal immune system affect the disease course of pre-existing skin conditions during pregnancy, and pharmacotherapy may be limited due to effects on the fetus. Some dermatological conditions arise de novo during pregnancy. Women may present to maternity services directly; therefore obstetricians must be able to diagnose, investigate and initiate management of pregnancy dermatoses, with input from dermatologists where available.

Background The coexistence of falcine and occipital sinuses is rare and its natural course has not been reported. Case reports Two patients with persistent falcine and occipital sinuses are described. Both patients had straight sinuses. In one, both the transverse and sigmoid sinuses were hypoplastic and the patient had an acquired Chiari I malformation. The other patient had no other venous anomalies and had a normal posterior cranial fossa. Conclusion The coexistence of falcine and occipital sinuses can lead to an acquired Chiari I malformation. These cases suggest the importance of checking other venous and brain anomalies in this situation.

Objective Cataplexy is a pathognomonic symptom of narcolepsy type 1. This study was conducted to clarify the clinical characteristics of cataplexy by staging, and to further analyse the correlations of clinical features and cataplectic stages in patients with narcolepsy type 1 (NT1). Methods We experimentally triggered patients with NT1 into cataplexy while under video-polysomnography (v-PSG) monitoring in the sleep lab. The most serious cataplectic attack from each patient was analysed. Each cataplectic episode was segmented into four stages according to the v-PSG. Correlations were analysed between cataplectic stages in pairs, and between cataplectic stages and other clinical features. Results We observed 81 cataplectic episodes in 21 patients with diverse triggers, including humorous or exciting videos, tickling, recalling horrible memories and exercising. Nine patients (43%) went through complete cataplectic attacks while the others experienced partial attacks. Four cataplectic stages (ie, triggering, resisting, atonic, and recovering) were identified according to clinical and electromyograms characteristics. Resisting stage is predominant (56.4%) in cataplexy, while atonic stage is most related with the total duration of cataplexy. The Epworth Sleepiness Scale score (ESS) has a positive correlation with the total duration of cataplexy. Both duration of cataplexy and ESS score are negatively correlated with disease course. However, medication history seems have no influence on either cataplexy duration or ESS score. Conclusion Four-stage segmentation shows the dynamic process of the cataplectic attack, which is different from the traditional classification of complete or partial cataplexy. Resisting stage is necessary for every cataplexy and might reflect the compensation mechanism, while atonic stage may be omitted in some patients. The severity of narcolepsy reduces with the extension of natural course regardless of medication history.

Recent findings have highlighted the association between changes in the activity of the HPA axis, primarily its end-hormone, cortisol and OCD. However, to date, cortisol levels of OCD patients have been assessed mainly in body fluids, such as serum, saliva or urine, frequently leading to ambiguous results because of their inherent lack of stability. The aim of this study was to investigate time-integrated levels of stress exposure in 32 OCD patients and 32 sex and age-matched healthy controls by measuring endogenous cortisol in hair segments reflecting the last 3 months preceding hair collection. Psychometric parameters, including BDI, FQ, STAI, PSS and ECQ-R, were obtained in all participants; Y-BOCS was performed in the OCD patients. The OCD patients exhibited significantly higher scores in all psychometric instruments administered and lower hair cortisol concentrations than the healthy controls (p = 0.001, r = 0.41). No significant correlations were found between the HCC and the Y-BOCS total scores. After having sorted OCD patients into subtypes, according to the nature of their symptomatology, the “washers/cleaners” category showed the lowest HCC (compared to the “checking/harming”, “ordering/symmetry” and “sexual/religious obsessions” categories). The novel finding of chronic low cortisol secretion in OCD patients could be attributed to a possible down-regulation of the HPA axis, as an adaptive response to chronic stress exposure. Given that the OCD subtypes reflect the great heterogeneity in the OCD spectrum, studies with larger samples should extend the investigation of HCC in patients with distinctive symptomatology, so as to develop a basis for better neuroendocrine profiling and understanding of the pathophysiology of OCD. Further work is needed in exploring HPA axis’ activity over the natural course and treatments of the disorder.

Background/purpose Clinical outcomes in pediatric ulcerative colitis (UC) in the era of biologic agents are poorly defined. We aimed to describe risk factors for colectomy in pediatric UC in the era of infliximab therapy. Methods We reviewed 217 pediatric patients at Texas Children's Hospital with newly diagnosed UC between 2003 and 2015; 117 had a minimum of 5 years of follow-up. Extent of disease at diagnosis, medication exposure, the presence of extraintestinal manifestations (EIMs), and need for surgery were noted. Results Average length of follow up was 5.02 ± 2.27 years. Forty-two percent presented with pancolitis. Infliximab was used in 39%, immunomodulators in 65%, and steroids in 89% of patients. EIMs occurred in 24.9% of patients. The cumulative rate of colectomy was 12.9% at 5 years. Children presenting as E2 (Paris Classification) and children prescribed oral steroid monotherapy at diagnosis progressed to surgery faster than any other group. Of the children who received infliximab, females and children less than 5 years old were less likely to respond to therapy. Conclusions The natural course of pediatric UC remains aggressive despite the addition of infliximab to the standard of care and suggests a need for early aggressive clinical intervention. Level-of-evidence rating Level IV.

