Azienda USL di Bologna

BACKGROUND: Suicide is a leading cause of death worldwide; however, the prevalence and risk factors for the immediate precursors to suicide - suicidal ideation, plans and attempts - are not wellknown, especially in low- and middle-income countries. AIMS: To report on the prevalence and risk factors for suicidal behaviours across 17 countries. METHOD: A total of 84 850 adults were interviewed regarding suicidal behaviours and socio-demographic and psychiatric risk factors. RESULTS: The cross-national lifetime prevalence of suicidal ideation, plans, and attempts is 9.2% (s.e.=0.1), 3.1% (s.e.=0.1), and 2.7% (s.e.=0.1). Across all countries, 60% of transitions from ideation to plan and attempt occur within the first year after ideation onset. Consistent cross-national risk factors included being female, younger, less educated, unmarried and having a mental disorder. Interestingly, the strongest diagnostic risk factors were mood disorders in high-income countries but impulse control disorders in low- and middle-income countries. CONCLUSION: There is cross-national variability in the prevalence of suicidal behaviours, but strong consistency in the characteristics and risk factors for these behaviours. These findings have significant implications for the prediction and prevention of suicidal behaviours.

BACKGROUND: Little is known about the epidemiology of adult attention-deficit hyperactivity disorder (ADHD). AIMS: To estimate the prevalence and correlates of DSM-IV adult ADHD in the World Health Organization World Mental Health Survey Initiative. METHOD: An ADHD screen was administered to respondents aged 18-44 years in ten countries in the Americas, Europe and the Middle East (n=11422). Masked clinical reappraisal interviews were administered to 154 US respondents to calibrate the screen. Multiple imputation was used to estimate prevalence and correlates based on the assumption of cross-national calibration comparability. RESULTS: Estimates of ADHD prevalence averaged 3.4% (range 1.2-7.3%), with lower prevalence in lower-income countries (1.9%) compared with higher-income countries (4.2%). Adult ADHD often co-occurs with other DSM-IV disorders and is associated with considerable role disability. Few cases are treated for ADHD, but in many cases treatment is given for comorbid disorders. CONCLUSIONS: Adult ADHD should be considered more seriously in future epidemiological and clinical studies than is currently the case.

