Unwarranted death of neurons is a major cause of neurodegenerative diseases.Since mature neurons are postmitotic and do not replicate,their death usually constitutes an irreversible step in pathology.A logical strateg...Unwarranted death of neurons is a major cause of neurodegenerative diseases.Since mature neurons are postmitotic and do not replicate,their death usually constitutes an irreversible step in pathology.A logical strategy to prevent neurodegeneration would then be to save all neurons that are still alive,i.e.protecting the ones that are still healthy as well as trying to rescue the ones that are damaged and in the process of dying.Regarding the latter,recent experiments have indicated that the possibility of reversing the cell death process and rescuing dying cells is more significant than previously anticipated.In many situations,the elimination of the cell death trigger alone enables dying cells to spontaneously repair their damage,recover,and survive.In this review,we explore the factors,which determine the fate of neurons engaged in the cell death process.A deeper insight into cell death mechanisms and the intrinsic capacity of cells to recover could pave the way for novel therapeutic approaches to neurodegenerative diseases.展开更多
Background:Magnetic resonance imaging(MRI)is crucial in modern medical diagnostics,providing detailed insights into soft tissue structures and pathological changes.Traditional grayscale images can sometimes obscure cr...Background:Magnetic resonance imaging(MRI)is crucial in modern medical diagnostics,providing detailed insights into soft tissue structures and pathological changes.Traditional grayscale images can sometimes obscure critical details,complicating accurate interpretations.Automated color coding of the MRI signal intensities may enhance the visualization of various pa-thologies,potentially leading to improved diagnostic accuracy and image quality.This paper aims to explore the effectiveness of color-coded MR image reconstruction in enhancing both diagnostic precision and overall image quality in musculoskeletal MRI.Methods:Two fellowship-trained musculoskeletal radiologists evaluated the images reconstructed with color coding,rating their diagnostic value,image quality,and visual appeal using a five-point Likert scale.To assess interrater reliability,Cohen's Kappa statistical analysis was performed.Additionally,descriptive statistics summarizing the Likert scores for diagnostic value,image quality,and visual appeal of the reconstructed images have been described.Results:Statistical analysis of the data revealed that the diagnostic value,image value,and visual appeal of the color-coded MR images were excellent in almost two-thirds of the data set.The minimum Likert score recorded was 3,signifying a good quality rating.Conclusion:Our study shows positive results,supporting the efficiency of color-coded MR imaging in aiding the conventional gray scale MR imaging to improve its diagnostic efficiency.展开更多
Background Conditional relative survival(CRS),the probability of survival given that an individual has already survived a certain period post-diagnosis,is a more clinically relevant measure for long-term survival than...Background Conditional relative survival(CRS),the probability of survival given that an individual has already survived a certain period post-diagnosis,is a more clinically relevant measure for long-term survival than standard relative survival(RS).This study aims to evaluate the 5-year CRS among adolescent and young adult(AYA)breast cancer patients by age,tumor stage,and receptor subtype to guide disclosure periods for insurance.Methods Data of all females aged 18–39 years and diagnosed with invasive breast cancer between 2003 and 2021(n=13,075)were obtained from The Netherlands Cancer Registry(NCR).The five-year CRS was calculated annually up to 10 years post-diagnosis using a hybrid analysis approach.Results For the total AYA breast cancer study population the 5-year CRS exceeded 90%from diagnosis and increased beyond 95%7 years post-diagnosis.Patients aged 18–24 reached 95%9 years post-diagnosis,those aged 25–29 after 5 years,and those aged 30–34 and 35–39 after 8 years.For stage I,the 5-year CRS reached 95%from diagnosis,for stage II after 6 years,while the 5-year CRS for stages III and IV did not reach the 95%threshold during the 10-year follow-up.Triple-negative tumors exceeded 95%after 4 years,human epidermal growth factor receptor 2(HER2)positive tumors after 6 years,while hormone receptor(HR)positive tumors did not reach 95%.Conclusion Excess mortality among AYA breast cancer patients tends to be little(CRS 90%–95%)from diagnosis and becomes minimal(CRS>95%)over time compared to the general population.These results can enhance expectation management and inform policymakers,suggesting a shorter disclosure period.展开更多
Background There is insufficient evidence to provide recommendations for leisure-time physical activity among workers across various occupational physical activity levels.This study aimed to assess the association of ...Background There is insufficient evidence to provide recommendations for leisure-time physical activity among workers across various occupational physical activity levels.This study aimed to assess the association of leisure-time physical activity with cardiovascular and all-cause mortality across occupational physical activity levels.Methods This study utilized individual participant data from 21 cohort studies,comprising both published and unpublished data.Eligibility criteria included individual-level data on leisure-time and occupational physical activity(categorized as sedentary,low,moderate,and high)along with data on all-cause and/or cardiovascular mortality.A 2-stage individual participant data meta-analysis was conducted,with separate analysis of each study using Cox proportional hazards models(Stage 1).These results were combined using random-effects models(Stage 2).Results Higher leisure-time physical activity levels were associated with lower all-cause and cardiovascular mortality risk across most occupational physical activity levels,for both males and females.Among males with sedentary work,high compared to sedentary leisure-time physical activity was associated with lower all-cause(hazard ratios(HR)=0.77,95%confidence interval(95%CI):0.70-0.85)and cardiovascular mortality(HR=0.76,95%CI:0.66-0.87)risk.Among males with high levels of occupational physical activity,high compared to sedentary leisure-time physical activity was associated with lower all-cause(HR=0.84,95%CI:0.74-0.97)and cardiovascular mortality(HR=0.79,95%CI:0.60-1.04)risk,while HRs for low and moderate levels of leisure-time physical activity ranged between 0.87 and 0.97 and were not statistically significant.Among females,most effects were similar but more imprecise,especially in the higher occupational physical activity levels.Conclusion Higher levels of leisure-time physical activity were generally associated with lower mortality risks.However,results for workers with moderate and high occupational physical activity levels,especially women,were more imprecise.Our findings suggests that workers may benefit from engaging in high levels of leisure-time physical activity,irrespective of their level of occupational physical activity.展开更多
