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2024年中国专家关于慢性阻塞性肺疾病的新观点英文版Title: New Perspectives on Chronic Obstructive Pulmonary Disease in China by Experts in 2024In 2024, experts in China have put forward new perspectives on Chronic Obstructive Pulmonary Disease (COPD). This respiratory disease is a significant health concern globally, with a high prevalence in China. The experts have highlighted the importance of early detection and intervention in managing COPD. They emphasize the role of personalized treatment plans tailored to the individual needs of patients. Additionally, they stress the importance of lifestyle modifications, such as smoking cessation and regular exercise, in improving COPD outcomes.Furthermore, the experts have proposed novel approaches to COPD management, including the use of telemedicine and digital health technologies to monitor patients remotely. They also advocate for greater awareness and education about COPD among healthcareproviders and the general public. The experts believe that a multi-disciplinary approach involving collaboration between pulmonologists, primary care physicians, and respiratory therapists is essential for optimal COPD care.In conclusion, the new perspectives on COPD in China by experts in 2024 underscore the need for a comprehensive and holistic approach to managing this complex respiratory condition. By adopting personalized treatment plans, leveraging technology, and promoting education and awareness, it is hoped that the burden of COPD can be reduced and patient outcomes improved in the years to come.。

Ann.N.Y.Acad.Sci.ISSN0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue:The Year in Diabetes and ObesityCardiovascular disease and glycemic control in type2 diabetes:now that the dust is settling from largeclinical trialsFrancesco Giorgino,Anna Leonardini,and Luigi LaviolaDepartment of Emergency and Organ Transplantation,Section of Internal Medicine,Endocrinology,Andrology and Metabolic Diseases,University of Bari Aldo Moro,Bari,ItalyAddress for correspondence:Francesco Giorgino,M.D.,Ph.D.,Department of Emergency and Organ Transplantation, Section of Internal Medicine,Endocrinology,Andrology and Metabolic Diseases,University of Bari Aldo Moro,Piazza Giulio Cesare,11,I-70124Bari,Italy.francesco.giorgino@uniba.itThe relationship between glucose control and cardiovascular outcomes in type2diabetes has been a matter of controversy over the years.Although epidemiological evidence exists in favor of an adverse role of poor glucose control on cardiovascular events,intervention trials have been less conclusive.The Action to Control Cardiovascular Risk in Diabetes(ACCORD)study,the Action in Diabetes and Vascular Disease(ADV ANCE)study,and the Veterans Affairs Diabetes Trial(V ADT)have shown no beneficial effect of intensive glucose control on primary cardiovascular endpoints in type2diabetes.However,subgroup analysis has provided evidence suggesting that the potential beneficial effect largely depends on patients’characteristics,including age,diabetes duration,previous glucose control,presence of cardiovascular disease,and risk of hypoglycemia.The benefit of strict glucose control on cardiovascular outcomes and mortality may be indeed hampered by the extent and frequency of hypoglycemic events and could be enhanced if glucose-lowering medications,capable of exerting favorable effects on the cardiovascular system,were used.This review examines the relationship between intensive glucose control and cardiovascular outcomes in type2diabetes,addressing the need for individualization of glucose targets and careful consideration of the benefit/risk profile of antidiabetes medications.Keywords:type2diabetes;HbA1c;macrovascular disease;blood pressure;lipids;hypoglycemia;glucagon-like peptide-1;ADV ANCE;ACCORD;V ADTIntroductionCardiovascular disease(CVD)is the major cause of death in patients with type2diabetes(T2D), as more than60%of T2D patients die of my-ocardial infarction(MI)or stroke,and an even greater proportion of patients have serious burden-some complications.1The impact of glucose low-ering on cardiovascular complications is a hotly debated issue.The United Kingdom Prospective Di-abetes Study(UKPDS)was thefirst clinical trial to provide key evidence of the importance of using in-tensive therapy for diabetes control in individuals with newly diagnosed T2D.However,although the insulin or sulphonylurea-based intensified glucose-control treatment was effective in reducing the risk of major microvascular endpoints,the effects on CVD risk were modest and did not reach statisti-cal significance.2Recent large clinical trials(often referred to as“megatrials”),the Action in Diabetes and Vascular Disease(ADV ANCE),3Action to Con-trol Cardiovascular Risk in Diabetes(ACCORD),4 and the Veterans Affairs Diabetes Trial(V ADT),5 reported no significant decrease in primary cardio-vascular endpoints with intensive glucose control. In the ADV ANCE study,11,140type2diabet-ics were randomly assigned to receive either stan-dard or intensive glucose control,defined as the use of gliclazide plus any other drug required to achieve a glycosylated hemoglobin(HbA1c)level of 6.5%or less(Table1).3After a median follow-up of 5.0years,the mean HbA1c was lower in thedoi:10.1111/nyas.12044Giorgino et al.Intensive glucose control and cardiovascular risk Table1.Age,diabetes duration,median follow-up,HbA1c values,and outcomes in the ACCORD and ADV ANCE studies and the V ADTDiabetes HbA1c(%):duration(year):Median intensive Primary All-cause Age intensive follow-up History versus endpoint HR mortality HR Study(year)versus standard(year)of CVD standard Primary endpoint(95%CI)(95%CI)ACCORD(n=10,251)62.2±6.810vs.10 3.435% 6.4vs.7.5Nonfatal MI,nonfatalstroke,or death fromCVD0.90(0.78–1.04) 1.22(1.01–1.46)ADV ANCE (n=11,140)66±6.08.0±6.4vs.7.9±6.35.032%6.53±0.91vs.7.30±1.26Death fromcardiovascular causes,nonfatal MI,ornonfatal stroke0.94(0.84–1.06)0.93(0.83–1.06)V ADT(n=1,791)60±9.011.5±8vs.11.5±75.640%6.9vs.8.4MI,stroke,death fromCVD,CHF,surgery forvascular disease,inoperable CAD,oramputation forischemic gangrene0.88(0.74–1.05) 1.07(0.81–1.42)intensive control group(6.5%vs.7.3%),with a reduction in the incidence of combined major macrovascular and microvascular events primarily because of a reduction in the incidence of nephropa-thy.There were no significant effects of the inten-sive glucose control on major macrovascular events, death from cardiovascular causes,or death from any cause.Similarly,in the V ADT,1,791suboptimally controlled type2diabetics,40%with established CVD,were randomized to receive either intensive glucose control,targeting an absolute reduction of 1.5%in HbA1c levels,or standard glucose control (Table1).5After a median follow-up of5.6years, HbA1c was lower in the intensive-therapy group (6.9%vs.8.4%).Nevertheless,there was no sig-nificant difference between the two groups in the incidence of major cardiovascular events,or in the rate of death from any cause.ACCORD was another study designed to determine whether intensive glu-cose control would reduce the rate of cardiovas-cular events(Table1).4In this study,10,251type 2diabetics with median baseline HbA1c of8.1% were randomly assigned to receive either intensive therapy targeting an HbA1c level within the normal range,that is,below6.0%,or standard therapy tar-geting HbA1c between7.0%and7.9%.The primary outcome was a composite of nonfatal MI,nonfatal stroke,or death from cardiovascular causes.Even though the rate of nonfatal MI was significantly lower in the intensive therapy arm,thefinding of higher all-cause and cardiovascular cause mortal-ity in this group led to discontinuation of the in-tensive therapy after a mean follow-up of3.5years (Fig.1).Notably,hypoglycemia requiring assistance and weight gain of more than10kg were more fre-quent in the intensive therapy group.The results of the ACCORD study raised concern about not only the effectiveness but also the safety of inten-sive glycemic control in type2diabetics.Prespec-ified subgroup analysis of the participants in this trial suggested that patients in the intensive group without history of cardiovascular event before ran-domization or whose baseline HbA1c level was8.0% or less may have had fewer fatal or nonfatal car-diovascular events than did patients in the standard therapy group.Several recent meta-analyses of randomized con-trolled trials have also investigated the effects of intensive glucose lowering on all-cause mortal-ity,cardiovascular death,and vascular events in T2D.6–10In the largest and most recent meta-analysis by Boussageon et al.,13studies were in-cluded.6Of the34,533patients evaluated,18,315 received intensive glucose-lowering treatment and 16,218standard treatment.Intensive treatment did not significantly affect all-cause mortality or cardiovascular death.The results of this meta-analysis showed limited benefit of intensive glucose-lowering therapy on all-cause mortality and deaths from cardiovascular causes,and a10%reduction in the risk of microalbuminuria.6Results from other meta-analyses have also shown no effects ofIntensive glucose control and cardiovascular risk Giorgino etal.Figure 1.Effects of intensive glucose control on all-cause and cardiovascular mortality and myocardial infarction in the ACCORD study.CV,cardiovascular.∗P<0.05.Adapted from Ref.4.intensive glucose control on all-cause or cardiovas-cular mortality,while indicating a modest15–17% reduction in the incidence of nonfatal MI in these cohorts.7–10Several potential factors could have contributed to limit the potential benefit of intensive glucose-lowering therapies on CVD prevention in T2D in-dividuals in studies such as the ACCORD and AD-V ANCE and the V ADT:(1)Concomitant targeting of other potentiallymore potent cardiovascular risk factors,suchas blood pressure and lipids,might havedampened the favorable effects of controllinghyperglycemia.(2)Intensive control of hyperglycemia could havebeen directed to patients unable to exhibit theexpected benefit due to their specific clinicalcharacteristics(“wrong”patients).(3)Limited benefit might have derived from usingglucose-lowering drugs with no favorable im-pact on the global cardiovascular risk profile.