Ulcerative colitis [UC] is a chronic inflammatory bowel disease [IBD] characterised by colonic inflammation extending to a variable extent from the rectum. Care of the patient with UC requires appropriate input from across the multiprofessional team. These guidelines summarise the recommended medical treatment for adults with UC. Other ECCO guidelines consider the approach to UC diagnosis and monitoring,1–3 nursing care,4 management of disease complications,5–7 risk of infection,8 and technical aspects of surgery.9 This document was prepared as part of a process that also led to the publication of a related guideline with recommendations on the surgical care of the patients with UC and on the medical aspects of the management of the patient hospitalised with severe UC. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Surgical Treatment. Patients living with UC can have a variable disease course.10 In this document, we discuss therapeutic approaches stratified by disease severity [mildly-to-moderately active and moderately-to-severely active disease]. Attempts to define disease severity are widely used in setting clinical trial inclusion criteria and can be measured according to several different definitions.11 Trial populations will inevitably vary, and we reflect the continuum of disease severity by having the moderate disease category span both broad categories. It is also important to remember that these definitions capture severity at a given point in time and may not reflect the cumulative long-term burden of disease experienced by a patient.12 It is also important to consider disease extent when planning treatment in UC, as this may affect the optimal route of drug administration. This is typically defined according to disease involving the rectum only [proctitis], disease distal to the splenic flexure [left-sided UC], or disease extending proximal to the splenic flexure [extensive UC].13 These definitions of disease extent are recognised as somewhat arbitrary; in clinical practice, topically administered therapies are often used for UC whose extent is limited to the rectum and a portion of the sigmoid colon [proctosigmoiditis], with the term ‘distal colitis’ used to describe this disease distribution. It should be remembered that disease distribution can change10,14 and that proximal disease extension can be a negative prognostic marker.15 This document was compiled following the ‘Grading of Recommendations Assessment, Development, and Evaluation’ [GRADE] methodology.16 A panel of 33 experts was selected by the Guidelines Committee of ECCO from a competitive pool of applicants and worked with a team of methodologists and librarians. All panellists received training in the GRADE methodology. Additionally, six patients with UC, representing the European Federation of Crohn’s and Colitis Associations [EFCCA], were invited to participate in all face-to-face meetings as full voting members. Two domains for the medical treatment of UC were identified and used as the basis for the following two working groups based upon disease severity: mildly-to-moderately active disease and moderately-to-severely active disease. We recognise that these divisions are somewhat arbitrary, partially overlapping, and inconsistently defined; therefore, we ensured close collaboration between the working groups to ensure that key topics were covered appropriately with the aim of providing guidance applicable across the continuum of UC severity encountered in clinical practice. Working group participants first formulated a series of specific questions using the Population, Intervention, Comparator, Outcomes [PICO] system, which were deemed to be clinically important for the medical treatment of UC. These questions were debated in a series of telephone conferences before final agreement at a meeting of the full guideline group in Vienna in November 2019. Voting on the inclusion of PICO questions was conducted, and only those achieving agreement of >80% by the panel were included in the next phase of the process. At this meeting, the panellists also ranked each outcome’s importance on a scale of 1 to 9 based on the GRADE definitions.16 Scores of 7‒9 indicated an outcome that is critical to patients for decision making; scores of 4‒6 indicated an important outcome, but not critical; and scores of 1‒3 indicated an outcome of limited importance. The panellists’ agreement on outcomes’ importance was assessed using the Disagreement Index, as described in the RAND/UCLA appropriateness method.17 The team of librarians performed a comprehensive literature search on PubMed/Medline, Embase, and the Cochrane Central databases, using specific search strings for each PICO question [available as Supplementary data at ECCO-JCC online]. Two working group members [one assigned to the PICO question and another from the same group as second reviewer] independently screened titles and abstracts to exclude any irrelevant reports. Subsequently, the working group members assigned to each PICO question assessed the full text of the selected publications for relevance to the specific PICO. Note that were only selected the PICO as data on at of the of for the of the In this that of a drug of were not included for not at outcome defined as of critical importance. of the the guidelines in this document from in patients with UC. The methodologists performed the The risk was used to treatment with were in with the in group of a we used a that was to the of the the we prepared and the using and We used for All are all for a and we on the in the The was based on the and the risk in the The of was using the following and each PICO we the of for each outcome, and the of across a guideline the of the extent to which the in the is to a the of the for each outcome across all we with the from as and assessed the following that to the of risk of and publication of was assessed using the Cochrane was assessed with the Cochrane a and the was according to the a different but related or outcome from the of was based on the of of was by when the of was and by two when was was assessed using and the and only were at included in the The of was a of the of across all critical for decision making; the of for any of the critical the of all used in each key data and for each outcome of and each of the of are as Supplementary with of the of We of of each of the the risk with the risk with the the and any the data in the with of the of across The of each was as that the of an the or or as that the is also the of and of between and and All recommendations were to voting by the panel the ECCO for each with six from the European of and from a of ECCO members in ECCO guideline The final of all was panel members a final meeting in and to a final recommendations were at of the panellists with the and The of text and and were by the ECCO also the final of these These guidelines are to and in on the medical treatment of should not be used to a of should not be used for and should not be as the of any or All with the and publication of this guideline were by The of ECCO in the of panel members or the or of PICO A of of the key from ECCO UC guidelines is in the Supplementary These guidelines the for the of different medical therapies in the treatment of UC. were and in a by the which were typically from clinical and based upon of an the medical care of a patient with UC the between a given drug and patients encountered in the not the of a given clinical trial It is important that these guidelines are used first to the of the of any given which the with the in a treatment A key of is when to is in UC in Crohn’s disease on the importance of treatment At the same the of can to and as can to the of an is a in the GRADE process when the of as guidelines will be that this document can not is that appropriate and of patients for is critical to optimal The of treatment in UC is to of and is important to not only of clinical but also as this is with long-term The importance of these was in the decision by the panel to and clinical as of critical importance. The term widely used in the to as and from therapies and This is somewhat as the of and to therapies with the of and are as a part of UC the of this we to the term as in the of any widely also the of this specific definitions of have used in these are in the for of the we typically in a both for patients disease or in appropriate or can a in clinical practice, are trial data in this and are to several of this we have recommendations to the in a in clinical In to the and of medical for UC, and when to consider or treatment to the and burden to patients of drug is an important The limited on treatment and is the of this We at a of to in patients with mildly-to-moderately active UC of We performed a of with a of patients for a in achieving clinical the clinical in at was for with in of patients with of those The of on as in with patients was with was The in with patients for a of was in the The of was as to and publication and for as Supplementary data at ECCO-JCC online]. A Cochrane the of or across This not any in between different of of colonic distribution of different in were in any this patients with active UC to with appropriately are to upon to an The same Cochrane not for of across when with of the same of the a of of a of with in patients with active disease or in those with treatment with or UC a of data also of in the group in the In according to disease severity not any in between and in of a We at a of for the of in active distal colitis We identified that assessed a of for which we used for as Supplementary data at ECCO-JCC All of inflammation but in the proximal of disease extent a of from the to was a in clinical and clinical when with patients and In in that assessed 1 for as in distal was in patients with those with in between treatment and were the of was as is the clinical and related to administration. We the of with for of in patients with active UC of at extent a were that the of with as for of in patients with active UC as Supplementary data at ECCO-JCC In all of these the of with the of this the of is Two these two therapeutic for clinical in patients with disease of at The were in of of clinical and of clinical In the of in clinical was is to in clinical in active These included patients and treatment was All were in of patient criteria used to define disease and and was a of and a risk of as the of and were in of The of clinical between and treatment was was only trial on the of on of Patients of of those with of the was not The of for this outcome was of assessed of the outcome of which was an and in the It is to the of treatment only trial this with were patients in the treatment group and patients in the group experienced In to this was also a risk of the of the data for this outcome was assessed to be we that the for clinical and the and risk of the all a in of in patients for was We using for the of in patients with active distal colitis The of topically administered for the of in patients with and distal the of a treatment with may be by patients to the route of administration. have