Objective:two new cases of temporal bone squamous cell carcinoma(TBSCC)with a bilateral occurrence are presented.Furthermore,a review of the literature was performed and the yearly incidence was calculated.Methods:A s...Objective:two new cases of temporal bone squamous cell carcinoma(TBSCC)with a bilateral occurrence are presented.Furthermore,a review of the literature was performed and the yearly incidence was calculated.Methods:A systematic review of the literature was conducted using PRISMA guidelines.Results:Twenty-two more cases were found in literature.With a total of 24 cases,the calculated yearly incidence of bilateral TBSCC is 49:10^12 A history of chronic otitis or regional radiotherapy was found in respectively 50%and 12%of patients.In nine patients,the tumors developed synchronously(within 6 months)and in 13 metachronously.Conclusions:The calculated incidence is 89 times higher than mathematically expected considering the incidence of unilateral cases.An explanation might be a history of chronic otitis or prior radiotherapy.The tumor staging of both the first tumor group and the contralateral tumor group are similar to unilateral temporal bone squamous cell carcinoma series.展开更多
Development of therapeutics for brain diseases has remained challenging,in particular due to the difficulty of passing the blood-brain barrier.As a result,the current arsenal of therapeutics targeting the brain is lim...Development of therapeutics for brain diseases has remained challenging,in particular due to the difficulty of passing the blood-brain barrier.As a result,the current arsenal of therapeutics targeting the brain is limited to small,lipid-soluble drugs and there is a lack of options for treating neuroblastomas,Alzheimer’s disease,and many other devastating pathologies.Despite the advances in strategies for crossing the blood-brain barrier such as the use of nanoparticles(Hersh et al.,2022;Duan et al.,2023),such delivery systems have not yet reached clinical practice.Therefore,novel platforms for the transport of therapeutics across the blood-brain barrier remain highly desired.This specifically holds for large molecules such as monoclonal antibodies and recombinant proteins,as well as nucleotide-based therapeutics and cell therapies.Research efforts in this field are increasing exponentially,with thousands of publications in the last few years.展开更多
Maintenance of protein homeostasis or“proteostasis”is essential for the functioning and viability of cells.This is in particular the case for cells like neurons that cannot self-renew and acquire unique functional p...Maintenance of protein homeostasis or“proteostasis”is essential for the functioning and viability of cells.This is in particular the case for cells like neurons that cannot self-renew and acquire unique functional properties during their lifetime.Cellular proteostatic stress responses are in place to protect cells from damage in case of proteostatic challenges.The integrated stress response(ISR)is one of the key proteostatic stress responses in the cell(Costa-Mattioli and Walter,2020).The ISR is the downstream convergence point for the four stress-induced eIF2αkinases(EIF2AK1-4)that control stress-regulated protein translation via phosphorylation of the translation factor eIF2α.ISR activation results in a transient reduction of global translation while it concomitantly enhances the translation of specific mRNAs,including that encoding the activating transcription factor 4(ATF4).Together,the translational control mediated by the ISR results in a temporary reduction of the overall protein load and the selectively increased expression of proteins that contribute to restoration of the proteostatic balance.展开更多
BACKGROUND Lateral ankle sprains are the most common traumatic musculoskeletal injuries of the lower extremity,with an incidence rate of 15%-20%.The high incidence and prevalence highlights the economic impact of this...BACKGROUND Lateral ankle sprains are the most common traumatic musculoskeletal injuries of the lower extremity,with an incidence rate of 15%-20%.The high incidence and prevalence highlights the economic impact of this injury.Ankle sprains lead to a high socioeconomic burden due to the combination of the high injury incidence and high medical expenses.Up to 40%of patients who suffer from an ankle sprain develop chronic ankle instability.Chronic instability can lead to prolonged periods of pain,immobility and injury recurrence.Identification of factors that influence return to work(RTW)and return to sports(RTS)after a lateral ankle sprain(LAS)may help seriously reduce healthcare costs.AIM To explore which factors may potentially affect RTW and RTS after sustaining an LAS.METHODS EMBASE and PubMed were systematically searched for relevant studies published until June 2023.Inclusion criteria were as follows:(1)Injury including LAS or chronic ankle instability;(2)Described any form of treatment;(3)Assessment of RTW or RTS;(4)Studies published in English;and(5)Study designs including randomized controlled clinical trials,clinical trials or cohort studies.Exclusion criteria were:(1)Studies involving children(age<16 year);or(2)Patients with concomitant ankle injury besides lateral ankle ligament damage.A quality assessment was performed for each of the included studies using established risk of bias tools.Additionally quality of evidence was assessed using the GRADEpro tool in cases where outcomes were included in the quantitative analysis.A best evidence synthesis was performed in cases of qualitative outcome analysis.For all studied outcomes suitable for quantitative analysis a forest plot was created to calculate the effect on RTW and RTS.RESULTS A total of 8904 patients were included in 21 studies,10 randomized controlled trials,7 retrospective cohort studies and 4 prospective cohort studies.Fifteen studies were eligible for meta-analysis.The overall RTS rate ranged were 80%and 