(4)Glucose-lowering drugs might have producedadverse effects on the cardiovascular systemby inducing weight gain and hypoglycemicevents,resulting in somewhat increased riskfor CVD and mortality(“imperfect”drugs).(5)Excess mortality might have potentially re-sulted from using too many drugs and/or toocomplex drug regimens,leading to undesir-able drug–drug interactions with a potentiallyharmful impact on patients’health.These diverse factors and their potential role in the relationship between intensive glucose control and CVD/mortality are outlined in Figure2,and will be discussed individually below.Limited benefit due to other therapies Although several studies have focused on intensive glycemic control to decrease the risks of macrovas-cular and microvascular diseases in T2D,glucose control is only one of the factors to be considered. Comprehensive risk factor management,including blood pressure control,lipid management,weight reduction in overweight or obese individuals,and smoking cessation,are also needed.The results of the ACCORD and ADV ANCE studies and the V ADT should be interpreted in the context of comprehen-sive care of patients with diabetes.Interventions for simultaneous optimal control of comorbidities of-ten present in type2diabetics,such as hyperten-sion and hyperlipidemia,have been shown to be a more effective strategy in reducing cardiovascular risk than targeting only blood glucose levels per se.11 Evidence for an aggressive approach to lipid and blood pressure control was supported by the re-sults from the Steno-2study.11,12In Steno-2,inves-tigators used intensified multifactorial intervention with improved glycemia,renin–angiotensin system blockers,aspirin,and lipid-lowering agents and evaluated whether this approach would have an ef-fect on the rates of death from cardiovascular causes and from any cause.11,12The primary endpoint at 13.3years of follow-up was the time to death from any cause.Intensive therapy was also associated with a significantly lower risk of death from cardiovascu-lar causes and of cardiovascular events.The Steno-2study did demonstrate a difference in levels of glycemia achieved when compared with the AC-CORD study:4,11HbA1c was a mean of8.4%at study entry and7.9%at end of study intervention for the intensively treated group,whereas it was8.8%at baseline and9.0%at study end for conventional treatment.In addition,only a limited proportion of subjects in the intensively treated group reached an HbA1c level of less than6.5%(i.e.,∼15%),and this proportion was not statistically different than in the conventionally treated group,indicating poor success in achieving the prespecified glucose target and somewhat reducing the relevance of the spe-cific intervention on the hyperglycemia component for CVD and microvascular disease prevention.The observational study has continued,and the differ-ences observed in glycemia between intensive andGiorgino et al.Intensive glucose control and cardiovascularriskFigure2.Relationship between intensive glucose control and cardiovascular outcomes and mortality in the ACCORD study and other megatrials.The potential mechanisms affecting this relationship and limiting the clinical benefit are outlined in the box on the left.CV,cardiovascular;CVD,cardiovascular disease.conventional treatments are much less than at endof intervention.Nevertheless,over the long-termperiod of follow-up,intensive intervention with avaried drug regimen and lifestyle modification hadsustained beneficial effects with respect to vascularcomplications and rates of death from any cause andfrom cardiovascular causes.12Blood pressureThe ACCORD study also had an embedded bloodpressure trial that examined whether blood pressurelowering to systolic blood pressure(SBP)less than120mm Hg provided greater cardiovascular protec-tion than a SBP of130–140mm Hg in T2D patientsat high risk for CVD.13A total of4,733participantswere randomly assigned to intensive therapy(SBP <120mm Hg)or standard therapy(SBP<140mm Hg),with the mean follow-up being4.7years.Theblood pressure levels achieved in the intensive andstandard groups were119/64mm Hg and133/70mm Hg,respectively;this difference was attainedwith an average of3.4medications per participantin the intensive group and2.1in the standard ther-apy group.The intensive antihypertensive therapyin the ACCORD blood pressure trial did not consid-erably reduce the primary cardiovascular outcomeor the rate of death from any cause.However,theintensive arm of blood pressure control reduced therate of total stroke and nonfatal stroke,with the estimated number needed to treat with intensive blood pressure therapy to prevent one stroke over five years being89.There were indicators of possi-ble harm associated with intensive blood pressure lowering(SBP<120mm Hg),including a rate of serious adverse events in the intensive arm.It should be noted that of the subjects investigated in the ACCORD glucose control trial∼85%were on antihypertensive medications,and their blood pres-sure levels were126.4/66.9and127.4/67.7in the intensive and standard groups,respectively,a differ-ence that was statistically significant(P<0.001) (Table2).4Thus,the effects of intensive glucose lowering on the CVD and other outcomes were ex-amined in a context in which blood pressure was being actively targeted,with possible differences between the intensively and conventionally treated cohorts.The ADV ANCE study also included a blood pres-sure intervention trial.In this study,treatment with an angiotensin converting enzyme(ACE)inhibitor and a thiazide-type diuretic reduced the rate of death but not the composite macrovascular out-come.However,this trial had no specified targets for the randomized comparison,and the mean SBP in the intensive group(135mm Hg)was not as low as the mean SBP in the ACCORD standard-therapy group.14However,a post hoc analysis of blood pres-sure control in6,400patients with diabetes andIntensive glucose control and cardiovascular risk Giorgino et al. Table2.Blood pressure and lipid levels and use of statin,antihypertensive medications,and aspirin in the ACCORD and ADV ANCE studies and the V ADT participants at study end(adapted from Refs.3–5)ACCORD(n=10,251)aADV ANCE(n=11,140)b V ADT(n=1,791)cStandard Intensive Standard Intensive Standard Intensive Blood pressure(mm Hg)Systolic128±16126±17137±18135±17125±15127±16 Diastolic68±1067±1074±1073±1069±1068±10 Cholesterol(mg/dL)LDL87±3387±33103±41102±3880±3180±33 HDL49±13(♂)49±13(♂)48±1448±1441±1240±1140±11(♀)40±10(♀)Total164±42163±42153±40150±40 Triglycerides(mg/dL)166±114160±125161±102151±94159±104151±173 On statin(%)888848468385 On antihypertensivemedications(%)858389887576 On aspirin(%)767655578586a Intensive(target HbA1c<6%)vs.standard(HbA1c7–7.9%).b Intensive(target HbA1c<6.5%)vs.standard(HbA1c>6.5%).c Intensive(target HbA1c4.8–6.0%)vs.standard(HbA1c8–9.0%).Abbreviations:HDL,high-density lipoprotein;LDL,low-density lipoprotein;♂,men;♀,women.coronary artery disease enrolled in the International Verapamil/Trandolapril Study(INVEST)demon-strated that tight control(<130mm Hg)was not associated with improved cardiovascular outcomes compared with usual care(130–140mm Hg).15In the V ADT,blood pressure,lipids,diet,and lifestyle were treated identically in both arms.By improving blood pressure control in an identical manner in both glucose arms,the V ADT excluded the effect of blood pressure differences on cardiovas-cular events between treatment arms and reduced the overall risk of macrovascular complications dur-ing the trial.5Participants in the V ADT(n=1,791) with hypertension(72.1%of total)received stepped treatment to maintain blood pressure below the tar-get of130/80mm Hg in standard and intensive glycemic treatment groups.Blood pressure levels of all subjects at baseline and on-study were analyzed to detect associations with cardiovascular risk.The primary outcome was the time from randomiza-tion to thefirst occurrence of MI,stroke,conges-tive heart failure,surgery for vascular disease,in-operable coronary disease,amputation for ischemic gangrene,or cardiovascular death.From data analy-sis,increased risk of cardiovascular events with SBP ≥140mm Hg emphasizes the need for treatment of systolic hypertension.Also,this study for the first time demonstrated that diastolic blood pressure (DBP)<70mm Hg in T2D patients was indepen-dently associated with elevated cardiovascular risk, even when SBP was on target.16Lipid profileIt has been widely demonstrated that intensive targeting of low-density lipoprotein(LDL)choles-terol contributes to CVD prevention in T2D.As a consequence,most guidelines suggest a target LDL-cholesterol level below100mg/dL as the primary goal in T2D individuals,with the option of achieving an LDL-cholesterol level below70mg/dL in those with overt CVD.Regarding the overall lipid-lowering approach in the ACCORD glucose control study,it should be observed that mean LDL cholesterol was below90mg/dL in both the intensive and standard glucose control arms,and that88%of subjects were on statin therapy.4Thus, the results from this study do not clarify whether lipid control and glycemic control,respectively,areGiorgino et al.Intensive glucose control and cardiovascularriskFigure3.All-cause mortality in intensive versus standard glycemia groups according to use of antihypertensive medications, statins,and aspirin in the ACCORD and ADV ANCE studies.