Objective Because of the limited number of studies and small sample sizes,whether metabolic syndrome(MS)leads to the occurrence and progression of osteoporosis and the possible underlying mechanisms require further in...Objective Because of the limited number of studies and small sample sizes,whether metabolic syndrome(MS)leads to the occurrence and progression of osteoporosis and the possible underlying mechanisms require further investigation.This study aimed to investigate the association between MS and osteoporosis,along with its influencing factors.Methods This observational cross-sectional study included 139,470 individuals aged≥18 years who underwent health examinations from September 2014 to March 2022.Based on bone mineral density(BMD)screening results,the participants were categorized into a suspected osteoporosis or non-osteoporosis group(control).Participants were further divided into those who met 0 MS criteria,1 MS criterion,2 MS criteria,and≥3 MS criteria(MS group).Participants who had undergone health examinations at least twice formed the follow-up cohort;a self-matched analysis was performed on those with follow-up periods≥5 years and unchanged MS grouping.Results Several examination indicators in the suspected osteoporosis group showed statistically significant differences compared with the control group.The proportion of suspected osteoporosis in the MS group was significantly increased compared with that in the 0 MS criteria group(odds ratio[OR]:1.215,Z=29.11,P<0.001,95%confidence interval:1.199-1.231).After adjusting for age,sex,smoking,and alcohol consumption,the 2 MS criteria group and MS group still had OR values>1(P<0.001).In the follow-up cohort,the proportion of suspected osteoporosis increased gradually with an increase in the number of MS criteria met at baseline and during each follow-up visit(P<0.05),with the highest proportion observed in the MS group.However,the proportion of suspected osteoporosis did not increase significantly over time in the different MS groups(P>0.05).In the follow-up cohort,the proportion of individuals transitioning from normal BMD to suspected osteoporosis was higher in the MS group after≥5 years of follow-up compared with the group meeting 0 MS criteria(0.08%versus 1.15%,χ^(2)=10.76,P=0.001).There was no significant difference in BMD values for the 0 MS criteria group after 5 years(P>0.05),whereas the other three groups experienced a significant decrease in BMD values after 5 years(P<0.05).Conclusion MS is an independent risk factor for osteoporosis,and the effect of risk factors related to MS on osteoporosis may exceed that of aging alone.The specific mechanisms warrant further investigation.展开更多
AIM To examine healthcare resource utilizationpatterns and costs accrued by carcinoid syndrome （CS）patients with and without diarrhea.METHODS： We conducted a retrospective cohort studyusing MarketScan data from 1/1...AIM To examine healthcare resource utilizationpatterns and costs accrued by carcinoid syndrome （CS）patients with and without diarrhea.METHODS： We conducted a retrospective cohort studyusing MarketScan data from 1/1/2002-12/31/2012.Newly diagnosed CS patients had 1 medical claim forCS （ICD-9-CM code 259.2） plus either ≥ 1 additionalclaim for CS or for carcinoid tumors （ICD-9-CM 209.x）, and had no evidence of CS for 1 year prior to index CS diagnosis, in commercially-insured patients 〈 65years old. Patients were required to have continuousenrollment one year prior and after index date （firstclaim with CS diagnosis in the ID period）. We identifiedpatients with evidence of non-infectious diarrhea （ICD-9-CM codes 564.5 and 787.91） within one year from theindex date. Overall and CS-related healthcare resourceutilization and costs were compared between patientswith and without non-infectious diarrhea during theone year period after the index date.RESULTS： There were 2822 newly diagnosed CSpatients; 534 （18.9%） had evidence of non-infectiousdiarrhea. Compared to patients without non-infectiousdiarrhea, non-infectious diarrhea patients morecommonly had at ≥ 1 CS-related hospitalization（13.7% vs 7.2%）, ≥ 1 CS-related ED visit （11.0% vs4.4%）, and CS-related office visits in one year （6.9 vs4.1; all p 〈 0.001）. After adjusting for demographics,region, number of chronic conditions and the CharlsonComorbidity Index, the proportions of patients withany and with CS-related hospitalizations were 9.7%and 6.8% higher, respectively, among non-infectiousdiarrhea patients compared to those with without noninfectiousdiarrhea （p 〈 0.001）. Unadjusted costs weresignificantly higher among non-infectious diarrheapatients vs those without non-infectious diarrhea. Thenon-infectious diarrhea group was also more costly,with adjusted mean annual costs of $81610, comparedto $51719 in the group without non-infectious diarrhea（p 〈 0.001）.CONCLUSION： Diarrhea is burdensome and costlyin CS patients. Reduction of CS-related healthcareexpenditures may be achievable through preventivetreatment and appropriate management of diarrhea inCS.展开更多
As the treatment landscape for advanced melanoma continues to evolve, it is critical to focus on unmet needs and understand the cost of therapy. While Ipilimumab (IPI), an immunotherapy indicated for unresectable adva...As the treatment landscape for advanced melanoma continues to evolve, it is critical to focus on unmet needs and understand the cost of therapy. While Ipilimumab (IPI), an immunotherapy indicated for unresectable advanced melanoma, has been a mainstay of 1<sup>st</sup>-line treatment, there was no standard of care following progression until recently. The objective of this study was to examine real-world treatment patterns and healthcare costs following IPI use in advanced melanoma patients prior to the anti-PD-1 class approval. Adult stage III or IV melanoma patients treated with IPI were selected between April 1, 2011, and September 30, 2013, from a large U.S. commercial and Medicare claims database. Patients were evaluated for therapy after IPI, with an index date set as the first systemic therapy after IPI. Per-Patient Per-Month (PPPM) healthcare costs while on active treatment were evaluated from index until treatment discontinuation, inpatient death, end of insurance enrollment, or September 30, 2013. Of 361 eligible patients, 111 (30.7%) initiated subsequent systemic therapy (mean age, 57 years;64.9% male). The most common therapies, single-agent or combination, included vemurafenib (32.4%), paclitaxel (28.8%), temozolomide (20.7%), and carboplatin (17.1%). During a median follow-up of 130 days, mean [standard deviation] PPPM all-cause total healthcare costs were $20,383 [$18,988], of which $4800 (23.6%), $5899 (28.9%), and $9684 (47.5%) were related to melanoma drug costs, medical claims with a diagnosis of melanoma, and other (non-specified) utilization, respectively. When considering total care, the costs of U.S. patients with advanced melanoma post-IPI were substantial across all commonly used agents.展开更多