Background Symptomatic intramedullary arachnoid cysts are rarely observed lesions, particularly in the pediatric age group. Treatment includes cyst fenestration or resection of the cyst wall, and recurrence after surgery has never been reported. We report a rare case of a spinal intramedullary arachnoid cyst, which recurred after cyst fenestration and required reoperation after a certain period. Case Description A 4-year-old boy presented to our hospital with tetraparesis and bladder and rectum disorder. A cystic intramedullary lesion in the cervical spinal cord was detected in preoperative imaging. An emergency fenestration of cyst was performed, and his symptoms were resolved immediately. One month after the operation, the symptoms and cyst recurred. The symptoms improved in the natural course without reoperation. However, the cyst increased in size and the symptoms recurred after 27 months from the first relapse and the cyst was removed urgently. The diagnosis was an arachnoid cyst. After the reoperation, the cyst has disappeared and not recurred. Conclusions To the best of our knowledge, this is the first report of recurrence of an intramedullary arachnoid cyst. This case indicates the importance of considering the resection of cyst wall as possible because of the probability of cyst recurrence after fenestration, while careful observation is the option in the short term, especially for children or high-risk cases.

All screening programs have the potential to result in harmful overdiagnosis and overtreatment. Sound evidence, policy, and standards are needed to keep this harm to a minimum. Screening for and “treating” cervical cytological abnormalities provides a sobering example. The term “carcinoma in situ” came into use from 1950 and implied—misleadingly—that an inevitable malignant process had been identified. Hysterectomy became widely used to “treat” it. New Zealand's Herbert Green was one of a minority of gynecologists around the world who recognized the possible dangers of harmful overtreatment. Green developed and monitored more conservative management approaches to avoid women being “subjected to hysterectomy”. By the mid-1980s, his approaches had been adopted not only within National Women's Hospital in Auckland, but more widely. In 1987, it was alleged in a magazine article that an “experimental” research program had been undertaken at National Women's Hospital to study the natural course of untreated cervical “carcinoma in situ”; that this had entailed withholding “conventional treatment” from some patients indefinitely; and that some patients had died as a result. A public furore resulted and led 2 weeks later to the creation of a judicial inquiry—the Cartwright Inquiry—which reported the following year. The findings of the Inquiry, which criticized Green's practice, have been both disputed and defended ever since, often by individuals with competing interests. In the recently published 2nd edition of their book Screening: Evidence and Practice, Angela Raffle, Anne Mackie, and Muir Gray have provided a fresh analysis. This concludes (see accompanying article) that the Cartwright Inquiry provides no trustworthy evidence of harm from the adoption of the conservative management introduced by Green and adopted by some of his colleagues at National Women's Hospital. It is now clear that the treatment and monitoring methods introduced by Herb Green have benefited numerous women through avoidance of major surgery and preservation of fertility.

Background Several conservative treatment methods, from intrinsic muscle exercises to orthoses, including insoles or specially designed shoes, have been introduced for pediatric flexible flat foot (PFFF). However, the structural effects of a long-term use of medial arch support insole remain unclear because the normal physiological maturation of the medial longitudinal arch cannot be ruled out. Methods From January 2005 to June 2015, 18 patients (34 feet) in group 1 (continuously insole applied group) and 13 patients (26 feet) in group 2 (untreated group) were enrolled. Medial arch support insole was applied from the age 10–11 years to radiographic physeal closure. Results In group 1, talonavicular coverage angle, lateral talo-1st metatarsal angle, calcaneal pitch angle and medial cuneiform height were significantly changed at final follow-up, although all values were still within the abnormal range. Further, no significant differences were found in any of the increments of the radiographic parameters between group 1 and 2. Conclusions Radiographic improvements were found in both of medial arch support insole treated or untreated group despite all radiographic values were still within the abnormal range. It was meaningful that the PFFF could be improved somewhat until the physes were closed. And the hindfoot alignment remained unchanged regardless of medial arch support insole application.

Isolated celiac artery dissection (ICAD) is a rare entity with over 160 cases described in literature. We report a case of incidentally detected isolated celiac artery dissection during computed tomography evaluation for occult gastrointestinal bleeding. Though most cases of isolated celiac artery dissection are initially managed conservatively with antiplatelet and anticoagulants, some patients may require endovascular or occasionally surgical treatment. In our case, the celiac artery dissection had already progressed to cause hepatic artery occlusion and secondary collateral formation in the porta hepatis region. We retrospectively analyze the natural course of celiac artery dissection with hepatic artery occlusion in an asymptomatic patient for over 3 years. Keywords: Celiac, Isolated, Dissection, Hepatic, Artery, Occlusion