83%in the all treatments pool and surgical treatments pool,respectively.The pooled mean days to RTS ranged from 23-93 d.The overall RTW rate was 89%.The pooled mean time to RTW ranged from 5.8-8.1 d.For patients with chronic ankle instability,higher preoperative motivation was the sole factor significantly and independently(P=0.001)associated with the rate of and time to RTS following ligament repair or reconstruction.Higher body mass index was identified as a significant factor(P=0.04)linked to not resuming sports or returning at a lower level(median 24,range 20-37),compared to those who resumed at the same or higher level(median 23,range 17-38).Patients with a history of psychological illness or brain injury,experienced a delay in their rehabilitation process for sprains with fractures and unspecified sprains.The extent of the delayed rehabilitation was directly proportional to the increased likelihood of experiencing a recurrence of the ankle sprain and the number of ankle-related medical visits.We also observed that 10%of athletes who did return to sport after lateral ankle sprain without fractures described non-ankle-related reasons for not returning.CONCLUSION All treatments yielded comparable results,with each treatment potentially offering unique advantages or benefits.Preoperative motivation may influence rehabilitation after LAS.Grading which factor had a greater impact was not possible due to the lack of comparability among the included patients.展开更多
BACKGROUND Over the years,strides in colon cancer detection and treatment have boosted survival rates;yet,post-colon cancer survival entails cardiovascular disease(CVD)risks.Research on CVD risks and acute cardiovascu...BACKGROUND Over the years,strides in colon cancer detection and treatment have boosted survival rates;yet,post-colon cancer survival entails cardiovascular disease(CVD)risks.Research on CVD risks and acute cardiovascular events in colorectal cancer survivors has been limited.AIM To compare the CVD risk and adverse cardiovascular outcomes in current colon cancer survivors compared to a decade ago.METHODS We analyzed 2007 and 2017 hospitalization data from the National Inpatient Sample,studying two colon cancer survivor groups for CVD risk factors,mortality rates,and major adverse events like pulmonary embolism,arrhythmia,cardiac arrest,and stroke,adjusting for confounders via multivariable regression analysis.RESULTS Of total colon cancer survivors hospitalized in 2007(n=177542)and 2017(n=178325),the 2017 cohort often consisted of younger(76 vs 77 years),male,African-American,and Hispanic patients admitted non-electively vs the 2007 cohort.Furthermore,the 2017 cohort had higher rates of smoking,alcohol abuse,drug abuse,coagulopathy,liver disease,weight loss,and renal failure.Patients in the 2017 cohort also had higher rates of cardiovascular comorbidities,including hypertension,hyperlipidemia,diabetes,obesity,peripheral vascular disease,congestive heart failure,and at least one traditional CVD(P<0.001)vs the 2007 cohort.On adjusted multivariable analysis,the 2017 cohort had a significantly higher risk of pulmonary embolism(PE)(OR:1.47,95%CI:1.37-1.48),arrhythmia(OR:1.41,95%CI:1.38-1.43),atrial fibrillation/flutter(OR:1.61,95%CI:1.58-1.64),cardiac arrest including ventricular tachyarrhythmia(OR:1.63,95%CI:1.46-1.82),and stroke(OR:1.28,95%CI:1.22-1.34)with comparable all-cause mortality and fewer routine discharges(48.4%vs 55.0%)(P<0.001)vs the 2007 cohort.CONCLUSION Colon cancer survivors hospitalized 10 years apart in the United States showed an increased CVD risk with an increased risk of acute cardiovascular events(stroke 28%,PE 47%,arrhythmia 41%,and cardiac arrest 63%).It is vital to regularly screen colon cancer survivors with concomitant CVD risk factors to curtail long-term cardiovascular complications.展开更多
BACKGROUND A large proportion of patients with Hirschsprung disease experience persistent obstructive symptoms after corrective surgery.Persistent obstructive symptoms may result in faecal stasis that can develop into...BACKGROUND A large proportion of patients with Hirschsprung disease experience persistent obstructive symptoms after corrective surgery.Persistent obstructive symptoms may result in faecal stasis that can develop into Hirschsprung-associated enterocolitis,a potential life-threatening condition.Important treatment to improve faecal passage is internal anal sphincter relaxation using botulinum toxin injections.AIM To give an overview of all empirical evidence on the effectiveness of botulinum toxin injections in patients with Hirschsprung disease.METHODS A systematic review and meta-analysis was done by searching PubMed,EMBASE and the Cochrane Library,using entry terms related to:(1)Hirschsprung disease;and(2)Botulinum toxin injections.14 studies representing 278 patients met eligibility criteria.Data that were extracted were proportion of patients with improvement of obstructive symptoms or less enterocolitis after injection,proportion of patients with adverse effects and data on type botulinum toxin,mean dose,average age at first injection and patients with associated syndromes.Random-effects meta-analysis was used to aggregate effects and random-effects meta-regression was used to test for possible confounding factors.RESULTS Botulinum toxin injections are effective in treating obstructive symptoms in on average 66%of patients[event rate(ER)=0.66,P=0.004,I2=49.5,n=278 patients].Type of botulinum toxin,average dose,average age at first injections and proportion of patients with associated syndromes were not predictive for this effect.Mean 7 duration of improvement after one botulinum toxin injections was 6.4 mo and patients needed on average 2.6 procedures.There was a significant higher response rate within one month after botulinum toxin injections compared to more than one month after Botulinum toxin injections(ER=0.79,vs ER=0.46,Q=19.37,P<0.001).Botulinum toxin injections were not effective in treating enterocolitis(ER 0.58,P=0.65,I2=71.0,n=52 patients).There were adverse effects in on average 17%of patients(ER=0.17,P<0.001,I2=52.1,n=187 patients),varying from temporary incontinence to mild anal pain.CONCLUSION Findings from this systematic review and meta-analysis indicate that botulinum toxin injections are effective in treating obstructive symptoms and that adverse effects were present,but mild and temporary.展开更多