∗P=0.0305for subjects on aspirin versus subjects not on aspirin. Adapted from Refs.3and18.related or synergistic,since the large majority of enrolled subjects were already receiving a lipid control regimen.Data from the Steno-2trial on combined control of glucose,lipids,and blood pressure levels demonstrated significant short-and long-term benefits from this multifactorial approach.11In the study,the effect seemed to be cumulative rather than synergistic.Recent results from the ACCORD-LIPID study indicate that intensive lipid control(i.e.,addition of afibrate to statin therapy)does not reduce car-diovascular events.17Specifically,the lipid-lowering arm of ACCORD failed to demonstrate any ben-efit of add-on therapy with fenofibrate to LDL-lowering treatment with HMG-CoA reductase in-hibitors(statins)on vascular outcomes in patients with diabetes.However,data from earlier studies and from a subgroup analysis of ACCORD indi-cate a probable benefit of adding treatment with fibric acid derivatives to individuals with persis-tently elevated triglyceride levels and low high-density lipoprotein(HDL)cholesterol despite statin therapy.17In the ACCORD and ADV ANCE studies and the V ADT,a large proportion of subjects,ranging from55%to85%,were also treated with aspirin (Table2).Thus,results from ADV ANCE,ACCORD, and V ADT suggest that a large proportion of par-ticipants in these trials,which were being treated intensively or less intensively for glucose targets, received extensive antihypertensive,lipid-lowering, and antiplatelet medications.Median levels of SBP, SDP,and LDL cholesterol in these cohorts were also indicative of a significant proportion of them be-ing adequately controlled for blood pressure and lipid targets(Table2).Therefore,the possibility ex-ists that active interventions for simultaneous con-trol of hypertension and hyperlipidemia and use of aspirin may have affected the impact of intensive glucose control on cardiovascular outcomes in the megatrials.Subgroups analyses,however,do not ap-parently support this conclusion(Fig.3).Whether patients were on antihypertensive or lipid-lowering medications was not associated with a different out-come of the intensive glucose control on mortality in ACCORD and ADV ANCE patients,even thoughIntensive glucose control and cardiovascular risk Giorgino et al.the different groups were largely unbalanced in size. Only aspirin use in the ACCORD study seemed to modulate the effects of intensive versus standard glucose control on mortality.18The“wrong patient”concept and the need for individualization of glucose targets The ADV ANCE and ACCORD studies and the V ADT provide conflicting evidence of mortality risk with intensive glycemic control.These trials showed an approximate15%reduction in nonfatal MI with no benefit or harm in all-cause or cardiovascular mortality.Potential explanations for the lack of im-pact of intensive glycemic control on CVD can be found in the patients’characteristics.Indeed,these studies were of shorter duration and enrolled gener-ally older patients than previous studies,including the DCCT and UKPDS in which the intensive con-trol had shown better outcomes.In addition,mean diabetes duration was longer and a greater portion of patients had established CV disease in the mega-trials(approximately32–40%)than in earlier trials (Table1).It is also possible that the follow-up of these studies was too short to detect a clinical ben-efit.Consistent with this hypothesis,in the UKPDS no macrovascular benefit was noted in the inten-sive control arm in thefirst10years of follow-up. Nevertheless,posttrial monitoring for an additional 10years(UKPDS80)revealed a15%risk reduction in MI and13%reduction in all-cause mortality in the intensive treatment group.19A possible explanation is that the wrong patients were investigated in the megatrials(Fig.2).Indeed, the population of the ACCORD study may not rep-resent the average patient with T2D in clinical prac-tice.Participants in this trial had T2D on average for10years at the time of enrollment,had higher HbA1c levels than most type2diabetic patients in the United States and most Western countries to-day(average of8.2%at baseline),and had known heart disease or at least two risk factors in addi-tion to diabetes,such as high blood pressure,high cholesterol levels,obesity,and smoking.4In the UKPDS,the benefits of intensive glycemic control on CVD were observed only after a long duration of intervention in newly diagnosed younger patients.2 In older patients with T2D with longer disease dura-tion,atherosclerotic disease may already have been established and thus intensive glucose control may have had little benefit.Conversely,patients with shorter disease duration,lower HbA1c,and/or lack of established CVD might have benefited signifi-cantly from more intensive glycemic control.20,21 Relevant to this concept,the V ADT showed that ad-vanced CVD,as demonstrated by computed tomog-raphy(CT)-detectable coronary artery calcium,was associated with negative outcomes.In a substudy co-hort of301T2D participants in V ADT,the ability of intensive glucose therapy compared with standard therapy to reduce cardiovascular events was exam-ined based on the extent of coronary atherosclerosis as measured by a CT-detectable coronary artery cal-cium score(CAC).The data showed that there was a progressive diminution of the benefit of intensive glucose control with increasing CAC.In patients with CAC≤100,1of52individuals experienced an event(HR for intensive therapy=0.08;range, 0.008–0.770;P=0.03),whereas11of62patients with a CAC>100had an event(HR=0.74;range, 0.46–1.20;P=0.21).Thus,this subgroup analy-sis indicates that intensive glycemic therapy may be most effective in those with less extensive coronary atherosclerosis.22Why does intensive treatment of hyperglycemia appear to be ineffective in reducing cardiovascular events in T2D with advanced atherosclerosis?Two potential mechanisms may be involved.First,once the atherosclerotic plaque has developed,modified lipoproteins,activated vascular cells,and altered im-mune cell signaling may generate a self-propagating process that maintains atherogenesis,even in the face of improved glucose control.Second,advanced glycosylation end-product formation,which may be involved in CVD,is not readily reversible and may require more than three tofive years of in-tensive glucose control to be reverted.Thus,the presence of multiple cardiovascular risk factors or established CVD may have reduced the benefits of intensive glycemic control in the high-risk cohort of ACCORD,ADV ANCE,and V ADT compared with the low-risk population of the UKPDS cohort,of whom only a minority had prior CVD.23The pres-ence of long-standing disease and prolonged prior poor glycemic control may be additional factors ac-celerating the progression of atherosclerotic lesions in T2D.The goal of individualizing HbA1c targets has gained more attraction after these recent clinical trials in older patients with established T2D failed to show a benefit from intensive glucose-loweringGiorgino et al.Intensive glucose control and cardiovascular riskTable3.Potential criteria for individualization of glucose targets in type2diabetes2–5,25,29HbA1c HbA1c Criterion<6.5–7.0%7.0–8.0% Age(years)<55>60 Diabetes duration(years)<10>10Life expectancy(years)>5<5 Possibility to performIGC for>5yearsYes No Usual HbA1c level(%)<8.0>8.0 CVD No Yes Prone to hypoglycemia No No Reduction of HbA1clevel upon IGCYes NoAbbreviations:CVD,cardiovascular disease;IGC,in-tensive glucose control.therapies on CVD outcomes.Recommendations suggest that the goals should be individualized,such that(1)certain populations(children,pregnant women,and elderly patients)require special con-siderations and(2)more stringent glycemic goals (i.e.,a normal HbA1c<6.0%)may further re-duce complications at the cost of increased risk of hypoglycemia.24For the latter,the recommen-dations also suggest that less intensive glycemic goals may be indicated in patients with severe or frequent hypoglycemia.With regard to the less intensive glycemic goals,perhaps consideration should be given to the high-risk patient with mul-tiple risk factors and CVD,as evaluated in the ACCORD study.4Thus,aiming for a HbA1c of 7.0–8.0%may be a reasonable goal in patients with very long duration of diabetes,history of se-vere hypoglycemia,advanced atherosclerosis,sig-nificant comorbidities,and advanced age/frailty (Table3),even though with what priority each one of these criteria should be considered is not clear at present(current recommendations from scientific societies also do not provide this spe-cific information).In younger patients without documented macrovascular disease or the above-mentioned conditions,the goal of attaining an HbA1c<6.5–7.0%may provide long-lasting bene-fits.In patients with limited life expectancy,more liberal HbA1c values may be pursued.In deter-mining the HbA1c target for CVD prevention,one should consider that at least three tofive years are usually required before possible differences in the incidence of nonfatal MI in T2D are observed.2 Thus,a clinical setting that allows tight glucose control to be implemented for this period of time should be available.Finally,an excess mortality was observed in the ACCORD study in those T2D in-dividuals who showed an unexpected increase in HbA1c levels upon institution of intensive glucose control.25Accordingly,patients exhibiting the pat-tern of worsening glycemic control when exposed to intensive treatment should be set at higher glucose targets(Table3).The above guidelines are apparently incorpo-rated into the updated version of the American Diabetes Association and the European Associa-tion for the Study of Diabetes recommendations on the management of hyperglycemia in nonpreg-nant adults with T2D.The new recommendations are less prescriptive and more patient centered.In-dividualized treatment is explicitly defined as the cornerstone of success.Treatment strategies should be tailored to individual patient needs,preferences, and tolerances and based on differences in age and disease course.Other factors affecting individual-ized treatment plans include specific symptoms,co-morbid conditions,weight,race/ethnicity,sex,and lifestyle.26Current“imperfect”glucose-lowering drugsThe inability of ACCORD,ADV ANCE,and V ADT to demonstrate significant reductions in CVD out-comes with intensive glycemic control also suggests that current pharmacological tools for treating hy-perglycemia in patients with more advanced T2D may have counterbalancing consequences for the cardiovascular system.The available agents used to treat diabetes have not been conclusively shown to reduce macrovascular disease and,in some in-stances,their chronic use may promote negative cardiovascular effects in diabetic subjects despite improvement of hyperglycemia.Importantly,these adverse cardiovascular side effects appear in several instances to be directly due to the mode of drug ac-tion.Selection of a treatment regimen for patients with T2D includes evaluation of the effects of med-ications on overall cardiovascular risk.27 Sulfonylureas have the benefit of acting rapidly to lower glucose levels but,unfortunately,on a。