The natural course of chronic pancreatitis(CP) and its complications has been inadequately explored. We aimed to describe the natural history and factors affecting the progression of alcoholic(ACP), idiopathic juvenile(IJCP) and idiopathic senile(ISCP) variants of CP.This study was a retrospective analysis from a prospectively maintained database of patients with CP following up at a tertiary care centre from 1998 to 2019. Cumulative rates of pain resolution, diabetes, steatorrhea, pseudocysts and pancreatic cancer were computed using Kaplan-Meier analysis, and the factors affecting their incidence were identified on multivariable-adjusted Cox-proportional-hazards model.A total of 1415 patients were included, with 540(38.1%) ACP, 668(47.2%) IJCP and 207(14.6%) ISCP with a median follow-up of 3.5 years(Inter-quartile range: 1.5-7.5 years). Diabetes occurred at 11.5, 28 and 5.8 years(p 0.001) while steatorrhea occurred at 16, 24 and 18 years(p = 0.004) after onset for ACP, IJCP and ISCP respectively. Local complications including pseudocysts occurred predominantly in ACP(p 0.001). Ten-year risk of pancreatic cancer was 0.9%, 0.2% and 5.2% in ACP, IJCP and ISCP, respectively(p 0.001). Pain resolution occurred more frequently in patients with older age of onset[Multivariate Hazard Ratio(HR):1.7(95%CI:1.4-2.0; p 0.001)], non-smokers[HR:0.51(95%CI:0.34-0.78); p = 0.002] and in non-calcific CP[HR:0.81(0.66-1.0); p = 0.047]. Occurrence of steatorrhea[HR:1.3(1.03-1.7); p = 0.028] and diabetes[HR:2.7(2.2-3.4); p 0.001] depended primarily on age at onset. Occurrence of pancreatic cancer depended on age at onset[HR:12.1(4.7-31.2); p 0.001], smoking-history[HR:6.5(2.2-19.0); p 0.001] and non-alcoholic etiology[HR:0.14(0.05-0.4); p 0.001].ACP, IJCP and ISCP represent distinct entities with different natural course. Age at onset of CP plays a major prognostic role in all manifestations, with alcohol predominantly causing local inflammatory complications.

Objective To reveal the changes of centrotemporal spikes that occur during the disease course of self-limited epilepsy with centrotemporal spikes (SLECTS). Method We retrospectively reviewed the serial EEGs of 63 patients with SLECTS from initial diagnosis to remission. There were 32 patients who did not undergo treatment and 31 patients who underwent treatment with oxcarbazepine (OXC). The change of occurrence or abundance, voltage, and location of centrotemporal spikes of serial EEGs were analyzed and compared between the two groups. Clinical seizure evidenced and reported was counted. The time gap between seizure remission and EEG remission was measured in the two groups. Result Changes of occurrence or abundance of the centrotemporal spikes were either abrupt (sudden disappearance of the frequent spikes on following EEG) or gradual (decline in number over 2 or more serial EEGs). Pattern of spike disappearance was not significantly different between the medication naive group and OXC treated group. The spike voltage or the location of centrotemporal spikes did not change during the disease course in most cases. Delay between seizure remission and EEG normalization was 3.34 ± 1.75 (mean ± standard deviation, range: 0.77–7.97) years in untreated patients and 3.03 ± 1.41 (0.95–6.61) years in OXC-treated group. Conclusion Pattern of spike disappearance in SLECTS was either abrupt or gradual. Treatment with OXC had no effect in the disappearance pattern. Precise data regarding the pattern of disappearance and delay between seizure remission and EEG normalization can help to understand the evolution of spike in SLECTS and to predict the timing of normalization of EEG after seizure remission.

Background Anxiety disorders frequently have an onset during adolescence, which when left untreated could lead to a chronic course and outcome. This study aimed to examine the way in which a cognitive behaviour therapy-based programme (Super Skills for Life – adolescent version; SSL-A) could change the course of anxiety symptoms through adolescent's behavioural performance and cardiac function. Method Sixty-one adolescents at risk of developing an anxiety disorder (45.30% boys; M = 13.76 years, SD = 0.32) were randomly assigned to either an intervention (IG), placebo (PG), or a waitlist group (WG). Adolescents in the IG participated in SSL-A over an 8-week period. Adolescents in the PG participated in an 8-session school-work programme. Adolescents in the WG did not receive any intervention. Anxiety symptoms were assessed every six months, twice before the intervention, as well as at the post-intervention and six months after the intervention. Participants in the IG additionally underwent a stressful task to assess behavioural performance and cardiac adjustment. Results Adolescents in the IG significantly reported lower levels of social phobia and generalised anxiety symptoms at the follow-up assessment compared to the adolescents in the PG and the WG. They also showed a significant improvement in vocal quality and lower discomfort during a stressful task at post-intervention, and showed attenuated cardiac recovery indexes, in terms of sample entropy. Limitations The study has a small sample size. Conclusion SSL-A changed the natural course of anxiety symptoms, as shown by a significant reduction in social phobia and generalised anxiety symptoms, and a significant improvement in behaviour and physiological (cardiac) function during a stressful situation.

An outbreak of respiratory illness proved to be infected by a 2019 novel coronavirus, officially named Coronavirus Disease 2019 (COVID-19), was notified first in Wuhan, China, and has spread rapidly in China and to other parts of the world. Herein, we reported the first confirmed case of novel coronavirus pneumonia (NCP) imported from China in Taiwan. This case report revealed a natural course of NCP with self-recovery, which may be a good example in comparison with medical treatments. Keywords: COVID-19, First case, Pneumonia, Taiwan