BACKGROUND Despite the emerging knowledge about colorectal anastomotic leakage(CAL)through the increasing number of clinical and experimental studies, there is no generally accepted definition of CAL. Because of the w...BACKGROUND Despite the emerging knowledge about colorectal anastomotic leakage(CAL)through the increasing number of clinical and experimental studies, there is no generally accepted definition of CAL. Because of the wide variety of definitions used in literature, comparison of study outcomes and quality of care is complicated.AIM To reach consensus on the definition of CAL using a modified Delphi method.METHODS The RAND/UCLA appropriateness method was used. The expert panel consisted of international colorectal surgeons and researchers who had published three or more articles about CAL. The consensus process consisted of two online distributed questionnaires and a third round with a recommendation. In the questionnaires participants were asked to rate the appropriateness of statements using a 1-9 Likert scale. Consensus was defined as a panel median between 1-3 or 7-9 without disagreement. In the final round a recommendation was formed regarding the definition of CAL and the expert panel was asked if they agreed or disagreed.RESULTSTwenty-three authors participated in the first round and twenty-one finished the second round. After two rounds consensus was reached on 37 items(80%) in nine different categories. The International Study Group of Rectal Cancer definition is the most frequently advised general definition by our panel. Consensus was reached regarding the clinical symptoms of CAL, which serum markers contributes to the suspicion of CAL, which radiological and perioperative findings should be considered as CAL, which grading system is appropriate and if there should be a range of postoperative days in the definition. Eventually, 19 experts completed all three rounds of which 16(84%) agreed with our final recommendations for the definition of CAL.CONCLUSION A consensus-based recommendation for the definition of CAL was formed using our modified Delphi method that can be widely incorporated in the field.展开更多
Ordinary chronic pancreatitis is a well-known risk factor for pancreatic cancer,whereas such an association with autoimmune pancreatitis(AIP)is widely debated.Due to the rarity of the latter disorder,there are few spe...Ordinary chronic pancreatitis is a well-known risk factor for pancreatic cancer,whereas such an association with autoimmune pancreatitis(AIP)is widely debated.Due to the rarity of the latter disorder,there are few specific clinical and epidemiological studies investigating the relation between AIP and pancreatic cancer,which do not seem to support it.However,these studies are affected by several limitations and,therefore,a link between AIP(and,specifically,type 1 AIP)and pancreatic cancer cannot be ruled out definitively on this basis.Moreover,several immunopathological aspects of type 1 AIP and,in general,immunoglobulin G4-related disease can create an immunological context that may impair the tumoral immunosurveillance and promote the pancreatic carcinogenesis and its progression.In detail,Th2 immunological dominance,type 2 macrophage polarization and basophil infiltration observed in type 1 AIP,may play a permissive role in creating a favorable immunological environment for pancreatic carcinogenesis,in addition to the immunosuppressive therapies that can be used in these patients.展开更多
Metastatic prostate cancer patients present in two waysdwith already disseminated disease at the time of presentation or with disease recurrence after definitive local therapy.Androgen deprivation therapy is given as ...Metastatic prostate cancer patients present in two waysdwith already disseminated disease at the time of presentation or with disease recurrence after definitive local therapy.Androgen deprivation therapy is given as the most effective initial treatment to patients.However,after the initial response,almost all patients will eventually progress despite the low levels of testosterone.Disease at this stage is termed castration resistant prostate cancer(CRPC).Before 2010,the taxane docetaxel was the first and only life prolonging agent for metastatic CRPC(mCRPC).The last decade has witnessed robust progress in CRPC therapeutics development.Abiraterone,enzalutamide,apalutamide and sipuleucel-T have been evaluated as first-and second-line agents in mCRPC patients,while cabazitaxel was approved as a second-line treatment.Radium-223 dichloride was approved in symptomatic patients with bone metastases and no known visceral metastases pre-and post-docetaxel.However,despite significant advances,mCRPC remains a lethal disease.Both primary and acquired resistance have been observed in CRPC patients treated by these new agents.It could be solely cell intrinsic or it is possible that the clonal heterogeneity in treated tumors may result from the adaptive responses to the selective pressures within the tumor microenvironment.The aim of this review is to list current treatment agents of CRPC and summarize recent findings in therapeutic resistance mechanisms.展开更多
In this review, combined post-mortem brain magnetic resonance imaging(MRI) and histology studies are highlighted, illustrating the relevance of translational approaches to de?ne novel MRI signatures of neuropathologic...In this review, combined post-mortem brain magnetic resonance imaging(MRI) and histology studies are highlighted, illustrating the relevance of translational approaches to de?ne novel MRI signatures of neuropathological lesions in neuroin?ammatory and neurodegenerative disorders. Initial studies combining post-mortem MRI and histology have validated various MRI sequences,assessing their sensitivity and speci?city as diagnostic biomarkers in neurologic disease. More recent studies have focused on de?ning new radiological(bio)markers and implementing them in the clinical(research) setting. By combining neurological and neuroanatomical expertise with radiological development and pathological validation,a cycle emerges that allows for the discovery of novel MRI biomarkers to be implemented in vivo. Examples of this cycle are presented for multiple sclerosis, Alzheimer's disease, Parkinson's disease, and traumatic brain injury.Some applications have been shown to be successful, while others require further validation. In conclusion, there is much to explore with post-mortem MRI and histology studies, which can eventually be of high relevance for clinical practice.展开更多
基金supported by the following foundations:“Stichting Oogfonds Nederland(No.2023-26)”the“Landelijke Stichting voor Blinden en Slechtzienden(No.2023-24)”that contributed through UitZicht,ZonMw grant(No.435005020)a grant of the Chinese Scholarship Council(No.201809110169)(to TGMFG,CPMR,and WY).