on this but included all of the that was identified we performed a of that with as Supplementary data at ECCO-JCC were to in of clinical clinical and not with The of patients included in each was and the of was This was to and identified for the outcome critical outcome, critical were to have we that the with in clinical practice, the between and was in between and the of as an for of in patients with active UC. We treatment with for of in patients with active distal UC of The of treatment with at a or or for of in patients with active distal UC in We performed a of these which included a of patients with at or or with at as Supplementary data at ECCO-JCC online]. were for the of clinical but were not in clinical In patients for was to be with or In the of not between or the of was as patients should be with a is to that and may be of This may be appropriate for patients to to It is also important to be of between in of and all of which may have in patient It is appropriate to a patient a trial of an are to an We the of for of in patients with active UC of The of treatment with using 9 for of in patients with active UC in as Supplementary data at ECCO-JCC online]. A of patients with were included and for were to in clinical and clinical and In two patients for was to be with in with In all the of and of any not between and and The of in a of for this critical to A of data from both phase a clinical and of for 9 for of these data that this was in patients with the between drug and was not in those with disease. data for the of as a This that the appropriate of may be in patients with mildly-to-moderately active disease are not to or are to 9 with in patients with mildly-to-moderately active UC a in the of clinical and and in the treatment We the of as for the of in patients with active UC of Two have on the of as with for of in patients with only patients in two were and assessed for clinical with given a of We performed a of these and not a between and for of clinical as Supplementary data at ECCO-JCC online]. data on clinical or were It should be that to the of of may be appropriate to in patients with active disease with is but only when given an We not any using or for the of to related of we the of in of across the We the of at a for of in UC patients of We identified two involving participants with of which to PICO We these in a as Supplementary data at ECCO-JCC online]. clinical was that was to for in patients with UC was the of but this not for with was with the of was to be to with data for we appropriate to a given the and of this may be the of this inconsistently in the literature and may reflect in We the of for the of in patients with distal UC We identified that assessed as in patients with distal UC or as Supplementary data at ECCO-JCC used between 1 and 1 administered as or a of to [one The of was as a to risk of and The same were identified in a Cochrane The of as in patients with distal UC or was in of clinical with the of data on the of in distal UC or are for patients the of was to These not data on A Cochrane in the of patients or in the of to with with the of is is based on the clinical of and of of with the of this It is important to consider patient for the of the route for both in to and a of the route of may for with patients in and and may or should be We with for the of in patients with UC or are to moderate of We identified on treatment with in patients with UC were or to as Supplementary data at ECCO-JCC In patients for 1 was to for the of clinical data on or clinical or were In to clinical different disease and definitions were with and are the clinical of we not the of for of is important that any with is an We not any of but to related we across the drug with the of This is in patients of should be in this the of for the of in of to any in of clinical We for of in patients with moderately-to-severely active UC of a limited the of for the of in moderately-to-severely active UC is in clinical practice. The limited is in part to the and limited at the time of the A included only two of used we performed a of these two and an of for the of clinical The of was as to a risk of and part the of patients included in each was as Supplementary data at ECCO-JCC online]. with treatment was in these two Other the of in both and also in both UC and Crohn’s to the for of which are a outcome for we that the with in clinical and the between and used limited the of another as or as an for of in patients with moderately-to-severely active UC. these is as the of A identified six that with and a of of but with of these used a We recommendations for in active and in moderately-to-severely active UC, to reflect the populations of the identified and the in these different It is important to that are data the of as and limited data on the of these to Additionally, is with to with the of with to we of in patients with UC. should be for any patient disease or of or to Additionally, of should be to a of and with a should be for any patient requires a of in a or a disease upon We treatment with and to in patients with UC have or to We identified that with in patients with moderately-to-severely active UC as Supplementary data at ECCO-JCC an to or of which were defined as or both in also to or of of for of clinical and clinical We data for which is related to but defined from the outcome of used in this guideline was to was in of when of treatment data for from were that are not Two that performed that is to for the of clinical and The first also that is to and for of clinical and and and for of and and patients with a of of are limited data to treatment of a phase trial that the clinical of with were in patients with different from A of identified that the of when used in UC. was not to In patients with a of to or of clinical and were not are limited data on the of in A key question is to an with an The of with is data not for in with in UC, a for this and have in patients with Crohn’s patients of to a first used as and with of is in of of a to of to the second The optimal time point for the of to be in Crohn’s of used in the UC disease severe or as at first and inflammatory have to patients may from treatment the of this approach have not in any We treatment with for the of in patients with moderately-to-severely active UC have or to of Two were identified that PICO These included patients with moderately-to-severely active UC with or of clinical of clinical and were Patients were to as Supplementary data at ECCO-JCC online]. We included these two in a was often in patients with the of for clinical was the same as for clinical the between patients with and those was not of in patients with were not different from those data from also this was also for and data were of at in the phase were for patients with for patients In at in a phase not between and patients The of was The of was for clinical to and The of was moderate for clinical to The for both was to in between the two The of for was moderate to the was as the with the of in both and We treatment with to in patients with UC have or to moderate of We performed a of data from two to PICO These included patients with UC an of or were to or or a were with or as Supplementary data at ECCO-JCC was for in of clinical clinical and the was to and of on were were the was also to data are from of which should be when upon of The of an route of and the of should also be A of on data for clinical and in both the of patients to and the with were in of between these 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patients have to an is to for or the of therapeutic drug to clinical have an between of and and clinical in UC. these were all and any or a of based for of to in patients with disease of of patients with of to have that of or drug to with patients not to and to patients to to These data that by drug may be to be clinically decision but this requires in a The same and the to and not to the of of drug to in patients are not of in participants with UC, to with to at or by therapeutic drug The therapeutic drug was not to and was was a of clinical to were to drug with given the of appropriate we were to a as Supplementary data at ECCO-JCC and we in this We for of in patients with UC to with We identified that included patients with or which on of clinical and clinical in patients with moderately-to-severely active UC to as Supplementary data at ECCO-JCC Patients in these were for We performed a of from these was in received with clinical was also in patients with The of for these was 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were also The clinical was also to on were for in were to The was to an risk for was of the were of and and A of the of across inflammatory a risk of This was also in a of data from the in UC were and with a This risk to be and is with A in that the of with with this risk to be in patients or in those A of in patients with and with at risk a risk of in patients with with patients with This risk was not in patients with data are in patients with risk in the UC these the European recommended using at the and as treatment for patients with risk In this UC patients with for at and in for were to with the same or to clinical were and for the and in or were between the two were in the data that is also with an risk of and we the that the in patients with with the with and of recommendations for as a treatment in patients with UC, with the and to be for each We for the of in patients with UC to with moderate of A with for in UC in patients to The that treatment with at of when with in of clinical and of clinical at data were not for we used data for the related of and with was a in for those on the The of were also by the scores in patients the not in the treatment In to the also also for clinical clinical and with were but this not The between with and were in patients with a of These recommendations summarise the on the medical management of patients with UC. were identified the of the which should be by is or is and recommendations be ECCO as or It is important that these guidelines the of and to and the and of We recognise that on care are an important in recommendations can be for patients in The recommendations should be used to treatment and part of an treatment for patients with UC, which may also and ECCO will these guidelines by ECCO and and will any to ECCO Guidelines clinical the ECCO will as a to the guideline recommendations can be clinical and patient care The important not as to for both and negative of These treatment guidelines will be according to the Committee for the of guidelines on the ECCO will the GRADE approach and consider the from clinical in the The ECCO guidelines are at care only and are based on an process. treatment are a for the and should not be based on the of the ECCO ECCO or any of members any may not be for any in in the ECCO ECCO a of of The is based on a used by the Committee of The are not only at the ECCO and the of but are also to on the ECCO providing a comprehensive of of of the We the ECCO for and for the literature and for the on and on the