AIM:To review literature on efficacy and safety of octreotide-long-acting repeatable(LAR)used at doses higher than the Food and Drug Administration(FDA)-approved 30 mg/mo for treatment of neuroendocrine tumors(NETs).M...AIM:To review literature on efficacy and safety of octreotide-long-acting repeatable(LAR)used at doses higher than the Food and Drug Administration(FDA)-approved 30 mg/mo for treatment of neuroendocrine tumors(NETs).METHODS:We searched Pub Med and Cochrane Library from 1998-2012,5 conferences(American Society of Clinical Oncology,Endocrine Society,European Neuroendocrine Tumor Society,European Society for Medical Oncology,North American Neuroendocrine Tumor Society)from 2000-2013 using Me SH and keyterms including neuroendocrine tumors,carcinoid tumor,carcinoma,neuroendocrine,and octreotide.Bibliographies of accepted articles were also searched.Two reviewers reviewed titles,abstracts,and full-length articles.Studies that reported data on efficacy and safety of≥30 mg/mo octreotide-LAR for NETs in human subjects,published in any language were included in the review.RESULTS:The search identified 1086 publications,of which 238 underwent full-text review(20 were translated into English);17 were included in the review.Studies varied in designs,subjects,octreotide-LAR regimens,and definition of outcomes.Eleven studies reported use of higher doses to control symptoms and tumor progression,although symptom severity and formal quality-of-life analysis were not quantitatively measured.Ten studies reported efficacy,describing 260 subjects with doses ranging from 40 mg/mo or 30 mg/3 wk up to 120 mg/mo.Eight studies reported expert clinical opinion that supported dose escalation of octreotide-LAR up to 60 mg/mo for symptom control and suggested increased doses may be effective at preventing tumor progression.Eight studies reported safety;there was no evidence of increased toxicity associated with doses of octreotide-LAR>30 mg/mo.CONCLUSION:As reported in this review,octreotide-LAR at doses>30 mg/mo is being prescribed for symptom and tumor control in NET patients.Furthermore,expert clinical opinion provided support for escalation of somatostatin analogs for refractory hormonal symptoms.展开更多
AIM To describe real-world treatment patterns of gastrointestinal neuroendocrine tumors(GI NET).METHODS In this retrospective cohort study,we used 2009-2014 data from 2 United States commercial claims databases to exa...AIM To describe real-world treatment patterns of gastrointestinal neuroendocrine tumors(GI NET).METHODS In this retrospective cohort study,we used 2009-2014 data from 2 United States commercial claims databases to examine newly pharmacologically treated patients using tabular and graphical techniques.Treatments included somatostatin analogues(SSA),cytotoxic chemotherapy(CC),targeted therapy(TT),interferon(IF)and combinations.We identified patients at least 18 years of age,with≥1 inpatient or≥2 outpatient claims for GI NET who initiated pharmacologic treatment from 7/1/09-6/30/14.A 6 mo clean period prior to first treatment ensured patients were newly treated.Patients were followed until end of enrollment or the study end date,whichever was first.RESULTS We identified 2258 newly treated GI NET patients:mean(SD)age was 55.6 years(SD=9.7),47.2%of the patients were between 55 and 64 years,and 48.8%were female.All regions of the United States were represented.59.6%started first-line therapy with SSA monotherapy(964 with octreotide LAR,380 with octreotide SA,and 1 with lanreotide),33.3%CC,3.6%TT,and 0.5%IF.The remainder received combinations.Mean follow up was 576 d.Overall mean first-line therapy duration was 361 d(449 d for SSA,215 for CC,267 for TT).58.9%of patients had no pharmacological treatment beyond first line.The most common secondline was combination therapy with SSA.In graphical pattern analysis,there was no clear pattern visible after first line therapy.CONCLUSION In this study,60%of patients initiated treatment with SSA alone or in combination.The relatively long time to discontinuation suggests possible sustained effectiveness and tolerability.展开更多
AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for p...AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs,angiogenesis inhibitors,inhibitors of mammalian target of rapamycinand cytotoxic agents.At this time,there is little data to guide treatment selection and sequence.We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations.Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process.After studying the literature,a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale.Ratings were done both before and after an extended discussion of the evidence.Quantitative measurements of agreement were made and consensus statements developed from the second round ratings.RESULTS:Specialties represented were medical and surgical oncology,interventional radiology,and gastroenterology.Panelists had practiced for a mean of15.5 years(range:6-33).Among 202 rated scenarios,disagreement decreased from 13.2%(26 scenarios)before the face-to-face discussion of evidence to 1%(2)after.In the final ratings,46.5%(94 scenarios)were rated inappropriate,21.8%(44)were uncertain,and30.7%(62)were appropriate.Consensus statements from the scenarios included:(1)it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic;(2)it is appropriate to use everolimus,sunitinib,or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors;and(3)beyond first line,these same agents can be used.In patients with uncontrolled secretory symptoms,octreotide LAR doses can be titrated up to 60 mg every4 wk or up to 40 mg every 3 or 4 wk.CONCLUSION:Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.展开更多
INTRODUCTION Gender dysphoria(GD),or gender identity disorder,is defined as persistent distress stemming from the incongruence between one's assigned sex at birth and gender identity.'GD has traditionally been...INTRODUCTION Gender dysphoria(GD),or gender identity disorder,is defined as persistent distress stemming from the incongruence between one's assigned sex at birth and gender identity.'GD has traditionally been introduced as a rare condition predominant in assigned males at birth(AMABs).2 However,recent studies have shown an upward trend in assigned females at birth(AFABs)with a dramatic reversal of the AMAB:AFAB ratio-.5-The actual AMAB:AFAB ratio varies by age group and study population.4-Questions have been raised concerning the increasing number of youth who seek professional care for GD,especially adolescent AFABs.展开更多