文摘Unwarranted death of neurons is a major cause of neurodegenerative diseases.Since mature neurons are postmitotic and do not replicate,their death usually constitutes an irreversible step in pathology.A logical strategy to prevent neurodegeneration would then be to save all neurons that are still alive,i.e.protecting the ones that are still healthy as well as trying to rescue the ones that are damaged and in the process of dying.Regarding the latter,recent experiments have indicated that the possibility of reversing the cell death process and rescuing dying cells is more significant than previously anticipated.In many situations,the elimination of the cell death trigger alone enables dying cells to spontaneously repair their damage,recover,and survive.In this review,we explore the factors,which determine the fate of neurons engaged in the cell death process.A deeper insight into cell death mechanisms and the intrinsic capacity of cells to recover could pave the way for novel therapeutic approaches to neurodegenerative diseases.
文摘Background:Magnetic resonance imaging(MRI)is crucial in modern medical diagnostics,providing detailed insights into soft tissue structures and pathological changes.Traditional grayscale images can sometimes obscure critical details,complicating accurate interpretations.Automated color coding of the MRI signal intensities may enhance the visualization of various pa-thologies,potentially leading to improved diagnostic accuracy and image quality.This paper aims to explore the effectiveness of color-coded MR image reconstruction in enhancing both diagnostic precision and overall image quality in musculoskeletal MRI.Methods:Two fellowship-trained musculoskeletal radiologists evaluated the images reconstructed with color coding,rating their diagnostic value,image quality,and visual appeal using a five-point Likert scale.To assess interrater reliability,Cohen's Kappa statistical analysis was performed.Additionally,descriptive statistics summarizing the Likert scores for diagnostic value,image quality,and visual appeal of the reconstructed images have been described.Results:Statistical analysis of the data revealed that the diagnostic value,image value,and visual appeal of the color-coded MR images were excellent in almost two-thirds of the data set.The minimum Likert score recorded was 3,signifying a good quality rating.Conclusion:Our study shows positive results,supporting the efficiency of color-coded MR imaging in aiding the conventional gray scale MR imaging to improve its diagnostic efficiency.
基金supported by The Netherlands Organization for Scientific Research VIDI(grant number:198.007).
文摘Background Conditional relative survival(CRS),the probability of survival given that an individual has already survived a certain period post-diagnosis,is a more clinically relevant measure for long-term survival than standard relative survival(RS).This study aims to evaluate the 5-year CRS among adolescent and young adult(AYA)breast cancer patients by age,tumor stage,and receptor subtype to guide disclosure periods for insurance.Methods Data of all females aged 18–39 years and diagnosed with invasive breast cancer between 2003 and 2021(n=13,075)were obtained from The Netherlands Cancer Registry(NCR).The five-year CRS was calculated annually up to 10 years post-diagnosis using a hybrid analysis approach.Results For the total AYA breast cancer study population the 5-year CRS exceeded 90%from diagnosis and increased beyond 95%7 years post-diagnosis.Patients aged 18–24 reached 95%9 years post-diagnosis,those aged 25–29 after 5 years,and those aged 30–34 and 35–39 after 8 years.For stage I,the 5-year CRS reached 95%from diagnosis,for stage II after 6 years,while the 5-year CRS for stages III and IV did not reach the 95%threshold during the 10-year follow-up.Triple-negative tumors exceeded 95%after 4 years,human epidermal growth factor receptor 2(HER2)positive tumors after 6 years,while hormone receptor(HR)positive tumors did not reach 95%.Conclusion Excess mortality among AYA breast cancer patients tends to be little(CRS 90%–95%)from diagnosis and becomes minimal(CRS>95%)over time compared to the general population.These results can enhance expectation management and inform policymakers,suggesting a shorter disclosure period.
基金The Trùndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology), Trùndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public HealthThe coordination of European Prospective Investigation into Cancer and Nutrition - Spain study (EPIC) is financially supported by the International Agency for Research on Cancer (IARC)+7 种基金by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC)supported by Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluc 1a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain)funded by The Netherlands Organisation for Health Research and DevelopmentZon Mw (Grant No.: 531-00141-3)Funding for the SHIP study has been provided by the Federal Ministry for Education and Research (BMBFidentification codes 01 ZZ96030, 01 ZZ0103, and 01 ZZ0701)support from the Swedish Research Council (2018-02527 and 2019-00193)financed by the Helmholtz Zentrum München - German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria.