关于惠更斯原理的英文作文The Huygens Principle is a fundamental concept in the field of wave theory, illustrating how each point on a wavefront can be considered as a source of secondary spherical wavelets.This principle, proposed by the Dutch scientist Christiaan Huygens in the 17th century, revolutionized our understanding of wave propagation. It posits that the wavefront at any given moment can be seen as the envelope of these secondary wavelets.In the context of light waves, the Huygens Principle helps explain phenomena such as reflection and refraction. When light encounters a boundary between two media, the principle suggests that each point on the wavefront generates new wavelets that interfere with each other, resulting in the observed bending of light.Moreover, the principle is instrumental in understanding diffraction, the bending of waves around obstacles and the spreading of waves through openings. It elegantly demonstrates how the wavefront continues to advance even when obstructed, a behavior crucial for technologies like optical fibers and diffractive lenses.Despite its simplicity, the Huygens Principle is not without its limitations. It does not account for the waveamplitude, which is essential for explaining the intensity of light. However, when combined with Fermat's Principle of Least Time, it provides a comprehensive framework for analyzing wave behavior.In essence, the Huygens Principle is a powerful tool in the study of wave phenomena, offering a visual and intuitive approach to understanding how waves interact with their environment and propagate through space. It remains a cornerstone of modern physics, with applications in various scientific and engineering disciplines.。