PURPOSE: Standard therapy for glioblastoma (GBM) is temozolomide (TMZ) administration, initially concurrent with radiotherapy (RT), and subsequently as maintenance therapy. The radiologic images obtained in this setting can be difficult to interpret since they may show radiation-induced pseudoprogression (psPD) rather than disease progression. METHODS: Patients with histologically confirmed GBM underwent radiotherapy plus continuous daily temozolomide (75 mg/m(2)/d), followed by 12 maintenance temozolomide cycles (150 to 200 mg/m(2) for 5 days every 28 days) if magnetic resonance imaging (MRI) showed no enhancement suggesting a tumor; otherwise, chemotherapy was delivered until complete response or unequivocal progression. The first MRI scan was performed 1 month after completing combined chemoradiotherapy. RESULTS: In 103 patients (mean age, 52 years [range 20 to 73 years]), total resection, subtotal resection, and biopsy were obtained in 51, 51, and 1 cases, respectively. MGMT promoter was methylated in 36 patients (35%) and unmethylated in 67 patients (65%). Lesion enlargement, evidenced at the first MRI scan in 50 of 103 patients, was subsequently classified as psPD in 32 patients and early disease progression in 18 patients. PsPD was recorded in 21 (91%) of 23 methylated MGMT promoter and 11 (41%) of 27 unmethylated MGMT promoter (P = .0002) patients. MGMT status (P = .001) and psPD detection (P = .045) significantly influenced survival. CONCLUSION: PsPD has a clinical impact on chemotherapy-treated GBM, as it may express the glioma killing effects of treatment and is significantly correlated with MGMT status. Improvement in the early recognition of psPD patterns and knowledge of mechanisms underlying this phenomenon are crucial to eliminating biases in evaluating the results of clinical trials and guaranteeing effective treatment.