AIM To discover unknown factors associated with carcinoid syndrome(CS)with the goal of earlier diagnosis of CS.METHODS In this retrospective case-control study using United States administrative claims,patients(≥18 y...AIM To discover unknown factors associated with carcinoid syndrome(CS)with the goal of earlier diagnosis of CS.METHODS In this retrospective case-control study using United States administrative claims,patients(≥18 years)newly-diagnosed with gastrointestinal neuroendocrine tumors(GI NETs)without CS(controls)were exactly matched to patients with CS(cases)based on NET diagnosis date at a 3-to-1 ratio.Study index date was first CS diagnosis(controls:same distance from NET diagnosis as cases).The most observed conditions,excluding CS-associated symptoms/diagnoses,during the year before index date were assessed.Forwardstepwise logistic regression models were used to derive predictors,and were validation within another claims database.RESULTS In the development database,1004 patients with GI NETs were identified;251(25%)had CS and 753(75%)were controls.In the validation database,724 patients with GI NETs were identified;181(25%)had CS and 543(75%)were controls.A total of 33 common diagnoses(excluding conditions already known to be associated with CS)in the development database were entered in forward step-wise logistic regression models.In the final,validated logistic regression model,three factors prior to CS diagnosis were found consistently associated with higher risks for CS,including liver disorder[odds ratio(95%CI):3.38(2.07-5.51)],enlargement of lymph nodes[2.13(1.10-4.11)],and abdominal mass[3.79(1.87-7.69)].CONCLUSION GI NET patients with CS were 2-4 times as likely to have preexisting diagnoses(i.e.,liver disorder,enlarged lymph nodes,abdominal mass)than non-CS patients.展开更多
Background: Melanoma is a rare but serious skin cancer that is responsible for >90% of skin cancer-related deaths. This retrospective data analysis quantifies the direct cost of medical care by disease stage at dia...Background: Melanoma is a rare but serious skin cancer that is responsible for >90% of skin cancer-related deaths. This retrospective data analysis quantifies the direct cost of medical care by disease stage at diagnosis for patients with metastatic melanoma. Methods: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was queried for patients diagnosed between 2004-2009 with stage IIIB/C and stage IV (M1a, M1b, M1c) melanoma. The primary outcome was overall medical utilization and associated costs from diagnosis to death, the end of Medicare enrolment, or 12/31/2010. Results are stratified by disease stage at diagnosis and presented as per-patient per-month (PPPM) costs. Results: Of the 1263 patients meeting the study criteria (mean age: 75 years;64% male, 92% white, mean duration of follow up: 37.5 months), 66.6% were diagnosed at stage IIIB/C and 33.4% at stage IV. Cost of care increased with disease stage. Total PPPM costs ranged from $1966 for patients diagnosed with stage IIIB to $4585 among patients diagnosed with stage M1c. Outpatient costs accounted 48.9% of total medical costs among stage IIIB patients, and 38.7% of total medical costs for stage M1c patients. Inpatient costs accounted for 37.1% (stage M1b) - 40.9% (stage M1c) of total medical costs. Conclusions: Healthcare costs for treating patients with metastatic melanoma increase by disease stage. The cost of care was more than double among patients with late stage compared to those with early stage. Treatments demonstrating ability to prevent disease progression from early stage to late stage may confer an economic benefit among other clinical advantages.展开更多
Objective‘Sludge’refers to administrative burdens or frictions that preclude people from getting what they want or need(eg,duplicative forms,complicated instructions,long waiting times).This mixed methods study eval...Objective‘Sludge’refers to administrative burdens or frictions that preclude people from getting what they want or need(eg,duplicative forms,complicated instructions,long waiting times).This mixed methods study evaluated patients’perceptions of sludge in the colorectal cancer(CRC)screening process and some impacts of this sludge.Design We employed an exploratory sequential mixed methods study design that comprised patient interviews and a patient survey.The interviews informed final survey revisions and captured contextual data about patients’experiences with sludge.Interview transcripts were inductively and deductively analysed to identify overarching themes.The survey quantified sludge,delayed or forgone screenings,screening experience(Net Promoter Score)and health system distrust(Health System Distrust Scale).We usedχ2 or t-tests for univariable comparisons and logistic or linear regressions to evaluate the association between cumulative sludge score and delayed or forgone screenings,screening experience and health system distrust.Results were integrated for interpretation.Setting Southeastern United States.Participants Patients who were 45–75 years of age,at average risk for CRC and had either completed or been referred for CRC screening(colonoscopy or stool-based test)within the previous 12 months.Results 22 interview participants and 255 survey participants completed the study.38(15%)survey participants rated their screening experience as poor(Net Promoter Score=0–7 out of 10).The mean(SD)Health System Distrust Scale score was 22.4(6.3)out of 45 possible points(higher score=greater distrust).Perceptions of sludge in the CRC screening process varied,with long waiting times and burdensome communication being the most common sources(58%and 35%of participants,respectively).Sludge was positively associated with delayed or forgone screenings(OR=1.42,95%CI 1.28,1.57,p<0.001),poor screening experience(OR=1.15,95%CI 1.04,1.28,p=0.009)and health system distrust(β=0.47,p<0.001).Qualitative findings add descriptive detail about sludge encountered,context to impacts experienced,and illustrate the heavy emotional impact of sludge:‘it just isn’t worth it’.Conclusion Efforts to reduce sludge in the CRC screening process may improve timely completion of CRC screening,enhance patient experience and restore trust in the health system.展开更多
Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without...Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without critical thought,we may simply have replaced one set of implausible assumptions(no unmeasured confounding or reverse causation)with another set of implausible assumptions(no pleiotropy or other instrument invalidity).The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables.Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy;in general,a biologically motivated strategy is preferred.In this review,we discuss various ways of implementing a biologically motivated selection strategy:using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels,using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy.In some cases,a genome-wide analysis can provide important complementary evidence,even when its reliability is questionable.In other cases,a biologically-motivated analysis may not be possible.The choice of genetic variants must be informed by biological and functional considerations where possible,requiring collaboration to combine biological and clinical insights with appropriate statistical methodology.展开更多
Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2.Kenya reported its first case on March 13,2020 and by March 16,2020 she instituted physical distancing strategies to reduce transmi...Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2.Kenya reported its first case on March 13,2020 and by March 16,2020 she instituted physical distancing strategies to reduce transmission and flatten the epidemic curve.An age-structured compartmental model was developed to assess the impact of the strategies on COVID-19 severity and burden.Contacts between different ages are incorporated via contact matrices.Simulation results show that 45%reduction in contacts for 60-days period resulted to 11.5e13%reduction of infections severity and deaths,while for the 190-days period yielded 18.8e22.7%reduction.The peak of infections in the 60-days mitigation was higher and happened about 2 months after the relaxation of mitigation as compared to that of the 190-days mitigation,which happened a month after mitigations were relaxed.Low numbers of cases in children under 15 years was attributed to high number of asymptomatic cases.High numbers of cases are reported in the 15e29 years and 30e59 years age bands.Two mitigation periods,considered in the study,resulted to reductions in severe and critical cases,attack rates,hospital and ICU bed demands,as well as deaths,with the 190-days period giving higher reductions.展开更多
Invariant natural killer T1(iNKT1)cells are characterized by the preferential expression of T-box transcription factor T-bet(encoded by Tbx21)and the production of cytokine IFN-γ,but the relationship between the deve...Invariant natural killer T1(iNKT1)cells are characterized by the preferential expression of T-box transcription factor T-bet(encoded by Tbx21)and the production of cytokine IFN-γ,but the relationship between the developmental process and iNKT1 lineage diversification in the thymus remains elusive.We report in the present study a crucial role of programmed cell death 5(PDCD5)in iNKT cell terminal maturation and iNKT1 fate determination.Mice with T cell-specific deletion of PDCD5 had decreased numbers of thymic and peripheral iNKT cells with a predominantly immature phenotype and defects in response toα-galactosylceramide.Loss of PDCD5 also selectively abolished the iNKT1 lineage by reducing T-bet expression in iNKT cells at an early thymic developmental stage(before CD44 upregulation).We further demonstrated that TOX2,one of the high mobility group proteins that was highly expressed in iNKT cells at stage 1 and could be stabilized by PDCD5,promoted the permissive histone H3K4me3 modification in the promoter region of Tbx21.These data indicate a pivotal and unique role of PDCD5/TOX2 in iNKT1 lineage determination.They also suggest that the fate of iNKT1 may be programmed at the developmental stage of iNKT cells in the thymus.展开更多
Newborn animals require tightly regulated local and systemic immune environments to govern the development and maturation of multiple organs/tissues even though the immune system itself is far from mature during the n...Newborn animals require tightly regulated local and systemic immune environments to govern the development and maturation of multiple organs/tissues even though the immune system itself is far from mature during the neonatal period.Regulatory T cells(Tregs)are essential for maintaining immune tolerance/homeostasis and modulating inflammatory responses.The features of Tregs in the neonatal liver under steady-state conditions are not well understood.The present study aimed to investigate the phenotype,functions,and significance of neonatal Tregs in the liver.We found a wave of thymus-derived Treg influx into the liver during 1–2 weeks of age.Depletion of these Tregs between days 7 and 11 after birth rapidly resulted in Th1-type liver inflammation and metabolic disorder.More Tregs in the neonatal liver than in the spleen underwent MHC II-dependent activation and proliferation,and the liver Tregs acquired stronger suppressive functions.The transcriptomic profile of these neonatal liver Tregs showed elevated expression of PPARγand T-bet and features of Tregs that utilize lipid metabolic machinery and are capable of regulating Th1 responses.The accumulation of Tregs with unique features in the neonatal liver is critical to ensure self-tolerance and liver maturation.展开更多
Thymic natural killer T(NKT)2 cells are a subset of invariant NKT cells with PLZF^(hi)GATA3^(hi)IL-4^(+).The differentiation of NKT2 cells is not fully understood.In the present study,we report an important role of TR...Thymic natural killer T(NKT)2 cells are a subset of invariant NKT cells with PLZF^(hi)GATA3^(hi)IL-4^(+).The differentiation of NKT2 cells is not fully understood.In the present study,we report an important role of TRAF3-interacting protein 3(TRAF3IP3)in the functional maturation and expansion of committed NKT2s in thymic medulla.Mice with T-cell-specific deletion of TRAF3IP3 had decreased thymic NKT2 cells,decreased IL-4-producing peripheral iNKTs,and defects in response toα-galactosylceramide.Positive selection and high PLZF expression in CD24^(+)CD44^(−) and CCR7^(+)CD44^(−) immature iNKTs were not affected.Only CD44^(hi)NK1.1^(−) iNKTs in Traf3ip3^(−/−) mice showed reduced expression of Egr2,PLZF,and IL-17RB,decreased proliferation,and reduced IL-4 production upon stimulation.This Egr2 and IL-4 expression was augmented by MEK1/ERK activation in iNKTs,and TRAF3IP3 at the trans-Golgi network recruited MEK1 and facilitated ERK phosphorylation and nuclear translocation.LT βR-regulated bone marrow-derived nonlymphoid cells in the medullary thymic microenvironment were required for MEK/ERK activation and NKT2 maturation.These data demonstrate an important functional maturation process in NKT2 differentiation that is regulated by MEK/ERK signaling at the trans-Golgi network.展开更多