fluorescenceFluorescence: An Insight into the Phenomenon, Applications, and Future PerspectivesIntroduction:Fluorescence is a fascinating natural phenomenon observed in various living organisms, minerals, and chemicals. It involves the emission of light by a substance after being exposed to electromagnetic radiation, typically ultraviolet (UV) light. This phenomenon has gained immense significance in scientific research and various technological applications. In this document, we will delve into the world of fluorescence, exploring its underlying principles, applications in diverse fields, and future perspectives.1. Principles of Fluorescence:Fluorescence revolves around the absorption and subsequent re-emission of light within the visible spectrum. When a fluorophore, a substance capable of fluorescing, absorbs energy from a photon, electrons within the molecule get excited and move to higher energy levels. As the electronsreturn to their ground state, they emit light of lower energy, resulting in fluorescence. This emission occurs at longer wavelengths than the absorbed light, thus producing a characteristic color glow.2. Exploring Fluorescent Probes:Fluorescent probes are crucial tools used to visualize and track specific molecules or cellular structures in biological systems. These probes are designed to selectively bind to the target of interest and emit fluorescence upon excitation. From traditional organic dyes to advanced quantum dots and genetically encoded fluorescent proteins, a wide range of probes have been developed to cater to various research needs. These probes have revolutionized biological imaging, enabling scientists to study cellular processes with high specificity and sensitivity.3. Applications in Biology and Medicine:Fluorescence imaging techniques, such as fluorescence microscopy and flow cytometry, have become cornerstones of modern biological research. They allow direct visualization and quantification of cellular events, such as protein localization, gene expression, and cellular interactions.Additionally, fluorescence-based methods are vital in clinical diagnostics, such as immunoassays, DNA sequencing, and fluorescence in situ hybridization (FISH). These techniques have facilitated early disease detection, drug discovery, and personalized medicine, leading to significant advancements in healthcare.4. Industrial and Environmental Applications:Fluorescence finds applications beyond the realm of biology and medicine. Industries harness its potential in various technologies and processes. For instance, fluorescence is exploited in the analysis of food and beverage quality, environmental monitoring, and detection of contaminants. The use of fluorescence in chemical sensors and biosensors has facilitated rapid and sensitive detection of analytes, helping ensure product safety and environmental health.5. Future Perspectives:As technology continues to advance, the field of fluorescence is poised for exciting developments. Researchers are actively exploring novel fluorophores with enhanced properties, such as brighter emission, improved photostability, and longer fluorescence lifetimes. The integration of fluorescencetechniques with other cutting-edge technologies, like super-resolution microscopy and optogenetics, holds great potential for pushing the boundaries of scientific discovery. Furthermore, the emerging field of nanotechnology promises innovative applications of fluorescence, including targeted drug delivery systems and ultra-sensitive biosensors.Conclusion:Fluorescence is a captivating phenomenon that has revolutionized scientific research and technological advancements. From its fundamental principles to its diverse applications, fluorescence has transformed the way we understand and interact with the world around us. Its contribution to biology, medicine, industry, and the environment cannot be overstated. As we move forward, embracing the rapid advancements in the field, the future of fluorescence holds immense promise for furthering human knowledge and improving our lives in countless ways.。