Immunotherapy is a promising area of therapy in patients with neuro-oncological malignancies. However, early-phase studies show unique challenges associated with the assessment of radiological changes in response to immunotherapy reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumour regression, can still occur after initial disease progression or after the appearance of new lesions. Refinement of the response assessment criteria for patients with neuro-oncological malignancies undergoing immunotherapy is therefore warranted. Herein, a multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describe immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria based on guidance for the determination of tumour progression outlined by the immune-related response criteria and the RANO working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease within 6 months of initiating immunotherapy, including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for the use of corticosteroids. We review the role of advanced imaging techniques and the role of measurement of clinical benefit endpoints including neurological and immunological functions. The iRANO guidelines put forth in this Review will evolve successively to improve their usefulness as further experience from immunotherapy trials in neuro-oncology accumulate.

The paper advances a relational perspective to studying creativity at the individual level. Building on social network theory and techniques, we examine the role of social networks in shaping individuals' ability to generate a creative outcome. More specifically, we argue that individuals who occupy an intermediate position between the core and the periphery of their social system are in a favorable position to achieve creative results. In addition, the benefits accrued through an individual's intermediate core/periphery position can also be observed at the team level, when the same individual works in a team whose members come from both ends of the core/periphery continuum. We situate the analysis and test our hypotheses within the context of the Hollywood motion picture industry, which we trace over the period 1992–2003. The theoretical implications of the results are discussed. This work is licensed under a Creative Commons Attribution 4.0 International License. You are free to copy, distribute, transmit and adapt this work, but you must attribute this work as “Organization Science. Copyright © 2017 INFORMS. https://doi.org/10.1287/orsc.1070.0350 , used under a Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ .”

This paper reports cross-national data concerning back or neck pain comorbidity with mental disorders. We assessed (a) the prevalence of chronic back/neck pain, (b) the prevalence of mental disorders among people with chronic back/neck pain, (c) which mental disorder had strongest associations with chronic back/neck pain, and (d) whether these associations are consistent across countries. Population surveys of community-dwelling adults were carried out in 17 countries in Europe, the Americas, the Middle East, Africa, Asia, and the South Pacific (N=85,088). Mental disorders were assessed with the Composite International Diagnostic Interview, third version (CIDI 3.0): anxiety disorders (generalized anxiety disorder, panic disorder/agoraphobia, posttraumatic stress disorder, and social anxiety disorder), mood disorders (major depression and dysthymia), and alcohol abuse or dependence. Back/neck pain was ascertained by self-report. Between 10% and 42% reported chronic back/neck pain in the previous 12 months. After adjusting for age and sex, mental disorders were more common among persons with back/neck pain than among persons without. The pooled odds ratios were 2.3 [95% CI=2.1-2.5] for mood disorders, 2.2 [95% CI=2.1-2.4] for anxiety disorders, and 1.6 [95% CI=1.4-1.9] for alcohol abuse/dependence in people with versus without chronic back/neck pain. Although prevalence rates of back/neck pain were generally lower than in previous reports, mental disorders were associated with chronic back/neck pain. The strength of association was stronger for mood and anxiety disorders than for alcohol abuse/dependence. The association of mental disorders with back/neck pain showed a consistent pattern across both developed and developing countries.