文摘Objective Because of the limited number of studies and small sample sizes,whether metabolic syndrome(MS)leads to the occurrence and progression of osteoporosis and the possible underlying mechanisms require further investigation.This study aimed to investigate the association between MS and osteoporosis,along with its influencing factors.Methods This observational cross-sectional study included 139,470 individuals aged≥18 years who underwent health examinations from September 2014 to March 2022.Based on bone mineral density(BMD)screening results,the participants were categorized into a suspected osteoporosis or non-osteoporosis group(control).Participants were further divided into those who met 0 MS criteria,1 MS criterion,2 MS criteria,and≥3 MS criteria(MS group).Participants who had undergone health examinations at least twice formed the follow-up cohort;a self-matched analysis was performed on those with follow-up periods≥5 years and unchanged MS grouping.Results Several examination indicators in the suspected osteoporosis group showed statistically significant differences compared with the control group.The proportion of suspected osteoporosis in the MS group was significantly increased compared with that in the 0 MS criteria group(odds ratio[OR]:1.215,Z=29.11,P<0.001,95%confidence interval:1.199-1.231).After adjusting for age,sex,smoking,and alcohol consumption,the 2 MS criteria group and MS group still had OR values>1(P<0.001).In the follow-up cohort,the proportion of suspected osteoporosis increased gradually with an increase in the number of MS criteria met at baseline and during each follow-up visit(P<0.05),with the highest proportion observed in the MS group.However,the proportion of suspected osteoporosis did not increase significantly over time in the different MS groups(P>0.05).In the follow-up cohort,the proportion of individuals transitioning from normal BMD to suspected osteoporosis was higher in the MS group after≥5 years of follow-up compared with the group meeting 0 MS criteria(0.08%versus 1.15%,χ^(2)=10.76,P=0.001).There was no significant difference in BMD values for the 0 MS criteria group after 5 years(P>0.05),whereas the other three groups experienced a significant decrease in BMD values after 5 years(P<0.05).Conclusion MS is an independent risk factor for osteoporosis,and the effect of risk factors related to MS on osteoporosis may exceed that of aging alone.The specific mechanisms warrant further investigation.
基金Supported by Novartis Pharmaceuticals CorporationOne Health Plaza+2 种基金East HanoverNJ 07936-1080United States
文摘AIM To examine healthcare resource utilizationpatterns and costs accrued by carcinoid syndrome （CS）patients with and without diarrhea.METHODS： We conducted a retrospective cohort studyusing MarketScan data from 1/1/2002-12/31/2012.Newly diagnosed CS patients had 1 medical claim forCS （ICD-9-CM code 259.2） plus either ≥ 1 additionalclaim for CS or for carcinoid tumors （ICD-9-CM 209.x）, and had no evidence of CS for 1 year prior to index CS diagnosis, in commercially-insured patients 〈 65years old. Patients were required to have continuousenrollment one year prior and after index date （firstclaim with CS diagnosis in the ID period）. We identifiedpatients with evidence of non-infectious diarrhea （ICD-9-CM codes 564.5 and 787.91） within one year from theindex date. Overall and CS-related healthcare resourceutilization and costs were compared between patientswith and without non-infectious diarrhea during theone year period after the index date.RESULTS： There were 2822 newly diagnosed CSpatients; 534 （18.9%） had evidence of non-infectiousdiarrhea. Compared to patients without non-infectiousdiarrhea, non-infectious diarrhea patients morecommonly had at ≥ 1 CS-related hospitalization（13.7% vs 7.2%）, ≥ 1 CS-related ED visit （11.0% vs4.4%）, and CS-related office visits in one year （6.9 vs4.1; all p 〈 0.001）. After adjusting for demographics,region, number of chronic conditions and the CharlsonComorbidity Index, the proportions of patients withany and with CS-related hospitalizations were 9.7%and 6.8% higher, respectively, among non-infectiousdiarrhea patients compared to those with without noninfectiousdiarrhea （p 〈 0.001）. Unadjusted costs weresignificantly higher among non-infectious diarrheapatients vs those without non-infectious diarrhea. Thenon-infectious diarrhea group was also more costly,with adjusted mean annual costs of $81610, comparedto $51719 in the group without non-infectious diarrhea（p 〈 0.001）.CONCLUSION： Diarrhea is burdensome and costlyin CS patients. Reduction of CS-related healthcareexpenditures may be achievable through preventivetreatment and appropriate management of diarrhea inCS.
文摘As the treatment landscape for advanced melanoma continues to evolve, it is critical to focus on unmet needs and understand the cost of therapy. While Ipilimumab (IPI), an immunotherapy indicated for unresectable advanced melanoma, has been a mainstay of 1<sup>st</sup>-line treatment, there was no standard of care following progression until recently. The objective of this study was to examine real-world treatment patterns and healthcare costs following IPI use in advanced melanoma patients prior to the anti-PD-1 class approval. Adult stage III or IV melanoma patients treated with IPI were selected between April 1, 2011, and September 30, 2013, from a large U.S. commercial and Medicare claims database. Patients were evaluated for therapy after IPI, with an index date set as the first systemic therapy after IPI. Per-Patient Per-Month (PPPM) healthcare costs while on active treatment were evaluated from index until treatment discontinuation, inpatient death, end of insurance enrollment, or September 30, 2013. Of 361 eligible patients, 111 (30.7%) initiated subsequent systemic therapy (mean age, 57 years;64.9% male). The most common therapies, single-agent or combination, included vemurafenib (32.4%), paclitaxel (28.8%), temozolomide (20.7%), and carboplatin (17.1%). During a median follow-up of 130 days, mean [standard deviation] PPPM all-cause total healthcare costs were $20,383 [$18,988], of which $4800 (23.6%), $5899 (28.9%), and $9684 (47.5%) were related to melanoma drug costs, medical claims with a diagnosis of melanoma, and other (non-specified) utilization, respectively. When considering total care, the costs of U.S. patients with advanced melanoma post-IPI were substantial across all commonly used agents.