Optical coherence tomography (OCT) was used to assess serial changes in severe acute stent malapposition (ASM) after drug-eluting stent (DES) implantation.The maximal depth and axial lengths of ASM after DES implantation were serially quantified at percutaneous coronary intervention (PCI), and at 3 and 12-month follow-up, for 100 lesions in 96 patients. Severe ASM was defined as a maximal malapposed depth ≥400 μm or maximal malapposed axial length ≥1 mm.Of the 100 lesions, 23 lesions (23%) had a severe ASM depth at PCI. At 3 months, the maximal depth decreased to400 μm in 12 of 23 lesions (52%). At 12 months, the maximal depth further decreased to400 μm in 8 of the remaining 11 lesions (73%). Similarly, of 53 lesions (53%) with a severe ASM length at PCI, the maximal length decreased to 0 mm in 26 (49%) but remained severe in 17 lesions (32%) at 3 months. At 12 months, 9 of the 17 remaining lesions (53%) further decreased to 0 mm. The cut-off values for the maximal malapposed depth and length to predict the absence of stent malapposition at 12 months were 565 μm at PCI and 165 μm at 3 months, and were 2.7 mm at PCI and 0.1 mm at 3 months, respectively.Half of the severe ASM cases resolved within 3 months, and another half resolved during 3-12 months of follow-up. Our findings provide a better understanding of the time-dependent natural course of severe ASM using OCT.

Background Isolated, fusiform aneurysms, exclusively affecting the tubular portion of the ascending aorta, are rare. Surgical treatment aims to change their natural course, reducing individual and cumulative risks of rupture, dissection and death. Open tubular graft replacement still remains the procedure of choice, despite significant risks. In permanent pursuit for optimal, alternative surgical strategy in high-risk patients, less invasive and off-pump plicating ascending aortoplasty with modified external Dacron graft wrapping seems to be a reliable choice. Methods Two (2) consecutive patients were operated on. The same preoperative calculations and slightly different operative techniques were applied regarding surgical exposure and wrapping graft orientation. Immediate and late follow-up (5 years) results were compared. Results Absolute and indexed target ascending aortic diameters remained acceptable ( Conclusions Careful patient selection and using the current model of preoperative calculations and surgical technique resulted in acceptable and stable ascending aortoplasty in high-risk patients 5 years after surgery.

Coronary artery fistulas (CAFs) are accounted as the most congenital coronary anomalies. As their natural course is progressive dilatation of the feeder arteries and the fistula tract, so, catastrophic complications are frequently illustrated by aging. Even in those with asymptomatic small fistulas, close follow-up is mandatory to prevent subsequent sequelas. In patients with medium or large-sized fistulas, irrespective of symptoms, closure (either by surgical ligation or transcatheter closure) is recommended. In the current era of advances in the equipment and devices and also innovations in percutaneous closure techniques and preprocedural imaging, TCC is now regarded as the preferred strategy for CAF closure except in some high-risk cases. So, by appropriate case selection modalities, pre-procedural planning, and determining the closure techniques, recent small case-series studies have been reported good final angiographic and clinical results by TCC. In this article, we have introduced several transcatheter closure techniques by details; also, we have recommended more multi-center trials with long-term clinical follow-up to address the best treatment options in these patients.

Recent reports have described midterm natural courses of osteochondral lesion of the talus (OLT) and lack of progression of ankle osteoarthritis (OA) in adult patients. The relationship between the OLT managed with nonoperative treatment and development of OA in children remains unknown. We report the long-term course of medial OLT in a 12-year-old female who was treated nonoperatively for 10 years. Radiographically, no osteoarthritic changes were observed at the first examination. She initially returned to her basketball club after nonoperative treatment. Although daily activities were not restricted, limitation of recreational activities began to appear at 4 years of follow-up. Subsequently, plain radiographs revealed bone absorption around the osteochondral fragment and osteophyte formation at the medial gutter, then ankle OA was advanced at the final follow-up.

Scoliosis can cause various respiratory complications, even in the natural course, because of rearrangement of the intrathoracic anatomy owing to chest wall deformity. We experienced a patient with scoliosis who developed acute respiratory failure owing to bronchial obstruction induced by bronchial compression by the dorsal thoracic vertebra after right upper lobectomy for cancer. The symptom resolved after mobilization of the ipsilateral lower lobe, which was achieved by releasing the inferior pulmonary vein by U-shaped pericardial dissection with division of the pulmonary ligament. When planning lobectomy for patients with severe scoliosis, the anatomic changes caused by pulmonary resection must be considered.

Introduction Subclinical hypothyroidism is defined as elevation of thyroid-stimulating hormone (TSH) levels, with normal thyroid hormone levels and negative autoimmunity, in asymptomatic patients with no findings on examination. Because of the unwarranted increase in thyroid function tests in asymptomatic children, the main objective of this review was to analyze the course of these patients. Analysis of associated costs was a secondary objective. Material and methods A longitudinal, observational, retrospective study of patients referred to the endocrinology department of a tertiary hospital for high TSH levels (TSH 5–20 mIU/l). Clinical and laboratory variables, number of visits until discharge, need for treatment, monitoring time, and economic variables were collected. Results The study sample consisted of 155 patients with a mean age of 7.8 years ± 3.6 SD. Referrals to endocrinology accounted for 4% of first office visits. Baseline mean TSH level was 7.8 mU/l (5.03–15.8 mU/l). TSH levels normalized after the first repeated measurement during the subsequent month in 60% of cases. A total of 83.6% of patients were discharged within a maximum of 3 years, with a mean follow-up of 8.14 ± 6.8 months and 2.4 visits/patient. Average cost per patient was € 251.27 (range € 143.49–444.21). Conclusion It is essential not to alarm the family when subclinical hypothyroidism is detected, because this is a biochemical situation which normalizes in most cases. This fact, together with the mean cost of specialized care, suggests that the first step should be repeated TSH measurements in primary care.