文摘Background There is insufficient evidence to provide recommendations for leisure-time physical activity among workers across various occupational physical activity levels.This study aimed to assess the association of leisure-time physical activity with cardiovascular and all-cause mortality across occupational physical activity levels.Methods This study utilized individual participant data from 21 cohort studies,comprising both published and unpublished data.Eligibility criteria included individual-level data on leisure-time and occupational physical activity(categorized as sedentary,low,moderate,and high)along with data on all-cause and/or cardiovascular mortality.A 2-stage individual participant data meta-analysis was conducted,with separate analysis of each study using Cox proportional hazards models(Stage 1).These results were combined using random-effects models(Stage 2).Results Higher leisure-time physical activity levels were associated with lower all-cause and cardiovascular mortality risk across most occupational physical activity levels,for both males and females.Among males with sedentary work,high compared to sedentary leisure-time physical activity was associated with lower all-cause(hazard ratios(HR)=0.77,95%confidence interval(95%CI):0.70-0.85)and cardiovascular mortality(HR=0.76,95%CI:0.66-0.87)risk.Among males with high levels of occupational physical activity,high compared to sedentary leisure-time physical activity was associated with lower all-cause(HR=0.84,95%CI:0.74-0.97)and cardiovascular mortality(HR=0.79,95%CI:0.60-1.04)risk,while HRs for low and moderate levels of leisure-time physical activity ranged between 0.87 and 0.97 and were not statistically significant.Among females,most effects were similar but more imprecise,especially in the higher occupational physical activity levels.Conclusion Higher levels of leisure-time physical activity were generally associated with lower mortality risks.However,results for workers with moderate and high occupational physical activity levels,especially women,were more imprecise.Our findings suggests that workers may benefit from engaging in high levels of leisure-time physical activity,irrespective of their level of occupational physical activity.
文摘Objective:two new cases of temporal bone squamous cell carcinoma(TBSCC)with a bilateral occurrence are presented.Furthermore,a review of the literature was performed and the yearly incidence was calculated.Methods:A systematic review of the literature was conducted using PRISMA guidelines.Results:Twenty-two more cases were found in literature.With a total of 24 cases,the calculated yearly incidence of bilateral TBSCC is 49:10^12 A history of chronic otitis or regional radiotherapy was found in respectively 50%and 12%of patients.In nine patients,the tumors developed synchronously(within 6 months)and in 13 metachronously.Conclusions:The calculated incidence is 89 times higher than mathematically expected considering the incidence of unilateral cases.An explanation might be a history of chronic otitis or prior radiotherapy.The tumor staging of both the first tumor group and the contralateral tumor group are similar to unilateral temporal bone squamous cell carcinoma series.
基金supported by Amsterdam Neuroscience(project number NDIS-2019-03,to AEW and EVB).
文摘Development of therapeutics for brain diseases has remained challenging,in particular due to the difficulty of passing the blood-brain barrier.As a result,the current arsenal of therapeutics targeting the brain is limited to small,lipid-soluble drugs and there is a lack of options for treating neuroblastomas,Alzheimer’s disease,and many other devastating pathologies.Despite the advances in strategies for crossing the blood-brain barrier such as the use of nanoparticles(Hersh et al.,2022;Duan et al.,2023),such delivery systems have not yet reached clinical practice.Therefore,novel platforms for the transport of therapeutics across the blood-brain barrier remain highly desired.This specifically holds for large molecules such as monoclonal antibodies and recombinant proteins,as well as nucleotide-based therapeutics and cell therapies.Research efforts in this field are increasing exponentially,with thousands of publications in the last few years.
基金supported by ZonMW and Stichting Proefdiervrij (#114022506)PPP Allo wance made available by Health~Holland,Top Sector Life Sciences&Health,to stimulate public-private partnerships (#LSHM17014 and LSHM18024)+3 种基金Alzheimer Nederland (grant WE.03-2017-10)European Commission (Joint Programming Initiative Neurodegenerative Diseases/JPco-fuND (ZonMW#733051062)Weston Brain Institute (#NR1 60014)ZonMW Memorabel/Alzheimer Nederland (#733050101)(to WS)
文摘Maintenance of protein homeostasis or“proteostasis”is essential for the functioning and viability of cells.This is in particular the case for cells like neurons that cannot self-renew and acquire unique functional properties during their lifetime.Cellular proteostatic stress responses are in place to protect cells from damage in case of proteostatic challenges.The integrated stress response(ISR)is one of the key proteostatic stress responses in the cell(Costa-Mattioli and Walter,2020).The ISR is the downstream convergence point for the four stress-induced eIF2αkinases(EIF2AK1-4)that control stress-regulated protein translation via phosphorylation of the translation factor eIF2α.ISR activation results in a transient reduction of global translation while it concomitantly enhances the translation of specific mRNAs,including that encoding the activating transcription factor 4(ATF4).Together,the translational control mediated by the ISR results in a temporary reduction of the overall protein load and the selectively increased expression of proteins that contribute to restoration of the proteostatic balance.