基金Supported by Novartis Pharmaceuticals Corporation,One Health Plaza,East Hanover,NJ 07936-1080,United States
文摘AIM:To review literature on efficacy and safety of octreotide-long-acting repeatable(LAR)used at doses higher than the Food and Drug Administration(FDA)-approved 30 mg/mo for treatment of neuroendocrine tumors(NETs).METHODS:We searched Pub Med and Cochrane Library from 1998-2012,5 conferences(American Society of Clinical Oncology,Endocrine Society,European Neuroendocrine Tumor Society,European Society for Medical Oncology,North American Neuroendocrine Tumor Society)from 2000-2013 using Me SH and keyterms including neuroendocrine tumors,carcinoid tumor,carcinoma,neuroendocrine,and octreotide.Bibliographies of accepted articles were also searched.Two reviewers reviewed titles,abstracts,and full-length articles.Studies that reported data on efficacy and safety of≥30 mg/mo octreotide-LAR for NETs in human subjects,published in any language were included in the review.RESULTS:The search identified 1086 publications,of which 238 underwent full-text review(20 were translated into English);17 were included in the review.Studies varied in designs,subjects,octreotide-LAR regimens,and definition of outcomes.Eleven studies reported use of higher doses to control symptoms and tumor progression,although symptom severity and formal quality-of-life analysis were not quantitatively measured.Ten studies reported efficacy,describing 260 subjects with doses ranging from 40 mg/mo or 30 mg/3 wk up to 120 mg/mo.Eight studies reported expert clinical opinion that supported dose escalation of octreotide-LAR up to 60 mg/mo for symptom control and suggested increased doses may be effective at preventing tumor progression.Eight studies reported safety;there was no evidence of increased toxicity associated with doses of octreotide-LAR>30 mg/mo.CONCLUSION:As reported in this review,octreotide-LAR at doses>30 mg/mo is being prescribed for symptom and tumor control in NET patients.Furthermore,expert clinical opinion provided support for escalation of somatostatin analogs for refractory hormonal symptoms.
基金Supported by Novartis Pharmaceuticals,One Health Plaza,East Hanover,No.NJ 07936-1080,United State
文摘AIM To describe real-world treatment patterns of gastrointestinal neuroendocrine tumors(GI NET).METHODS In this retrospective cohort study,we used 2009-2014 data from 2 United States commercial claims databases to examine newly pharmacologically treated patients using tabular and graphical techniques.Treatments included somatostatin analogues(SSA),cytotoxic chemotherapy(CC),targeted therapy(TT),interferon(IF)and combinations.We identified patients at least 18 years of age,with≥1 inpatient or≥2 outpatient claims for GI NET who initiated pharmacologic treatment from 7/1/09-6/30/14.A 6 mo clean period prior to first treatment ensured patients were newly treated.Patients were followed until end of enrollment or the study end date,whichever was first.RESULTS We identified 2258 newly treated GI NET patients:mean(SD)age was 55.6 years(SD=9.7),47.2%of the patients were between 55 and 64 years,and 48.8%were female.All regions of the United States were represented.59.6%started first-line therapy with SSA monotherapy(964 with octreotide LAR,380 with octreotide SA,and 1 with lanreotide),33.3%CC,3.6%TT,and 0.5%IF.The remainder received combinations.Mean follow up was 576 d.Overall mean first-line therapy duration was 361 d(449 d for SSA,215 for CC,267 for TT).58.9%of patients had no pharmacological treatment beyond first line.The most common secondline was combination therapy with SSA.In graphical pattern analysis,there was no clear pattern visible after first line therapy.CONCLUSION In this study,60%of patients initiated treatment with SSA alone or in combination.The relatively long time to discontinuation suggests possible sustained effectiveness and tolerability.
基金Supported by Grants from Novartis Pharmaceuticals Corporation,One Health Plaza,East Hanover,NJ 07936-1080,United States
文摘AIM:To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors(PNETs)and provide consensus treatment recommendations.METHODS:Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs,angiogenesis inhibitors,inhibitors of mammalian target of rapamycinand cytotoxic agents.At this time,there is little data to guide treatment selection and sequence.We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations.Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process.After studying the literature,a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale.Ratings were done both before and after an extended discussion of the evidence.Quantitative measurements of agreement were made and consensus statements developed from the second round ratings.RESULTS:Specialties represented were medical and surgical oncology,interventional radiology,and gastroenterology.Panelists had practiced for a mean of15.5 years(range:6-33).Among 202 rated scenarios,disagreement decreased from 13.2%(26 scenarios)before the face-to-face discussion of evidence to 1%(2)after.In the final ratings,46.5%(94 scenarios)were rated inappropriate,21.8%(44)were uncertain,and30.7%(62)were appropriate.Consensus statements from the scenarios included:(1)it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic;(2)it is appropriate to use everolimus,sunitinib,or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors;and(3)beyond first line,these same agents can be used.In patients with uncontrolled secretory symptoms,octreotide LAR doses can be titrated up to 60 mg every4 wk or up to 40 mg every 3 or 4 wk.CONCLUSION:Using the Delphi process allowed physician experts to systematically obtain a consensus on the appropriateness of a variety of medical therapies in patients with PNETs.
文摘INTRODUCTION Gender dysphoria(GD),or gender identity disorder,is defined as persistent distress stemming from the incongruence between one's assigned sex at birth and gender identity.'GD has traditionally been introduced as a rare condition predominant in assigned males at birth(AMABs).2 However,recent studies have shown an upward trend in assigned females at birth(AFABs)with a dramatic reversal of the AMAB:AFAB ratio-.5-The actual AMAB:AFAB ratio varies by age group and study population.4-Questions have been raised concerning the increasing number of youth who seek professional care for GD,especially adolescent AFABs.