Spectroscopic Study of the Interaction between Small Molecules and Large Proteins1. IntroductionThe study of drug-protein interactions is of great importance in drug discovery and development. Understanding how small molecules interact with proteins at the molecular level is crucial for the design of new and more effective drugs. Spectroscopic techniques have proven to be valuable tools in the investigation of these interactions, providing det本人led information about the binding affinity, mode of binding, and structural changes that occur upon binding.2. Spectroscopic Techniques2.1. Fluorescence SpectroscopyFluorescence spectroscopy is widely used in the study of drug-protein interactions due to its high sensitivity and selectivity. By monitoring the changes in the fluorescence emission of either the drug or the protein upon binding, valuable information about the binding affinity and the binding site can be obt本人ned. Additionally, fluorescence quenching studies can provide insights into the proximity and accessibility of specific amino acid residues in the protein's binding site.2.2. UV-Visible SpectroscopyUV-Visible spectroscopy is another powerful tool for the investigation of drug-protein interactions. This technique can be used to monitor changes in the absorption spectra of either the drug or the protein upon binding, providing information about the binding affinity and the stoichiometry of the interaction. Moreover, UV-Visible spectroscopy can be used to study the conformational changes that occur in the protein upon binding to the drug.2.3. Circular Dichroism SpectroscopyCircular dichroism spectroscopy is widely used to investigate the secondary structure of proteins and to monitor conformational changes upon ligand binding. By analyzing the changes in the CD spectra of the protein in the presence of the drug, valuable information about the structural changes induced by the binding can be obt本人ned.2.4. Nuclear Magnetic Resonance SpectroscopyNMR spectroscopy is a powerful technique for the investigation of drug-protein interactions at the atomic level. By analyzing the chemical shifts and the NOE signals of the protein in thepresence of the drug, det本人led information about the binding site and the mode of binding can be obt本人ned. Additionally, NMR can provide insights into the dynamics of the protein upon binding to the drug.3. Applications3.1. Drug DiscoverySpectroscopic studies of drug-protein interactions play a crucial role in drug discovery, providing valuable information about the binding affinity, selectivity, and mode of action of potential drug candidates. By understanding how small molecules interact with their target proteins, researchers can design more potent and specific drugs with fewer side effects.3.2. Protein EngineeringSpectroscopic techniques can also be used to study the effects of mutations and modifications on the binding affinity and specificity of proteins. By analyzing the binding of small molecules to wild-type and mutant proteins, valuable insights into the structure-function relationship of proteins can be obt本人ned.3.3. Biophysical StudiesSpectroscopic studies of drug-protein interactions are also valuable for the characterization of protein-ligandplexes, providing insights into the thermodynamics and kinetics of the binding process. Additionally, these studies can be used to investigate the effects of environmental factors, such as pH, temperature, and ionic strength, on the stability and binding affinity of theplexes.4. Challenges and Future DirectionsWhile spectroscopic techniques have greatly contributed to our understanding of drug-protein interactions, there are still challenges that need to be addressed. For instance, the study of membrane proteins and protein-protein interactions using spectroscopic techniques rem本人ns challenging due to theplexity and heterogeneity of these systems. Additionally, the development of new spectroscopic methods and the integration of spectroscopy with other biophysical andputational approaches will further advance our understanding of drug-protein interactions.In conclusion, spectroscopic studies of drug-protein interactions have greatly contributed to our understanding of how small molecules interact with proteins at the molecular level. Byproviding det本人led information about the binding affinity, mode of binding, and structural changes that occur upon binding, spectroscopic techniques have be valuable tools in drug discovery, protein engineering, and biophysical studies. As technology continues to advance, spectroscopy will play an increasingly important role in the study of drug-protein interactions, leading to the development of more effective and targeted therapeutics.。

