Jefferson Einstein Philadelphia Hospital

Stanley Reitman, M.D., Sam Frankel, Ph.D.; A Colorimetric Method for the Determination of Serum Glutamic Oxalacetic and Glutamic Pyruvic Transaminases, Ame

PURPOSE: Promising results from new approaches such as radiosurgery or stereotactic surgery of brain metastases have recently been reported. Are these results due to the therapy alone or can the results be attributed in part to patient selection? An analysis of tumor/patient characteristics and treatment variables in previous Radiation Therapy Oncology Group (RTOG) brain metastases studies was considered necessary to fully evaluate the benefit of these new interventions. METHODS AND MATERIALS: The database included 1200 patients from three consecutive RTOG trials conducted between 1979 and 1993, which tested several different dose fractionation schemes and radiation sensitizers. Using recursive partitioning analysis (RPA), a statistical methodology which creates a regression tree according to prognostic significance, eighteen pretreatment characteristics and three treatment-related variables were analyzed. RESULTS: According to the RPA tree the best survival (median: 7.1 months) was observed in patients < 65 years of age with a Karnofsky Performance Status (KPS) of at least 70, and a controlled primary tumor with the brain the only site of metastases. The worst survival (median: 2.3 months) was seen in patients with a KPS less than 70. All other patients had relatively minor differences in observed survival, with a median of 4.2 months. CONCLUSIONS: Based on this analysis, we suggest the following three classes: Class 1: patients with KPS > or = 70, < 65 years of age with controlled primary and no extracranial metastases; Class 3: KPS < 70; Class 2- all others. Using these classes or stages, new treatment techniques can be tested on homogeneous patient groups.

Gastroesophageal reflux disease (GERD) is arguably the most common disease encountered by the gastroenterologist. It is equally likely that the primary care providers will find that complaints related to reflux disease constitute a large proportion of their practice. The following guideline will provide an overview of GERD and its presentation, and recommendations for the approach to diagnosis and management of this common and important disease. The document will review the presentations of any risk factors for GERD, the diagnostic modalities and their recommendation for use and recommendations for medical, surgical and endoscopic management including comparative effectiveness of different treatments. Extraesophageal symptoms and complications will be addressed as will the evaluation and management of “refractory” GERD. The document will conclude with the potential risks and side effects of the main treatments for GERD and their implications for patient management. Each section of the document will present the key recommendations related to the section topic and a subsequent summary of the evidence supporting those recommendations. An overall summary of the key recommendations is presented in Table 1. A search of OVID Medline, Pubmed and ISI Web of Science was conducted for the years from 1960–2011 using the following major search terms and subheadings including “heartburn”, “acid regurgitation”, “GERD”, “lifestyle interventions”, “proton pump inhibitor (PPI)”, “endoscopic surgery,” “extraesophageal symptoms,” “Nissen fundoplication,” and “GERD complications.” We used systematic reviews and meta-analyses for each topic when available followed by a review of clinical trials.Table 1: Summary and strength of recommendationsTable 1: (continued)The GRADE system was used to evaluate the strength of the recommendations and the overall level of evidence (1,2). The level of evidence could range from “high” (implying that further research was unlikely to change the authors’ confidence in the estimate of the effect) to “moderate” (further research would be likely to have an impact on the confidence in the estimate of effect) or “low” (further research would be expected to have an important impact on the confidence in the estimate of the effect and would be likely to change the estimate). The strength of a recommendation was graded as “strong” when the desirable effects of an intervention clearly outweigh the undesirable effects and as “conditional” when there is uncertainty about the trade-offs. It is important to be aware that GERD is defined by consensus and as such is a disease comprising symptoms, end-organ effects and complications related to the reflux of gastric contents into the esophagus, oral cavity, and/or the lung. Taking into account the multiple consensus definitions previously published (3,4,5), the authors have used the following working definition to define the disease: GERD should be defined as symptoms or complications resulting from the reflux of gastric contents into the esophagus or beyond, into the oral cavity (including larynx) or lung. GERD can be further classified as the presence of symptoms without erosions on endoscopic examination (non-erosive disease or NERD) or GERD symptoms with erosions present (ERD). SYMPTOMS AND EPIDEMIOLOGY Epidemiologic estimates of the prevalence of GERD are based primarily on the typical symptoms of heartburn and regurgitation. A systematic review found the prevalence of GERD to be 10–20% of the Western world with a lower prevalence in Asia (6). Clinically troublesome heartburn is seen in about 6% of the population (7). Regurgitation was reported in 16% in the systematic review noted above. Chest pain may be a symptom of GERD, even the presenting symptom (2,3). Distinguishing cardiac from non-cardiac chest pain is required before considering GERD as a cause of chest pain. Although the symptom of dysphagia can be associated with uncomplicated GERD, its presence warrants investigation for a potential complication including an underlying motility disorder, stricture, ring, or malignancy (8). Chronic cough, asthma, chronic laryngitis, other airway symptoms and so-called extraesophageal symptoms are discussed in a subsequent section. Atypical symptoms including dyspepsia, epigastric pain, nausea, bloating, and belching may be indicative of GERD but overlap with other conditions. A systematic review found that ∼38% of the general population complained of dyspepsia. Dyspepsia was more frequent in GERD patients than those without. These patients were at risk for a new diagnosis of GERD. 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PURPOSE: To update the World Society of the Abdominal Compartment Syndrome (WSACS) consensus definitions and management statements relating to intra-abdominal hypertension (IAH) and the abdominal compartment syndrome (ACS). METHODS: We conducted systematic or structured reviews to identify relevant studies relating to IAH or ACS. Updated consensus definitions and management statements were then derived using a modified Delphi method and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines, respectively. Quality of evidence was graded from high (A) to very low (D) and management statements from strong RECOMMENDATIONS (desirable effects clearly outweigh potential undesirable ones) to weaker SUGGESTIONS (potential risks and benefits of the intervention are less clear). RESULTS: In addition to reviewing the consensus definitions proposed in 2006, the WSACS defined the open abdomen, lateralization of the abdominal musculature, polycompartment syndrome, and abdominal compliance, and proposed an open abdomen classification system. RECOMMENDATIONS included intra-abdominal pressure (IAP) measurement, avoidance of sustained IAH, protocolized IAP monitoring and management, decompressive laparotomy for overt ACS, and negative pressure wound therapy and efforts to achieve same-hospital-stay fascial closure among patients with an open abdomen. SUGGESTIONS included use of medical therapies and percutaneous catheter drainage for treatment of IAH/ACS, considering the association between body position and IAP, attempts to avoid a positive fluid balance after initial patient resuscitation, use of enhanced ratios of plasma to red blood cells and prophylactic open abdominal strategies, and avoidance of routine early biologic mesh use among patients with open abdominal wounds. NO RECOMMENDATIONS were possible regarding monitoring of abdominal perfusion pressure or the use of diuretics, renal replacement therapies, albumin, or acute component-parts separation. CONCLUSION: Although IAH and ACS are common and frequently associated with poor outcomes, the overall quality of evidence available to guide development of RECOMMENDATIONS was generally low. Appropriately designed intervention trials are urgently needed for patients with IAH and ACS.