Importance: Mortality among people with opioid dependence is higher than that of the general population. Opioid agonist treatment (OAT) is an effective treatment for opioid dependence; however, there has not yet been a systematic review on the relationship between OAT and specific causes of mortality. Objective: To estimate the association of time receiving OAT with mortality. Data Sources: The Embase, MEDLINE, and PsycINFO databases were searched through February 18, 2020, including clinical trial registries and previous Cochrane reviews. Study Selection: All observational studies that collected data on all-cause or cause-specific mortality among people with opioid dependence while receiving and not receiving OAT were included. Randomized clinical trials (RCTs) were also included. Data Extraction and Synthesis: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Data on study, participant, and treatment characteristics were extracted; person-years, all-cause mortality, and cause-specific mortality were calculated. Crude mortality rates and rate ratios (RRs) were pooled using random-effects meta-analyses. Main Outcomes and Measures: Overall all-cause and cause-specific mortality both by setting and by participant characteristics. Methadone and buprenorphine OAT were evaluated specifically. Results: Fifteen RCTs including 3852 participants and 36 primary cohort studies including 749 634 participants were analyzed. Among the cohort studies, the rate of all-cause mortality during OAT was more than half of the rate seen during time out of OAT (RR, 0.47; 95% CI, 0.42-0.53). This association was consistent regardless of patient sex, age, geographic location, HIV status, and hepatitis C virus status and whether drugs were taken through injection. Associations were not different for methadone (RR, 0.47; 95% CI, 0.41-0.54) vs buprenorphine (RR, 0.34; 95% CI, 0.26-0.45). There was lower risk of suicide (RR, 0.48; 95% CI, 0.37-0.61), cancer (RR, 0.72; 95% CI, 0.52-0.98), drug-related (RR, 0.41; 95% CI, 0.33-0.52), alcohol-related (RR, 0.59; 95% CI, 0.49-0.72), and cardiovascular-related (RR, 0.69; 95% CI, 0.60-0.79) mortality during OAT. In the first 4 weeks of methadone treatment, rates of all-cause mortality and drug-related poisoning were almost double the rates during the remainder of OAT (RR, 2.01; 95% CI, 1.55-5.09) but not for buprenorphine (RR, 0.58; 95% CI, 0.18-1.85). All-cause mortality was 6 times higher in the 4 weeks after OAT cessation (RR, 6.01; 95% CI, 4.32-8.36), remaining double the rate for the remainder of time not receiving OAT (RR, 1.81; 95% CI, 1.50-2.18). Opioid agonist treatment was associated with a lower risk of mortality during incarceration (RR, 0.06; 95% CI, 0.01-0.46) and after release from incarceration (RR, 0.09; 95% CI, 0.02-0.56). Conclusions and Relevance: This systematic review and meta-analysis found that OAT was associated with lower rates of mortality. However, access to OAT remains limited, and coverage of OAT remains low. Work to improve access globally may have important population-level benefits.

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.

This is the second of a series of two articles reporting the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of adult patients with ulcerative colitis [UC]. The first article is focused on medical management, and the present article addresses medical treatment of acute severe ulcerative colitis [ASUC] and surgical management of medically refractory UC patients, including preoperative optimisation, surgical strategies, and technical issues. The article provides advice for a variety of common clinical and surgical conditions. Together, the articles represent an update of the evidence-based recommendations of the ECCO for UC.

OBJECTIVE: To verify whether hypogonadism represents a risk factor for cardiovascular (CV) morbidity and mortality and to verify whether testosterone replacement therapy (TRT) improves CV parameters in subjects with known CV diseases (CVDs). DESIGN: Meta-analysis. METHODS: An extensive Medline search was performed using the following words 'testosterone, CVD, and males'. The search was restricted to data from January 1, 1969, up to January 1, 2011. RESULTS: Of the 1178 retrieved articles, 70 were included in the study. Among cross-sectional studies, patients with CVD have significantly lower testosterone and higher 17-β estradiol (E(2)) levels. Conversely, no difference was observed for DHEAS. The association between low testosterone and high E(2) levels with CVD was confirmed in a logistic regression model, after adjusting for age and body mass index (hazard ratio (HR)=0.763 (0.744-0.783) and HR=1.015 (1.014-1.017), respectively, for each increment of total testosterone and E(2) levels; both P<0.0001). Longitudinal studies showed that baseline testosterone level was significantly lower among patients with incident overall- and CV-related mortality, in comparison with controls. Conversely, we did not observe any difference in the baseline testosterone and E(2) levels between case and controls for incident CVD. Finally, TRT was positively associated with a significant increase in treadmill test duration and time to 1 mm ST segment depression. CONCLUSIONS: Lower testosterone and higher E(2) levels correlate with increased risk of CVD and CV mortality. TRT in hypogonadism moderates metabolic components associated with CV risk. Whether low testosterone is just an association with CV risk, or an actual cause-effect relationship, awaits further studies.

OBJECTIVE: Few randomized clinical studies have evaluated the impact of diet and physical activity on testosterone levels in obese men with conflicting results. Conversely, studies on bariatric surgery in men generally have shown an increase in testosterone levels. The aim of this study is to perform a systematic review and meta-analysis of available trials on the effect of body weight loss on sex hormones levels. DESIGN: Meta-analysis. METHODS: An extensive Medline search was performed including the following words: 'testosterone', 'diet', 'weight loss', 'bariatric surgery', and 'males'. The search was restricted to data from January 1, 1969 up to August 31, 2012. RESULTS: Out of 266 retrieved articles, 24 were included in the study. Of the latter, 22 evaluated the effect of diet or bariatric surgery, whereas two compared diet and bariatric surgery. Overall, both a low-calorie diet and bariatric surgery are associated with a significant (P<0.0001) increase in plasma sex hormone-binding globulin-bound and -unbound testosterone levels (total testosterone (TT)), with bariatric surgery being more effective in comparison with the low-calorie diet (TT increase: 8.73 (6.51-10.95) vs 2.87 (1.68-4.07) for bariatric surgery and the low-calorie diet, respectively; both P<0.0001 vs baseline). Androgen rise is greater in those patients who lose more weight as well as in younger, non-diabetic subjects with a greater degree of obesity. Body weight loss is also associated with a decrease in estradiol and an increase in gonadotropins levels. Multiple regression analysis shows that the degree of body weight loss is the best determinant of TT rise (B=2.50±0.98, P=0.029). CONCLUSIONS: These data show that weight loss is associated with an increase in both bound and unbound testosterone levels. The normalization of sex hormones induced by body weight loss is a possible mechanism contributing to the beneficial effects of surgery in morbid obesity.