基金Supported by Novartis Pharmaceuticals,One Health Plaza,East Hanover,NJ 07936-1080,United States
文摘AIM To discover unknown factors associated with carcinoid syndrome(CS)with the goal of earlier diagnosis of CS.METHODS In this retrospective case-control study using United States administrative claims,patients(≥18 years)newly-diagnosed with gastrointestinal neuroendocrine tumors(GI NETs)without CS(controls)were exactly matched to patients with CS(cases)based on NET diagnosis date at a 3-to-1 ratio.Study index date was first CS diagnosis(controls:same distance from NET diagnosis as cases).The most observed conditions,excluding CS-associated symptoms/diagnoses,during the year before index date were assessed.Forwardstepwise logistic regression models were used to derive predictors,and were validation within another claims database.RESULTS In the development database,1004 patients with GI NETs were identified;251(25%)had CS and 753(75%)were controls.In the validation database,724 patients with GI NETs were identified;181(25%)had CS and 543(75%)were controls.A total of 33 common diagnoses(excluding conditions already known to be associated with CS)in the development database were entered in forward step-wise logistic regression models.In the final,validated logistic regression model,three factors prior to CS diagnosis were found consistently associated with higher risks for CS,including liver disorder[odds ratio(95%CI):3.38(2.07-5.51)],enlargement of lymph nodes[2.13(1.10-4.11)],and abdominal mass[3.79(1.87-7.69)].CONCLUSION GI NET patients with CS were 2-4 times as likely to have preexisting diagnoses(i.e.,liver disorder,enlarged lymph nodes,abdominal mass)than non-CS patients.
文摘Background: Melanoma is a rare but serious skin cancer that is responsible for >90% of skin cancer-related deaths. This retrospective data analysis quantifies the direct cost of medical care by disease stage at diagnosis for patients with metastatic melanoma. Methods: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was queried for patients diagnosed between 2004-2009 with stage IIIB/C and stage IV (M1a, M1b, M1c) melanoma. The primary outcome was overall medical utilization and associated costs from diagnosis to death, the end of Medicare enrolment, or 12/31/2010. Results are stratified by disease stage at diagnosis and presented as per-patient per-month (PPPM) costs. Results: Of the 1263 patients meeting the study criteria (mean age: 75 years;64% male, 92% white, mean duration of follow up: 37.5 months), 66.6% were diagnosed at stage IIIB/C and 33.4% at stage IV. Cost of care increased with disease stage. Total PPPM costs ranged from $1966 for patients diagnosed with stage IIIB to $4585 among patients diagnosed with stage M1c. Outpatient costs accounted 48.9% of total medical costs among stage IIIB patients, and 38.7% of total medical costs for stage M1c patients. Inpatient costs accounted for 37.1% (stage M1b) - 40.9% (stage M1c) of total medical costs. Conclusions: Healthcare costs for treating patients with metastatic melanoma increase by disease stage. The cost of care was more than double among patients with late stage compared to those with early stage. Treatments demonstrating ability to prevent disease progression from early stage to late stage may confer an economic benefit among other clinical advantages.
基金supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health(award number UL1TR003015).
文摘Objective‘Sludge’refers to administrative burdens or frictions that preclude people from getting what they want or need(eg,duplicative forms,complicated instructions,long waiting times).This mixed methods study evaluated patients’perceptions of sludge in the colorectal cancer(CRC)screening process and some impacts of this sludge.Design We employed an exploratory sequential mixed methods study design that comprised patient interviews and a patient survey.The interviews informed final survey revisions and captured contextual data about patients’experiences with sludge.Interview transcripts were inductively and deductively analysed to identify overarching themes.The survey quantified sludge,delayed or forgone screenings,screening experience(Net Promoter Score)and health system distrust(Health System Distrust Scale).We usedχ2 or t-tests for univariable comparisons and logistic or linear regressions to evaluate the association between cumulative sludge score and delayed or forgone screenings,screening experience and health system distrust.Results were integrated for interpretation.Setting Southeastern United States.Participants Patients who were 45–75 years of age,at average risk for CRC and had either completed or been referred for CRC screening(colonoscopy or stool-based test)within the previous 12 months.Results 22 interview participants and 255 survey participants completed the study.38(15%)survey participants rated their screening experience as poor(Net Promoter Score=0–7 out of 10).The mean(SD)Health System Distrust Scale score was 22.4(6.3)out of 45 possible points(higher score=greater distrust).Perceptions of sludge in the CRC screening process varied,with long waiting times and burdensome communication being the most common sources(58%and 35%of participants,respectively).Sludge was positively associated with delayed or forgone screenings(OR=1.42,95%CI 1.28,1.57,p<0.001),poor screening experience(OR=1.15,95%CI 1.04,1.28,p=0.009)and health system distrust(β=0.47,p<0.001).Qualitative findings add descriptive detail about sludge encountered,context to impacts experienced,and illustrate the heavy emotional impact of sludge:‘it just isn’t worth it’.Conclusion Efforts to reduce sludge in the CRC screening process may improve timely completion of CRC screening,enhance patient experience and restore trust in the health system.
基金SB is supported by the Wellcome Trust(225790/Z/22/Z)the United Kingdom Research and Innovation Medical Research Council(MC_UU_00002/7)This research was supported by the National Institute for Health Research Cambridge Biomedical Research Centre(NIHR203312).
文摘Mendelian randomisation is an accessible and valuable epidemiological approach to provide insight into the causal nature of relationships between risk factor exposures and disease outcomes.However,if performed without critical thought,we may simply have replaced one set of implausible assumptions(no unmeasured confounding or reverse causation)with another set of implausible assumptions(no pleiotropy or other instrument invalidity).The most critical decision to avoid pleiotropy is which genetic variants to use as instrumental variables.Two broad strategies for instrument selection are a biologically motivated strategy and a genome-wide strategy;in general,a biologically motivated strategy is preferred.In this review,we discuss various ways of implementing a biologically motivated selection strategy:using variants in a coding gene region for the exposure or a gene region that encodes a regulator of exposure levels,using a positive control variable and using a biomarker as the exposure rather than its behavioural proxy.In some cases,a genome-wide analysis can provide important complementary evidence,even when its reliability is questionable.In other cases,a biologically-motivated analysis may not be possible.The choice of genetic variants must be informed by biological and functional considerations where possible,requiring collaboration to combine biological and clinical insights with appropriate statistical methodology.