Background The long-term natural course and outcomes of subsolid nodules (SSNs) in terms of true growth, substantial growth, and stage shift need to be clarified. Methods Between 2002 and 2016, 128 subjects with persistent SSNs of 3 cm or smaller were enrolled. The baseline and interval changes in the series computed tomography (CT) findings during the follow-up period were subsequently reviewed. Results The mean follow-up period was 3.57 ± 2.93 years. The cumulative percentage of growth nodules of the part-solid nodule (PSN) group was significantly higher than that of the ground-glass nodule (GGN) group by Kaplan-Meier estimation (all p Conclusions The natural course in terms of true growth, substantial growth, and stage shift differed significantly according to their nodule type, which could contribute to the development of follow-up guidelines and management strategy of pulmonary SSNs.

The natural course of chronic obstructive pulmonary disease usually includes exacerbations. chronic obstructive pulmonary disease patients suffer from 1-4 exacerbations per year on average. These are associated with worsening quality of life and increased mortality. Reducing and controlling the number of exacerbations is one of the main goals of chronic obstructive pulmonary disease treatment. Among current treatments, tiotropium is the active substance with the strongest evidence in the reduction of moderate/severe exacerbations, together with a good safety and tolerability profile. The addition of olodaterol to tiotropium offers well-tolerated and effective double bronchodilation for improving lung function, quality of life, and decreased dyspnoea compared to its single components. This also reduces the annual rate of moderate/severe exacerbations vs. tiotropium by 7%, although not reaching the pre-specified statistical significance level of P

Introduction Small ground-glass nodules (GGNs) or those with an indeterminate risk on low-dose computed tomography (LDCT) of the chest are recommended at 5-year follow-up, but the rationale for follow-up beyond 5 years is unclear. Methods An observational study was conducted to investigate the natural course of GGNs that had been stable for 5 years by LDCT over 10 years. All eligible GGNs were detected during regular health checkups. Baseline characteristics were compared between GGNs with and without growth. Risk factors for GGN growth were evaluated. Results A total of 208 GGNs were detected in 160 participants. GGN growth was identified in 27 (13.0%) GGNs during a follow-up of 136 months on LDCT scans. In approximately 95% of these GGNs, the initial size was less than 6 mm, with 3.2 mm of growth over 8.5 years. Biopsies were performed in 3 of 27 GGNs, revealing adenocarcinoma. In 8 of 27 cases, GGN growth preceded the development of a new solid component. In a multivariate analysis, bubble lucency (p = 0.001), a history of cancer other than lung cancer (p = 0.036), and development of a new solid component (p Conclusions GGNs should not be ignored, even when smaller than 6 mm and stable for 5 years, especially when a new solid component appears during follow-up.

Background We aimed to delineate the pattern of natural course, neuroimaging features, and the genotypic spectrum of cavitating leukoencephalopathies. Methods Children (age of onset ≤16 years) who met the criteria for cavitating leukoencephalopathies from January 2009 to October 2018 were identified. Whole-exome sequencing and prospective follow-up study of the natural history and brain magnetic resonance imaging (MRI) were performed. Results Thirty-seven children were clinically diagnosed with cavitating leukoencephalopathies. Pathogenic or likely pathogenic mutations in eight genes were identified in 31 individuals (83.78%): IBA57 (17/37), NDUFS1 (5/37), NDUFV1 (2/37), NDUFV2 (3/37), NDUFAF5 (1/37), LYRM7 (1/37), NDUFB8 (1/37), and GLRX5 (1/37). All genes were engaged in mitochondrial function. IBA57 was identified in half of children. Mutations in NDUFV2, NDUFAF5, NDUFB8, or GLRX5 were first found to be related to cavitating leukoencephalopathies. Follow-up with a median of 23.5 months (four to 107 months) was available. The median age at disease onset was 11 months. All cases presented acute or subacute onset, and the initial presentation was rapid motor regression in 35 cases. Thirty-five children (35/37) exhibited a stabilized or improved pattern. Cavities and high-intensity diffusion-weighted imaging signals were the common MRI features during the acute stage. Although clinically stable, 21 children had reserved high diffusion-weighted imaging signals for a long time. Patients with different gene mutations show different MRI patterns. Conclusions The study expands the number of genes involved in cavitating leukoencephalopathies to 22. IBA57 is the most common candidate gene. Most cases showed a stabilized or improved pattern after an acute or subacute onset, which is different from most other inherited metabolic diseases or leukodystrophies. More cases and a longer follow-up period are needed.

Reproducible skills are essential for successful induction of a rat model of anterior ischemic optic neuropathy (rAION). We established an in vivo validation index by measuring the natural course of optic nerve head (ONH) width and retinal nerve fiber layer (RNFL) thickness in the rAION model using optical coherence tomography (OCT). The rAION model was induced by photodynamic operations. We measured the ONH width, RNFL, Inner Plexiform layer (IPL) and Ganglion cell complex (GCC) thickness in the acute stage (3 days), subacute stage (day-7 to day-14) and later stage (day-14 to day-28) post-infarct by OCT. Retinal layers were measured by hematoxylin and eosin stain (HE) to confirm the OCT findings. The RGCs survival rate was determined by retrograde Fluoro-gold labeling, and the visual function was assessed with flash visual-evoked potentials (FVEPs) 4 weeks post-infarct. We observed significant thinning in GCC, IPL, and RNFL at day-14 and day-28 but only RNFL showed significant thinning between day-14 and day-28. The ONH showed significant swelling in the acute stage which correlated at a greater extent with RNFL than GCC and IPL. Further RNFL correlated at a greater extent at with GCC than IPL. HE-stained retina cross sections also showed IPL and RNFL thinning, which further confirmed our OCT findings. The RGC density and P1-N2 amplitude were significantly reduced in rAION. Our data suggest that Swelling, reduction of swelling, and atrophy of RNFL in acute, sub-acute, and later stage, respectively and ONH swelling in the acute stage are essential events for confirming the successful induction of rAION.