BACKGROUND: Evidence regarding functional hypogonadism, previously referred to as 'late-onset' hypogonadism, has increased substantially during the last 10 year. OBJECTIVE: To update the European Academy of Andrology (EAA) guidelines on functional hypogonadism. METHODS: Expert group of academicians appointed by the EAA generated a series of consensus recommendations according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. RESULTS: The diagnosis of functional hypogonadism should be based on both the presence of clinical symptoms supported by repeatedly low morning fasting serum total testosterone (T) measured with a well-validated assay, after exclusion of organic causes of hypogonadism. Lifestyle changes and weight reduction should be the first approach in all overweight and obese men. Whenever possible, withdrawal/modification of drugs potentially interfering with T production should be advised. Testosterone replacement therapy (TRT) is contraindicated in men with untreated prostate or breast cancer, as well as severe heart failure. Severe low urinary tract symptoms and haematocrit >48%-50% represent relative contraindications for TRT. Prostate-specific antigen and digital rectal examination of the prostate should be undertaken in men >40 years of age before initiating TRT to exclude occult prostate cancer. Transdermal T should be preferred for initiation of TRT, whereas gonadotrophin therapy is only recommended when fertility is desired in men with secondary hypogonadism. TRT is able to improve sexual function in hypogonadal men. Other potential positive outcomes of TRT remain uncertain and controversial. CONCLUSION: TRT can reliably improve global sexual function in men with hypogonadism in the short term. Long-term clinical benefits, and safety of TRT in functional hypogonadism, remain to be fully documented. Clinicians should therefore explicitly discuss the uncertainties and benefits of TRT and engage them in shared management decision-making.

INTRODUCTION: Metabolic syndrome (MetS) is often associated with male hypogonadism. Despite the well-known link, the role of testosterone replacement therapy (TRT) in MetS has not been completely clarified. AIM: To systematically analyse the relationship between androgen levels and MetS we performed a review and meta-analyses of available prospective and cross-sectional studies. In addition, a specific meta-analysis on the metabolic effects of TRT in available randomized clinical trials (RCTs) was also performed. METHODS: An extensive Medline search was performed including the following words "testosterone,""metabolic syndrome," and "males". MAIN OUTCOME MEASURES: Out of 323 retrieved articles, 302 articles were excluded for different reasons. Among the 20 published studies included, 13, 3, and 4 were cross-sectional, longitudinal, and RCTs, respectively. Another unpublished RCT was retrieved on http://www.clinicaltrials.gov. RESULTS: MetS patients showed significantly lower T plasma levels, as compared with healthy individuals. Similar results were obtained when MetS subjects with and without erectile dysfunction were analyzed separately or when NCEP-ATPIII MetS criteria were compared with other definitions. Meta-regression analysis demonstrated that type 2 diabetes (T2DM) increased the MetS-associated T fall. In a multiple regression model, after adjusting for age and BMI, both T2DM and MetS independently predicted low testosterone (adj. r = -0.752; P < 0.001 and -0.271; P < 0.05, respectively). Analysis of longitudinal studies demonstrated that baseline testosterone was significantly lower among patients with incident MetS in comparison with controls (2.17 [-2.41;-1.94] nmol/L; P < 0.0001). Combining the results of RCTs, TRT was associated with a significant reduction of fasting plasma glucose, homeostatic model assessment index, triglycerides, and waist circumference. In addition, an increase of high-density lipoprotein cholesterol was also observed. CONCLUSIONS: The meta-analysis of the available cross-sectional data suggests that MetS can be considered an independent association of male hypogonadism. Although only few RCTs have been reported, TRT seems to improve metabolic control, as well as central obesity.

BACKGROUND: Advocates of expanded mental health treatment assert that mental disorders are as disabling as physical disorders, but little evidence supports this assertion. AIMS: To establish the disability and treatment of specific mental and physical disorders in high-income and low- and middle-income countries. METHOD: Community epidemiological surveys were administered in 15 countries through the World Health Organization World Mental Health (WMH) Survey Initiative. RESULTS: Respondents in both high-income and low- and middle-income countries attributed higher disability to mental disorders than to the commonly occurring physical disorders included in the surveys. This pattern held for all disorders and also for treated disorders. Disaggregation showed that the higher disability of mental than physical disorders was limited to disability in social and personal role functioning, whereas disability in productive role functioning was generally comparable for mental and physical disorders. CONCLUSIONS: Despite often higher disability, mental disorders are under-treated compared with physical disorders in both high-income and in low- and middle-income countries.