文摘Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2.Kenya reported its first case on March 13,2020 and by March 16,2020 she instituted physical distancing strategies to reduce transmission and flatten the epidemic curve.An age-structured compartmental model was developed to assess the impact of the strategies on COVID-19 severity and burden.Contacts between different ages are incorporated via contact matrices.Simulation results show that 45%reduction in contacts for 60-days period resulted to 11.5e13%reduction of infections severity and deaths,while for the 190-days period yielded 18.8e22.7%reduction.The peak of infections in the 60-days mitigation was higher and happened about 2 months after the relaxation of mitigation as compared to that of the 190-days mitigation,which happened a month after mitigations were relaxed.Low numbers of cases in children under 15 years was attributed to high number of asymptomatic cases.High numbers of cases are reported in the 15e29 years and 30e59 years age bands.Two mitigation periods,considered in the study,resulted to reductions in severe and critical cases,attack rates,hospital and ICU bed demands,as well as deaths,with the 190-days period giving higher reductions.
基金This work was supported by grants from the National Key Research and Development Program of China,2017YFA0104500(Q.G.)the National Natural Science Foundation of China,81471525 and 31671244(Q.G.),31470843(J.Z.),31370898(Y.C.)+2 种基金the Foundation for Innovative Research Groups of the National Natural Science Foundation of China,81621001(Q.G.)Program for New Century Excellent Talents in University,NCET-13-0018(J.Z.)the Fundamental Research Funds for the Central Universities.
文摘Invariant natural killer T1(iNKT1)cells are characterized by the preferential expression of T-box transcription factor T-bet(encoded by Tbx21)and the production of cytokine IFN-γ,but the relationship between the developmental process and iNKT1 lineage diversification in the thymus remains elusive.We report in the present study a crucial role of programmed cell death 5(PDCD5)in iNKT cell terminal maturation and iNKT1 fate determination.Mice with T cell-specific deletion of PDCD5 had decreased numbers of thymic and peripheral iNKT cells with a predominantly immature phenotype and defects in response toα-galactosylceramide.Loss of PDCD5 also selectively abolished the iNKT1 lineage by reducing T-bet expression in iNKT cells at an early thymic developmental stage(before CD44 upregulation).We further demonstrated that TOX2,one of the high mobility group proteins that was highly expressed in iNKT cells at stage 1 and could be stabilized by PDCD5,promoted the permissive histone H3K4me3 modification in the promoter region of Tbx21.These data indicate a pivotal and unique role of PDCD5/TOX2 in iNKT1 lineage determination.They also suggest that the fate of iNKT1 may be programmed at the developmental stage of iNKT cells in the thymus.
基金by grants from the National Key Research and Development Program of China(2017YFA0104500)the National Natural Science Foundation of China(81471525,31671244,and 31872734,Q.G.+2 种基金81601975,K.Z.)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(81621001)the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2018PT31039).
文摘Newborn animals require tightly regulated local and systemic immune environments to govern the development and maturation of multiple organs/tissues even though the immune system itself is far from mature during the neonatal period.Regulatory T cells(Tregs)are essential for maintaining immune tolerance/homeostasis and modulating inflammatory responses.The features of Tregs in the neonatal liver under steady-state conditions are not well understood.The present study aimed to investigate the phenotype,functions,and significance of neonatal Tregs in the liver.We found a wave of thymus-derived Treg influx into the liver during 1–2 weeks of age.Depletion of these Tregs between days 7 and 11 after birth rapidly resulted in Th1-type liver inflammation and metabolic disorder.More Tregs in the neonatal liver than in the spleen underwent MHC II-dependent activation and proliferation,and the liver Tregs acquired stronger suppressive functions.The transcriptomic profile of these neonatal liver Tregs showed elevated expression of PPARγand T-bet and features of Tregs that utilize lipid metabolic machinery and are capable of regulating Th1 responses.The accumulation of Tregs with unique features in the neonatal liver is critical to ensure self-tolerance and liver maturation.
基金supported by grants from the National Key Research and Development Program of China(2017YFA0104500)the National Natural Science Foundation of China(81471525,31671244,31872734,Q.G.,31872824,H.Z.)+1 种基金the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(81621001)the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences,2018PT31039.
文摘Thymic natural killer T(NKT)2 cells are a subset of invariant NKT cells with PLZF^(hi)GATA3^(hi)IL-4^(+).The differentiation of NKT2 cells is not fully understood.In the present study,we report an important role of TRAF3-interacting protein 3(TRAF3IP3)in the functional maturation and expansion of committed NKT2s in thymic medulla.Mice with T-cell-specific deletion of TRAF3IP3 had decreased thymic NKT2 cells,decreased IL-4-producing peripheral iNKTs,and defects in response toα-galactosylceramide.Positive selection and high PLZF expression in CD24^(+)CD44^(−) and CCR7^(+)CD44^(−) immature iNKTs were not affected.Only CD44^(hi)NK1.1^(−) iNKTs in Traf3ip3^(−/−) mice showed reduced expression of Egr2,PLZF,and IL-17RB,decreased proliferation,and reduced IL-4 production upon stimulation.This Egr2 and IL-4 expression was augmented by MEK1/ERK activation in iNKTs,and TRAF3IP3 at the trans-Golgi network recruited MEK1 and facilitated ERK phosphorylation and nuclear translocation.LT βR-regulated bone marrow-derived nonlymphoid cells in the medullary thymic microenvironment were required for MEK/ERK activation and NKT2 maturation.These data demonstrate an important functional maturation process in NKT2 differentiation that is regulated by MEK/ERK signaling at the trans-Golgi network.