Persistence of thyroglobulin antibody (TgAb) in patients with papillary thyroid carcinoma (PTC) years after total thyroidectomy (TT) followed by ablation occurs even without any evidence of structural disease. Few studies have studied the natural course of TgAb positivity and factors that may influence this course. The present study evaluated the time trends of TgAb in ablated PTC patients and aimed to identify the predictive factors for the rate of negative conversion of TgAb.Overall, 1279 patients who underwent TT and subsequent ablation for PTC, with available data on thyroid peroxidase Ab (TPOAb) and TgAb prior to surgery (preop-) and ablation (abl-) were enrolled. Patients with initial distant metastasis or recurrence during follow-up were excluded.Preop-TgAb was positive in 24.9% of patients (n = 319), whereas abl-TgAb positivity decreased to 12.8% (n = 164). In 164 patients positive for abl-TgAb, TgAb in patients with higher abl-TgAb levels decreased more gradually than those observed in patients with lower abl-TgAb levels (p 0.001). Furthermore, in patients within the same range of abl-TgAb levels, patients positive for abl-TPOAb had a higher rate of negative conversion of TgAb compared with negative patients for abl-TPOAb (log rank p 0.001). TPOAb significantly increased the rate of negative conversion in multivariate analysis adjusted for abl-TgAb (odds ratio 1.59, 95% confidence interval 1.11-2.28, p = 0.011). This study clearly showed that abl-TgAb titers and abl-TPOAb status can predict the rate of negative conversion. These findings can guide the optimal timing for additional examination in patients positive for TgAb during follow-up.

Objective To present the natural course and treatment modalities of spontaneous cervical epidural hematoma (SCEH), by reporting two rare cases with spontaneous resolution in both clinical and radiologic findings without surgery. Material and methods One patient presenting with acute right side hemiparesis and another showing pure cervical radiculopathy were diagnosed with SCEH on magnetic resonance imaging (MRI). Both were both treated non-operatively. We also conducted a literature review of 19 cases of spontaneous spinal epidural hematoma (SSEH). Results These two patients achieved complete resolution in terms of both neurologic function and radiologic findings within 21 days after onset. In the literature review, 63.2% of cases experienced neurologic improvement in the first 24 h, 78.9% achieved complete neurologic recovery within 1 month, and radiological images showed complete resolution of hematoma in the first month for 73.7% of patients. Conclusions Atypical cervical SSEH can mimic cerebral stroke or a ruptured cervical disc. A high index of clinical suspicion followed by MRI examination is critical for diagnosis. Prompt surgical decompression and evacuation of the hematoma is generally regarded as first-line treatment. However, for patients without or with only slight neurologic symptoms, or showing early and sustained neurologic improvement, non-surgical therapy with close observation is a viable alternative. Both neurologic and radiologic resolution can be expected within the first month following onset in most cases of spontaneous resolution of SSEH.

Tardive dyskinesia (TD) is a common, iatrogenic movement disorder affecting many individuals treated with dopamine-receptor blocking agents (DRBAs). Studying treatment of TD can be complex, as the symptoms can be affected by changes in either dosage or type of DRBA, as well as by the variable natural course of the disease. Historically many pharmacological therapies have been studied in TD, finding varying degrees of treatment success. Most recently, the VMAT2 inhibitors valbenazine and deutetrabenazine were rigorously studied in TD in large, phase III clinical trials, and were shown to be beneficial in this population. In this article, we will review various treatments of TD, including manipulation of the offending agent, VMAT2 inhibitors, other non-VMAT2-inhibiting medications, and non-pharmacological approaches.

Background: An ongoing outbreak of the SARS-CoV-2 infection, known as COVID-19, has spread all around the world, causing a great number of deaths Given that t

Healthy hair is vital to identity. Understanding the intricate anatomy and physiology of hair provides insight into the aging process and the eventual loss of either hair pigmentation or hair shafts. Several biologics are available that have enabled altering or slowing the aging process of hair, but, unfortunately, no agent exists that can reverse the natural course. The commonly used biologics are discussed.