BACKGROUND: High-flow nasal cannula (HFNC) has become a frequently used noninvasive form of respiratory support in acute settings; however, evidence supporting its use has only recently emerged. These guidelines provide evidence-based recommendations for the use of HFNC alongside other noninvasive forms of respiratory support in adults with acute respiratory failure (ARF). MATERIALS AND METHODOLOGY: The European Respiratory Society task force panel included expert clinicians and methodologists in pulmonology and intensive care medicine. The task force used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methods to summarise evidence and develop clinical recommendations for the use of HFNC alongside conventional oxygen therapy (COT) and noninvasive ventilation (NIV) for the management of adults in acute settings with ARF. RESULTS: The task force developed eight conditional recommendations, suggesting the use of 1) HFNC over COT in hypoxaemic ARF; 2) HFNC over NIV in hypoxaemic ARF; 3) HFNC over COT during breaks from NIV; 4) either HFNC or COT in post-operative patients at low risk of pulmonary complications; 5) either HFNC or NIV in post-operative patients at high risk of pulmonary complications; 6) HFNC over COT in nonsurgical patients at low risk of extubation failure; 7) NIV over HFNC for patients at high risk of extubation failure unless there are relative or absolute contraindications to NIV; and 8) trialling NIV prior to use of HFNC in patients with COPD and hypercapnic ARF. CONCLUSIONS: HFNC is a valuable intervention in adults with ARF. These conditional recommendations can assist clinicians in choosing the most appropriate form of noninvasive respiratory support to provide to patients in different acute settings.

The intestinal epithelial barrier (IEB) is one of the largest interfaces between the environment and the internal milieu of the body. It is essential to limit the passage of harmful antigens and microorganisms and, on the other side, to assure the absorption of nutrients and water. The maintenance of this delicate equilibrium is tightly regulated as it is essential for human homeostasis. Luminal solutes and ions can pass across the IEB via two main routes: the transcellular pathway or the paracellular pathway. Tight junctions (TJs) are a multi-protein complex responsible for the regulation of paracellular permeability. TJs control the passage of antigens through the IEB and have a key role in maintaining barrier integrity. Several factors, including cytokines, gut microbiota, and dietary components are known to regulate intestinal TJs. Gut microbiota participates in several human functions including the modulation of epithelial cells and immune system through the release of several metabolites, such as short-chain fatty acids (SCFAs). Mediators released by immune cells can induce epithelial cell damage and TJs dysfunction. The subsequent disruption of the IEB allows the passage of antigens into the mucosa leading to further inflammation. Growing evidence indicates that dysbiosis, immune activation, and IEB dysfunction have a role in several diseases, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and gluten-related conditions. Here we summarize the interplay between the IEB and gut microbiota and mucosal immune system and their involvement in IBS, IBD, and gluten-related disorders.

PURPOSE: The aim of the present study was to evaluate factors predicting the recurrence pattern after the administration of temozolomide (TMZ), initially concurrent with radiotherapy (RT) and subsequently as maintenance therapy, which has become standard treatment for patients with newly diagnosed glioblastoma (GBM). PATIENTS AND METHODS: Ninety-five patients with newly diagnosed GBM were treated with RT plus TMZ (75 mg/m(2)/d) followed by maintenance TMZ cycles (150 to 200 mg/m(2) for 5 days every 28 days). Assessable MGMT methylation status and magnetic resonance imaging follow-up were mandatory in all cases. RESULTS: After a median follow-up of 18.9 months (range, 6.6 to 44.8 months), 79 patients (83%) had recurrence: inside the RT field in 57 patients (72.2%), outside in 17 patients (21.5%), and at RT margin in five patients (6.3%). MGMT status was correlated with the site of recurrence, which occurred inside, or at the margin of, the RT field in 51 patients (85%) with MGMT unmethylated status and in 11 patients (57.9%) with MGMT methylated status (P = .01). Recurrences outside the RT field occurred after a longer time interval than those inside the RT field (14.9 v 9.2 months, P = .02). CONCLUSION: After the administration of TMZ concomitant with and adjuvant to RT in patients with GBM, the pattern of, and time to, recurrence are strictly correlated with MGMT methylation status.

BACKGROUND: Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations. METHODS: GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds. FINDINGS: The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value. INTERPRETATION: We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales. FUNDING: Gates Foundation.

A clinical guideline aims to apply to all patients with a specific condition. However, there will inevitably be situations where its recommendations aren't suitable for a particular patient. While healthcare professionals and others are encouraged to consider these guidelines in their professional judgement, they don't override the responsibility of healthcare professionals to make decisions tailored to each patient's unique circumstances. Such decisions should be aligned with the latest official recommendations, guidelines from relevant public health authorities, and applicable rules and regulations. It is important that these decisions are made in collaboration with, and agreed upon by, the patient and/or their guardian or carer.