（1092）溶出度试验的开发和验证【中英文对照版】之巴公井开创作INTRODUCTION前言Purpose目的The Dissolution Procedure: Developmentand Validation<1092> provides a comprehensive approach covering items to considerfor developing and validating dissolution procedures and the accompanyinganalytical procedures. It addresses the use of automation throughout the testand provides guidance and criteria for validation. It also addresses thetreatment of the data generated and the interpretation of acceptance criteriafor immediate and modifiedrelease solid oral dosage forms.溶出实验:开发和验证（1092）指导原则提供了在溶出度方法开发和验证过程中以及采取相应分析方法时需要考虑的因素。

本指导原则贯穿溶出度实验的全部过程，并对方法提供了指导和验证尺度。

同时它还涉及对普通制剂和缓释制剂所生成的数据和接受尺度进行说明。

Scope范围Chapter <1092> addresses the development andvalidation of dissolution procedures, with a focus on solid oral dosage forms.Many of the concepts presented, however, may be applicable to other dosageforms and routes of administration. General recommendations are given with theunderstanding that modifications of the apparatus and procedures as given in USPgeneral chapters need to be justified.<1092>章节讨论了溶出度实验的开发和验证，重点是口服固体制剂。

弗兰西斯培根介绍英文English:Francis Bacon was an English philosopher, statesman, and scientist who was one of the most prominent figures of the scientific revolution of the seventeenth century. He is best known for his work in promoting scientific inquiry for the sake of improving the human condition, and for his contributions to the development of the scientific method. Bacon believed that the knowledge gained through the application of reason and empirical observation could be used to advance human welfare and progress. He wrote extensively on a wide range of topics, including politics, ethics, and metaphysics, but his most significant contributions were in the field of natural philosophy. In his influential work, Novum Organum, Bacon proposed a new method for acquiring knowledge about the natural world that emphasized experimentation and observation over dogmatic reliance on tradition or authority. This approach became known as the Baconian method and had a profound impact on the development of modern science. Bacon was also an important political figure in England, serving as Lord Chancellor under KingJames I. His tenure was marked by controversy and scandal, but he remained a respected intellectual figure until his death.Translated content:弗朗西斯・培根是英国的哲学家、政治家和科学家，他是17世纪科学革命中最重要的人物之一。

英文外刊，抗击疟疾的科学家们，陷入了生物伦理学的争论Scientists at this lab in Burkina Faso have deployed gene warfare against the parasite carrying mosquitoes that spread malaria.布基纳法索一个实验室的科学家已经对传播疟疾同时携带寄生虫的蚊子进行了基因改造。

The conventional tools at our disposal today have reached a ceiling and can't become more efficient than they are right now.我们现在使用的传统工具已经达到了极限，不能比现在的效率更高。

We have no choice but to look at complementary methods.我们别无选择，只能寻找辅助性疗法。

That is why we're using genetically modified mosquitoes.这就是我们对蚊子进行转基因的原因。

Professor Diabate runs the experiment for target malaria, a research consortium backed by the Bill and Melinda Gates Foundation.迪亚巴特教授为目标疟疾组织(比尔和梅琳达.盖茨基金会支持的研究联盟)开展了这项实验。

The group developed an enzyme that sterilizes male mosquitoes.研究小组研发出一种可以使雄蚊绝育的酶，可以使雄蚊绝育。

The action of the enzyme continues after fertilization which means if the male copulates with a female, the embryo is dead and the female can no longer have offspring.这种酶在雌蚊子受精后继续发挥作用，这意味着如果雄蚊子与雌蚊子交配，胚胎就会死亡，雌蚊子就不能再生育后代。