To clarify the effectiveness of anterior cervical fusion (ACF) in the treatment of Hirayama disease (HD).Sixty-nine HD patients who accepted ACF procedures underwent dynamic F-waves before and soon after operation, and 36 of the 69 patients underwent pre- and postoperative magnetic resonance imaging (MRI). Motor unit number estimation, handgrip strength (HGS) and disabilities of arm, shoulder and hand (DASH) were performed in these 36 HD patients and in the other 24 patients who accepted neither neck-collar support nor operation, and these tests were reassessed about one year after initial test.Postoperatively, dynamic F-wave abnormalities were observed in fewer HD cases (2/69 vs. 25/69), and neck-flexion MRI abnormalities decreased significantly (P 0.05). Compared with motor unit loss in patients who were untreated, follow-up analysis demonstrated no differences in motor unit, HGS or DASH in HD patients who underwent operation (P 0.05), and mild recovery of motor units was observed in patients with preoperative abnormal dynamic F-waves (P 0.05).ACF procedures can immediately remove neck-flexion abnormalities and prevent or delay the progression of HD.ACF procedures may provide effective, reliable and alternative methods for the treatment of HD, especially in HD patients with functional evidence of neck-flexion abnormalities.

Muscle injury accounts for about one-third of total sports-related injuries. The lower limb muscles have one of the highest predisposition for injury in high-level professional athletic sports, such as the National Football League. The commonest group of muscles injured among football players include the hamstrings, followed by the quadriceps. Muscle injuries lead to significant time, off the field and affect return to play. Sports physicians and teams have been keen on assessing such injuries and also relying on multiple tools to safely return the player back to the field. MRI plays a key role in evaluation, follow-up, and assessment for return to play (RTP). In this review, we will discuss details of muscle anatomy, incidence of muscle injuries, injury mechanisms, and use of MRI in assessment, grading, follow-up and in predicting the natural course of muscle injuries in the high-end athletic players. While the use of MRI is clear in diagnosis, and for follow up of muscle injuries, there is some limitation in its ability to predict RTP, based on current MRI classification systems. Footballers who have clinical injuries without MRI evidence of significant muscle injury (grade 0 and 1) have a shorter period of RTP. Injuries classified as high grade (3 and 4) on MRI do not correlate well with time to RTP. Further trials are required to improve the capability of MRI in its prediction of RTP.

After surgical bone tumor removal, filling of the bone defect is frequently performed using a bone graft or bone graft substitute. During follow-up, precise quantification of changes in bone mineral density, within the treated bone defect, is very difficult using conventional X-ray examinations. The objectives of this study were to characterize the pattern of resorption/biodegradation of a composite calcium sulfate/hydroxyapatite bone graft substitute and to quantify the bone defect healing with repeated dual-energy X-ray absorptiometry (DXA) measurements. Seventeen patients treated for 18 benign bone lesions, with subsequent defect filling using 2 variants of a composite ceramic bone graft substitute (CERAMENT™|BONE VOID FILLER or CERMAMENT™|G, BONESUPPORT AB, Lund, Sweden), were scanned postoperatively and after 2, 6, 12, 26, and 52 wk using DXA. After an initial increase in bone mineral density after implantation of the bone graft substitute, bone mineral density decreased in the bone defect region throughout the 52 wk: rapidly in the first 12 wk and slower in the remaining weeks. Despite this continuous decrease, bone mineral density remained, on average, 25% higher in the operated extremity, compared with the nonoperated extremity, after 52 wk. The observed pattern of reduction in bone mineral density is consistent with the anticipated resorption of calcium sulfate within the bone graft substitute during the first 12 wk after surgery. We believe the DXA technique provides a precise method for quantification of bone graft resorption, but for evaluation of new bone formation, 3-dimensional imaging is needed.

We investigated the trainability of the hemodynamic response as assessed with near-infrared spectroscopy (NIRS) during one neurofeedback (NF) session. Forty-eight participants were randomly assigned to four different groups that tried to either increase or decrease oxygenated (oxy-Hb) or deoxygenated hemoglobin (deoxy-Hb) over the inferior frontal gyrus during imagery of swallowing movements. Deoxy-Hb could be successfully up-regulated while oxy-Hb could be successfully down-regulated during NF. Participants were not able to down-regulate deoxy-Hb or to up-regulate oxy-Hb. These results show that the natural course of oxy- and deoxy-Hb during movement imagery can be reinforced by providing real-time feedback of the corresponding NIRS parameter since deoxy-Hb generally increases and oxy-Hb decreases during imagery of swallowing. Furthermore, signal-to-noise ratio of deoxy-Hb but not of oxy-Hb improved during training. Our results provide new insights into the trainability of the hemodynamic response as assessed with NIRS and have an impact on the application of NIRS-based real-time feedback.

Background: It is unclear whether moderate or less functional tricuspid regurgitation (TR) should be repaired during surgery for degenerative mitral valve (MV) disease. We studied the natural course of unaddressed moderate or less TR and identified risk factors for TR progression after surgery for degenerative MV disease. Methods: From 2001 to 2011, 2,982 patients with isolated degenerative MV disease and no evidence of coronary artery disease underwent MV surgery. To generate an enriched sample of patients with TR, by random selection 200 patients without TR, 197 with mild TR, and 177 with moderate TR were studied. A total of 1,150 echocardiograms were available for longitudinal analysis of TR progression after surgery in 550 of these 574 patients. Results: Overall prevalence of severe TR was 1.1%, 2.2%, 3.6%, and 4.4% by 1, 3, 5, and 7 years, respectively. Patients with moderate preoperative TR were more likely to progress to severe TR by 7 years (8.6%) than those with mild TR (3.2%) or no TR (1.3%) preoperatively (p p = 0.03), shorter right ventricular base-to-apex length (p = 0.0004), smaller tethering area (p = 0.01), older age, and preoperative heart failure. During follow-up, no patient underwent TV intervention. Conclusion: Routine repair of moderate or less functional TR during surgery for degenerative MV disease does not appear to be warranted, because progression to severe TR is uncommon. Instead, we suggest a tailored approach, reserving TR repair during surgery for degenerative MV disease for patients with known risk factors.