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. Online supplemental material is available for this article .

BACKGROUND: Despite notable technical advances in therapy for malignant gliomas during the past decade, improved patient survival has not been clearly documented, suggesting that pretreatment prognostic factors influence outcome more than minor modifications in therapy. Age, performance status, and tumor histopathology have been identified as the pretreatment variables most predictive of survival outcome. However, an analysis of the association of survival with both pretreatment characteristics and treatment-related variables is necessary to assure reliable evaluation of new approaches for treatment of malignant glioma. PURPOSE: This study of malignant glioma patients used a non-parametric statistical technique to examine the associations of both pretreatment patient and tumor characteristics and treatment-related variables with survival duration. This technique was used to identify subgroups with survival rates sufficiently different to create improvements in the design and stratification of clinical trials. METHODS: We used a recursive partitioning technique to analyze survival in 1578 patients entered in three Radiation Therapy Oncology Group malignant glioma trials from 1974 to 1989 that used several radiation therapy (RT) regimens with and without chemotherapy or a radiation sensitizer. This approach creates a regression tree according to prognostic variables that classifies patients into homogeneous subsets by survival. Twenty-six pretreatment characteristics and six treatment-related variables were analyzed. RESULTS: The years). Patients younger than 50 years old were categorized by histology (astrocytomas with anaplastic or atypical foci [AAF] versus glioblastoma multiforme [GBM]) and subsequently by normal or abnormal mental status for AAF patients and by performance status for those with GBM. For patients aged 50 years or older, performance status was the most important variable, with normal or abnormal mental status creating the only significant split in the poorer performance status group. Treatment-related variables produced a subgroup showing significant differences only for better performance status GBM patients over age 50 (by extent of surgery and RT dose). Median survival times were 4.7-58.6 months for the 12 subgroups resulting from this analysis, which ranged in size from 32 to 256 patients. CONCLUSIONS: This approach permits examination of the interaction between prognostic variables not possible with other forms of multivariate analysis. IMPLICATIONS: The recursive partitioning technique can be employed to refine the stratification and design of malignant glioma trials.