文摘BACKGROUND Lateral ankle sprains are the most common traumatic musculoskeletal injuries of the lower extremity,with an incidence rate of 15%-20%.The high incidence and prevalence highlights the economic impact of this injury.Ankle sprains lead to a high socioeconomic burden due to the combination of the high injury incidence and high medical expenses.Up to 40%of patients who suffer from an ankle sprain develop chronic ankle instability.Chronic instability can lead to prolonged periods of pain,immobility and injury recurrence.Identification of factors that influence return to work(RTW)and return to sports(RTS)after a lateral ankle sprain(LAS)may help seriously reduce healthcare costs.AIM To explore which factors may potentially affect RTW and RTS after sustaining an LAS.METHODS EMBASE and PubMed were systematically searched for relevant studies published until June 2023.Inclusion criteria were as follows:(1)Injury including LAS or chronic ankle instability;(2)Described any form of treatment;(3)Assessment of RTW or RTS;(4)Studies published in English;and(5)Study designs including randomized controlled clinical trials,clinical trials or cohort studies.Exclusion criteria were:(1)Studies involving children(age<16 year);or(2)Patients with concomitant ankle injury besides lateral ankle ligament damage.A quality assessment was performed for each of the included studies using established risk of bias tools.Additionally quality of evidence was assessed using the GRADEpro tool in cases where outcomes were included in the quantitative analysis.A best evidence synthesis was performed in cases of qualitative outcome analysis.For all studied outcomes suitable for quantitative analysis a forest plot was created to calculate the effect on RTW and RTS.RESULTS A total of 8904 patients were included in 21 studies,10 randomized controlled trials,7 retrospective cohort studies and 4 prospective cohort studies.Fifteen studies were eligible for meta-analysis.The overall RTS rate ranged were 80%and 83%in the all treatments pool and surgical treatments pool,respectively.The pooled mean days to RTS ranged from 23-93 d.The overall RTW rate was 89%.The pooled mean time to RTW ranged from 5.8-8.1 d.For patients with chronic ankle instability,higher preoperative motivation was the sole factor significantly and independently(P=0.001)associated with the rate of and time to RTS following ligament repair or reconstruction.Higher body mass index was identified as a significant factor(P=0.04)linked to not resuming sports or returning at a lower level(median 24,range 20-37),compared to those who resumed at the same or higher level(median 23,range 17-38).Patients with a history of psychological illness or brain injury,experienced a delay in their rehabilitation process for sprains with fractures and unspecified sprains.The extent of the delayed rehabilitation was directly proportional to the increased likelihood of experiencing a recurrence of the ankle sprain and the number of ankle-related medical visits.We also observed that 10%of athletes who did return to sport after lateral ankle sprain without fractures described non-ankle-related reasons for not returning.CONCLUSION All treatments yielded comparable results,with each treatment potentially offering unique advantages or benefits.Preoperative motivation may influence rehabilitation after LAS.Grading which factor had a greater impact was not possible due to the lack of comparability among the included patients.
文摘BACKGROUND Over the years,strides in colon cancer detection and treatment have boosted survival rates;yet,post-colon cancer survival entails cardiovascular disease(CVD)risks.Research on CVD risks and acute cardiovascular events in colorectal cancer survivors has been limited.AIM To compare the CVD risk and adverse cardiovascular outcomes in current colon cancer survivors compared to a decade ago.METHODS We analyzed 2007 and 2017 hospitalization data from the National Inpatient Sample,studying two colon cancer survivor groups for CVD risk factors,mortality rates,and major adverse events like pulmonary embolism,arrhythmia,cardiac arrest,and stroke,adjusting for confounders via multivariable regression analysis.RESULTS Of total colon cancer survivors hospitalized in 2007(n=177542)and 2017(n=178325),the 2017 cohort often consisted of younger(76 vs 77 years),male,African-American,and Hispanic patients admitted non-electively vs the 2007 cohort.Furthermore,the 2017 cohort had higher rates of smoking,alcohol abuse,drug abuse,coagulopathy,liver disease,weight loss,and renal failure.Patients in the 2017 cohort also had higher rates of cardiovascular comorbidities,including hypertension,hyperlipidemia,diabetes,obesity,peripheral vascular disease,congestive heart failure,and at least one traditional CVD(P<0.001)vs the 2007 cohort.On adjusted multivariable analysis,the 2017 cohort had a significantly higher risk of pulmonary embolism(PE)(OR:1.47,95%CI:1.37-1.48),arrhythmia(OR:1.41,95%CI:1.38-1.43),atrial fibrillation/flutter(OR:1.61,95%CI:1.58-1.64),cardiac arrest including ventricular tachyarrhythmia(OR:1.63,95%CI:1.46-1.82),and stroke(OR:1.28,95%CI:1.22-1.34)with comparable all-cause mortality and fewer routine discharges(48.4%vs 55.0%)(P<0.001)vs the 2007 cohort.CONCLUSION Colon cancer survivors hospitalized 10 years apart in the United States showed an increased CVD risk with an increased risk of acute cardiovascular events(stroke 28%,PE 47%,arrhythmia 41%,and cardiac arrest 63%).It is vital to regularly screen colon cancer survivors with concomitant CVD risk factors to curtail long-term cardiovascular complications.
文摘BACKGROUND A large proportion of patients with Hirschsprung disease experience persistent obstructive symptoms after corrective surgery.Persistent obstructive symptoms may result in faecal stasis that can develop into Hirschsprung-associated enterocolitis,a potential life-threatening condition.Important treatment to improve faecal passage is internal anal sphincter relaxation using botulinum toxin injections.AIM To give an overview of all empirical evidence on the effectiveness of botulinum toxin injections in patients with Hirschsprung disease.METHODS A systematic review and meta-analysis was done by searching PubMed,EMBASE and the Cochrane Library,using entry terms related to:(1)Hirschsprung disease;and(2)Botulinum toxin injections.14 studies representing 278 patients met eligibility criteria.Data that were extracted were proportion of patients with improvement of obstructive symptoms or less enterocolitis after injection,proportion of patients with adverse effects and data on type botulinum toxin,mean dose,average age at first injection and patients with associated syndromes.Random-effects meta-analysis was used to aggregate effects and random-effects meta-regression was used to test for possible confounding factors.RESULTS Botulinum toxin injections are effective in treating obstructive symptoms in on average 66%of patients[event rate(ER)=0.66,P=0.004,I2=49.5,n=278 patients].Type of botulinum toxin,average dose,average age at first injections and proportion of patients with associated syndromes were not predictive for this effect.Mean 7 duration of improvement after one botulinum toxin injections was 6.4 mo and patients needed on average 2.6 procedures.There was a significant higher response rate within one month after botulinum toxin injections compared to more than one month after Botulinum toxin injections(ER=0.79,vs ER=0.46,Q=19.37,P<0.001).Botulinum toxin injections were not effective in treating enterocolitis(ER 0.58,P=0.65,I2=71.0,n=52 patients).There were adverse effects in on average 17%of patients(ER=0.17,P<0.001,I2=52.1,n=187 patients),varying from temporary incontinence to mild anal pain.CONCLUSION Findings from this systematic review and meta-analysis indicate that botulinum toxin injections are effective in treating obstructive symptoms and that adverse effects were present,but mild and temporary.