The aim of this study was to determine the natural course of pain after tonsillectomy.This study included 119 patients that underwent tonsillectomy between November 2013 and November 2015. After undergoing tonsillectomy, patients scored their pain using the visual analogue scale three times daily (morning, midday, and evening) for 2 weeks. A linear mixed model was used for statistical analyses.Increasing postoperative days was negatively associated with pain following tonsillectomy surgery (estimated value [EV] of visual analogue score [VAS]/day=-0.42, 95% confidence interval [CI]=-0.43 to -0.41, P0.001); the post-tonsillectomy pain curve illustrated this negative correlation. Postoperative pain was less in children and adolescents (≤18years old) than in adults (18 years old) (EV=-0.81, 95% CI=-1.56 to -0.08, P=0.031). Mean tonsillectomy-associated pain on postoperative day 1 was 6.4 VAS. It decreased slightly to 5.3 VAS until postoperative day 7, after which it reduced sharply to 3.7 VAS within 3 days; on postoperative day 14 it had decreased to 1.6 VAS. Pain assessments were higher in the morning (EV=0.59, 95% CI=0.50 to 0.69, P0.001) compared with assessments conducted in the evening.The natural course of postoperative tonsillectomy pain follows a gradual decline for 1 week after surgery, but decreases more rapidly after this period.

In 2008, the Spanish Society of Pulmonology (SEPAR) published the first guidelines in the world on the diagnosis and treatment of bronchiectasis. Almost 10 years later, considerable scientific advances have been made in both the treatment and the evaluation and diagnosis of this disease, and the original guidelines have been updated to include the latest scientific knowledge on bronchiectasis. These new recommendations have been drafted following a strict methodological process designed to ensure the quality of content, and are linked to a large amount of online information that includes a wealth of references. These guidelines cover aspects ranging from a consensual definition of bronchiectasis to an evaluation of the natural course and prognosis of the disease. The topics of greatest interest and some new areas are addressed, including epidemiology and economic costs of bronchiectasis, pathophysiological aspects, the causes (placing particular emphasis on the relationship with other airway diseases such as chronic obstructive pulmonary disease and asthma), clinical and functional aspects, measurement of quality of life, radiological diagnosis and assessment, diagnostic algorithms, microbiological aspects (including the definition of key concepts, such as bacterial eradication or chronic bronchial infection), and the evaluation of severity and disease prognosis using recently published multidimensional tools.

Alzheimer's disease is the most common cause of dementia in the elderly population. Currently, there are no effective treatments to prevent or delay the natural course of the disease. Numerous studies have provided information about the molecular processes underlying biological ageing and, perhaps more importantly, potential interventions to slow ageing and promote healthy longevity in laboratory model systems. The main issue addressed in this review is whether an intervention that has anti-ageing properties can alter the appearance and/or progression of Alzheimer's disease, a disease in which age is the biggest risk factor. Different anti-ageing interventions have been shown to prevent (and in some cases possibly restore) several parameters recognised as central symptoms to the development of Alzheimer's disease. In addition, they are taking the first steps towards translating these laboratory discoveries into clinical applications.

Despite being the leading cause of spinal cord dysfunction among adults worldwide, little is known about the natural history of degenerative cervical myelopathy (DCM). There is mounting evidence of the effectiveness of surgery for DCM in halting progression of symptoms, and in fact, in improving neurologic outcomes, functional status, and quality of life. However, surgical decision making relies on a weighing of the risks and benefits of alternative strategies. We reviewed the available literature pertaining to the natural course of DCM and the predictors of outcome of nonoperative approaches.

Background: Assessment of clinical benefit of systemic treatments of rare diseases including gastroenteropancreatic neuroendocrine tumours (GEP-NET) is challenging. Recently several tools have been developed to grade the clinical benefit of cancer drugs. The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). The American Society of Clinical Oncology (ASCO) has developed and revised the ASCO framework consisting of the Net Health Benefit (NHB) score juxtaposed against the costs of the treatment. In this review, we graded systemic treatments for GEP-NET patients with both frameworks.Methods: The electronic databases (PubMed and EMBASE) were searched for papers reporting comparative trials, conducted in adult GEP-NET patients in the English language. Papers were assessed according to the ESMO-MCBS and the NHB part of the ASCO revised Framework (NHB-ASCO-F) by four independent assessors, and discrepancies were discussed.Results: The search yielded 32 trials of which 6 were eligible for grading with the ESMO-MCBS resulting in scores of 2 or 3. Eight trials were eligible for grading with the NHB-ASCO-F, resulting in scores between 37.6 and 57.4. Trials that were not primary assessable by the tools were analysed separately. Consensus between assessors was reached in 68% of trials with the ESMO-MCBS and in 23% of trials with the NHB-ASCO-F.Conclusion: The currently used systemic treatments for GEP-NET patients had low scores according to the NHB-ASCO-F and none could be graded as meaningful clinical beneficial according to the ESMO-MCBS. Despite the low incidence, the heterogeneous patient population and relatively long natural course of NET, future studies on new treatment modalities should aim for high clinical benefit outcomes.