关于抗老基金的英语作文The Fountain of Youth: Investing in an Anti-Aging FundAs we grow older, the relentless march of time takes its toll on our bodies and minds. Wrinkles deepen, hair grays, and energy levels decline. The prospect of growing old can be daunting, filled with concerns about declining health, loss of independence, and the specter of mortality. However, what if there was a way to slow down the aging process and maintain our youthful vigor well into our golden years? This is the promise of an anti-aging fund – a financial investment that aims to unlock the secrets of longevity and provide individuals with the resources to age gracefully.The concept of an anti-aging fund is built on the rapidly advancing field of rejuvenation biotechnology. Scientists around the world are making groundbreaking discoveries in areas such as stem cell therapy, gene editing, and cellular reprogramming, all with the goal of reversing the biological signs of aging. By investing in companies and research initiatives at the forefront of this field, an anti-aging fund seeks to capitalize on the potential breakthroughs that coulddramatically extend the human lifespan.One of the key components of an anti-aging fund is its focus on cutting-edge medical treatments and therapies. This might include investments in pharmaceutical companies developing novel drugs to combat age-related diseases, or biotech startups exploring innovative approaches to cellular rejuvenation. The fund could also allocate resources to research institutions conducting clinical trials on longevity-enhancing interventions, from calorie-restricted diets to nanorobotic therapies.Beyond medical advancements, an anti-aging fund may also invest in technologies that enhance human performance and delay the aging process. This could include wearable devices that monitor vital signs and provide personalized health recommendations, or smart home systems that optimize living environments for improved sleep, nutrition, and physical activity. The fund might even explore investments in space exploration, as the unique conditions of microgravity and cosmic radiation may yield insights into the fundamental mechanisms of aging.Of course, the prospect of an anti-aging fund is not without its critics and skeptics. Some argue that the pursuit of extended lifespan is unnatural and goes against the inherent order of the universe. Others raise ethical concerns about the potential for suchtechnologies to exacerbate social inequalities, as only the wealthy may have access to the most cutting-edge rejuvenation treatments.Despite these challenges, the proponents of anti-aging funds believe that the potential benefits far outweigh the risks. By investing in the science of longevity, they argue, we can not only improve the quality of life for individuals but also alleviate the societal burden of an aging population. Reduced healthcare costs, increased economic productivity, and a more vibrant and engaged older generation –these are just some of the potential upsides of successful anti-aging interventions.Moreover, the advocates of these funds contend that the pursuit of extended lifespan is not merely about personal vanity or the desire to cheat death. Rather, it is about empowering individuals to live fuller, more fulfilling lives, free from the constraints of age-related decline. Imagine a world where the elderly are not relegated to the sidelines, but instead remain active, engaged, and contributing members of their communities well into their later years. This, they argue, is the true promise of an anti-aging fund.Of course, investing in an anti-aging fund is not without its risks. The field of rejuvenation biotechnology is still in its infancy, and the path to commercialization for many of these technologies is uncertain. There is also the potential for unexpected side effects or unintendedconsequences, as with any emerging medical intervention. Investors in an anti-aging fund must be prepared to weather the ups and downs of this volatile and rapidly evolving market.Nevertheless, for those with a long-term vision and a willingness to embrace the unknown, an anti-aging fund may represent a unique opportunity to invest in the future of human health and longevity. By supporting the cutting-edge research and development that could unlock the secrets of aging, these investors are not only securing their own financial future, but also contributing to a broader societal transformation that could have profound implications for generations to come.In conclusion, the concept of an anti-aging fund is a fascinating and complex proposition that speaks to our deepest human desires – the desire to live longer, healthier, and more fulfilling lives. While the road ahead may be uncertain, the potential rewards of this investment are nothing short of transformative. As we continue to push the boundaries of what is possible in the realm of rejuvenation biotechnology, the anti-aging fund may well emerge as a critical catalyst in our quest for the fountain of youth.。

大连民族学院国际商学院英文翻译2007级毕业论文外文翻译资料Microfinance's Latest Growing Pains小额信贷业的发展阵痛《Knowledge Wharton》February 2nd 2011《沃顿知识》杂志 2011年2月2日译者：刘颖会大连民族学院国际商学院国际经济与贸易072班2011年6月小额信贷业发展阵痛近期的小额信贷危机源于印度南部城市安得拉邦，当地过度负债、暴力催款和借款者被迫自杀等问题引发了民众对小额信贷行业的广泛指责，并强烈呼吁政府加强监管。

10月，印度政府对损害信贷、强行控制回款天数并拖累印度最大的盈利性小额信贷公司SKS股价暴跌的小额信贷机构实施管制。

1月19日，印度储备银行发布Malegam委员会报告，建议对印度小额信贷机构施加一系列新的监管措施，包括设置利率上限、贷款限额以及对借款人的收入进行规定。

有些观察家对此表示欢迎，而悲观人士则认为此举难以避免信贷紧缩和行业崩溃。

尽管现在要分析行业前景还为时尚早，但安得拉邦的危机着实引发了民众对全球小额信贷行业的热烈讨论和深刻反省。

近期在沃顿阿瑞斯高级管理教育学院小额信贷管理培训班上，讨论的焦点集中在过度信贷、高速的行业增长以及如何在追求利润的同时更好地实现小额信贷的设立宗旨。

小额信贷业经历了一场由坏账“大地震”所引发的“痛苦的觉醒”，26名来自全球各地的社会财富计划参与者之一Kamran Azim在一堂主题为小额信贷业的增长与可持续发展的讨论中如此比喻道。

Azim是创立于1996年的巴基斯坦拉合尔小额信贷机构Kashf 基金的运营总监。

他指出，过去20到30年间，小额信贷的方式方法几乎都没有发生过变化。

但现在，突然之间，这个行业经历了一场地震。

正如该培训计划中一门课程的导言所说：“面对不断加速的变革，人们趋向于依赖传统的方式进行商业发展。

然而，正是在这样的时刻，创新方显得尤为重要。

”此外，几名学员也指出，小额信贷行业必须在兼顾客户需求的同时通过创新的方式来巩固发展。