基金Supported by the Dutch Research Council(NWO)research programme Vidi project,No.91719343。
文摘BACKGROUND Despite the emerging knowledge about colorectal anastomotic leakage(CAL)through the increasing number of clinical and experimental studies, there is no generally accepted definition of CAL. Because of the wide variety of definitions used in literature, comparison of study outcomes and quality of care is complicated.AIM To reach consensus on the definition of CAL using a modified Delphi method.METHODS The RAND/UCLA appropriateness method was used. The expert panel consisted of international colorectal surgeons and researchers who had published three or more articles about CAL. The consensus process consisted of two online distributed questionnaires and a third round with a recommendation. In the questionnaires participants were asked to rate the appropriateness of statements using a 1-9 Likert scale. Consensus was defined as a panel median between 1-3 or 7-9 without disagreement. In the final round a recommendation was formed regarding the definition of CAL and the expert panel was asked if they agreed or disagreed.RESULTSTwenty-three authors participated in the first round and twenty-one finished the second round. After two rounds consensus was reached on 37 items(80%) in nine different categories. The International Study Group of Rectal Cancer definition is the most frequently advised general definition by our panel. Consensus was reached regarding the clinical symptoms of CAL, which serum markers contributes to the suspicion of CAL, which radiological and perioperative findings should be considered as CAL, which grading system is appropriate and if there should be a range of postoperative days in the definition. Eventually, 19 experts completed all three rounds of which 16(84%) agreed with our final recommendations for the definition of CAL.CONCLUSION A consensus-based recommendation for the definition of CAL was formed using our modified Delphi method that can be widely incorporated in the field.
文摘Ordinary chronic pancreatitis is a well-known risk factor for pancreatic cancer,whereas such an association with autoimmune pancreatitis(AIP)is widely debated.Due to the rarity of the latter disorder,there are few specific clinical and epidemiological studies investigating the relation between AIP and pancreatic cancer,which do not seem to support it.However,these studies are affected by several limitations and,therefore,a link between AIP(and,specifically,type 1 AIP)and pancreatic cancer cannot be ruled out definitively on this basis.Moreover,several immunopathological aspects of type 1 AIP and,in general,immunoglobulin G4-related disease can create an immunological context that may impair the tumoral immunosurveillance and promote the pancreatic carcinogenesis and its progression.In detail,Th2 immunological dominance,type 2 macrophage polarization and basophil infiltration observed in type 1 AIP,may play a permissive role in creating a favorable immunological environment for pancreatic carcinogenesis,in addition to the immunosuppressive therapies that can be used in these patients.
基金Liang Dong is supported by Shanghai Natural Science Fund exploration project(17ZR1447400)Shanghai Jiao Tong University medicine-engineering cross project(YG2016QN56)Richard C.Zieren is supported by Stichting Cure for Cancer foundation,Amsterdam,The Netherlands.
文摘Metastatic prostate cancer patients present in two waysdwith already disseminated disease at the time of presentation or with disease recurrence after definitive local therapy.Androgen deprivation therapy is given as the most effective initial treatment to patients.However,after the initial response,almost all patients will eventually progress despite the low levels of testosterone.Disease at this stage is termed castration resistant prostate cancer(CRPC).Before 2010,the taxane docetaxel was the first and only life prolonging agent for metastatic CRPC(mCRPC).The last decade has witnessed robust progress in CRPC therapeutics development.Abiraterone,enzalutamide,apalutamide and sipuleucel-T have been evaluated as first-and second-line agents in mCRPC patients,while cabazitaxel was approved as a second-line treatment.Radium-223 dichloride was approved in symptomatic patients with bone metastases and no known visceral metastases pre-and post-docetaxel.However,despite significant advances,mCRPC remains a lethal disease.Both primary and acquired resistance have been observed in CRPC patients treated by these new agents.It could be solely cell intrinsic or it is possible that the clonal heterogeneity in treated tumors may result from the adaptive responses to the selective pressures within the tumor microenvironment.The aim of this review is to list current treatment agents of CRPC and summarize recent findings in therapeutic resistance mechanisms.
文摘In this review, combined post-mortem brain magnetic resonance imaging(MRI) and histology studies are highlighted, illustrating the relevance of translational approaches to de?ne novel MRI signatures of neuropathological lesions in neuroin?ammatory and neurodegenerative disorders. Initial studies combining post-mortem MRI and histology have validated various MRI sequences,assessing their sensitivity and speci?city as diagnostic biomarkers in neurologic disease. More recent studies have focused on de?ning new radiological(bio)markers and implementing them in the clinical(research) setting. By combining neurological and neuroanatomical expertise with radiological development and pathological validation,a cycle emerges that allows for the discovery of novel MRI biomarkers to be implemented in vivo. Examples of this cycle are presented for multiple sclerosis, Alzheimer's disease, Parkinson's disease, and traumatic brain injury.Some applications have been shown to be successful, while others require further validation. In conclusion, there is much to explore with post-mortem MRI and histology studies, which can eventually be of high relevance for clinical practice.