BACKGROUND: Previous studies have shown that calcium-channel blockers increase morbidity and mortality in patients with chronic heart failure. We studied the effect of a new calcium-channel blocker, amlodipine, in patients with severe chronic heart failure. METHODS: We randomly assigned 1153 patients with severe chronic heart failure and ejection fractions of less than 30 percent to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months, while their usual therapy was continued. The randomization was stratified on the basis of whether patients had ischemic or nonischemic causes of heart failure. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events. RESULTS: Primary end points were reached in 42 percent of the placebo group and 39 percent of the amlodipine group, representing a 9 percent reduction in the combined risk of fatal and nonfatal events with amlodipine (95 percent confidence interval, 24 percent reduction to 10 percent increase; P=0.31). A total of 38 percent of the patients in the placebo group died, as compared with 33 percent of those in the amlodipine group, representing a 16 percent reduction in the risk of death with amlodipine (95 percent confidence interval, 31 percent reduction to 2 percent increase; P=0.07). Among patients with ischemic heart disease, there was no difference between the amlodipine and placebo groups in the occurrence of either end point. In contrast, among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk of fatal and nonfatal events by 31 percent (P=0.04) and decreased the risk of death by 46 percent (P<0.001). CONCLUSIONS: Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.

BACKGROUND AND METHODS: Tamoxifen, a synthetic antiestrogen, increases disease-free and overall survival when used as adjuvant therapy for primary breast cancer. Because it is given for long periods, it is important to know whether tamoxifen affects the skeleton, particularly since it is used extensively in postmenopausal women who are at risk for osteoporosis. Using photon absorptiometry, we studied the effects of tamoxifen on the bone mineral density of the lumbar spine and radius and on biochemical measures of bone metabolism in 140 postmenopausal women with axillary-node-negative breast cancer, in a two-year randomized, double-blind, placebo-controlled trial. RESULTS: In the women given tamoxifen, the mean bone mineral density of the lumbar spine increased by 0.61 percent per year, whereas in those given placebo it decreased by 1.00 percent per year (P less than 0.001). Radial bone mineral density decreased to the same extent in both groups. In a subgroup randomly selected from each group, serum osteocalcin and alkaline phosphatase concentrations decreased significantly in women given tamoxifen (P less than 0.001 for each variable), whereas serum parathyroid hormone and 1,25-dihydroxyvitamin D concentrations did not change significantly in either group. CONCLUSIONS: In postmenopausal women, treatment with tamoxifen is associated with preservation of the bone mineral density of the lumbar spine. Whether this favorable effect on bone mineral density is accompanied by a decrease in the risk of fractures remains to be determined.

This article reports the development of a Sensation Seeking Scale (SSS) designed to quantify the construct: “optimal stimulation level.” Items were written, using the construct as a guide, and given to undergraduates. The items were factor analyzed. A general factor was found and the item-factor cor

BACKGROUND AND OBJECTIVES: Research on children's use of mobile media devices lags behind its adoption. The objective of this study was to examine young children's exposure to and use of mobile media devices. METHODS: Cross-sectional study of 350 children aged 6 months to 4 years seen October to November 2014 at a pediatric clinic in an urban, low-income, minority community. The survey was adapted from Common Sense Media's 2013 nationwide survey. RESULTS: Most households had television (97%), tablets (83%), and smartphones (77%). At age 4, half the children had their own television and three-fourths their own mobile device. Almost all children (96.6%) used mobile devices, and most started using before age 1. Parents gave children devices when doing house chores (70%), to keep them calm (65%), and at bedtime (29%). At age 2, most children used a device daily and spent comparable screen time on television and mobile devices. Most 3- and 4-year-olds used devices without help, and one-third engaged in media multitasking. Content delivery applications such as YouTube and Netflix were popular. Child ownership of device, age at first use, and daily use were not associated with ethnicity or parent education. CONCLUSIONS: Young children in an urban, low-income, minority community had almost universal exposure to mobile devices, and most had their own device by age 4. The patterns of use suggest early adoption, frequent and independent use, and media multitasking. Studies are urgently needed to update recommendations for families and providers on the use of mobile media by young children.

NSAIDs, non-steroidal anti-inflammatory drugs, are one of the most commonly prescribed pain medications. It is a highly effective drug class for pain and inflammation; however, NSAIDs are known for multiple adverse effects, including gastrointestinal bleeding, cardiovascular side effects, and NSAID induced nephrotoxicity. As our society ages, it is crucial to have comprehensive knowledge of this class of medication in the elderly population. Therefore, we reviewed the pharmacodynamics and pharmacokinetics, current guidelines for NSAIDs use, adverse effect profile, and drug interaction of NSAIDs and commonly used medications in the elderly.

The mechanisms by which hepatitis C virus (HCV) induces chronic infection in the vast majority of infected individuals are unknown. Sequences within the HCV E1 and E2 envelope genes were analyzed during the acute phase of hepatitis C in 12 patients with different clinical outcomes. Acute resolving hepatitis was associated with relative evolutionary stasis of the heterogeneous viral population (quasispecies), whereas progressing hepatitis correlated with genetic evolution of HCV. Consistent with the hypothesis of selective pressure by the host immune system, the sequence changes occurred almost exclusively within the hypervariable region 1 of the E2 gene and were temporally correlated with antibody seroconversion. These data indicate that the evolutionary dynamics of the HCV quasispecies during the acute phase of hepatitis C predict whether the infection will resolve or become chronic.

Serum immunoreactive parathyroid hormone (PTH) is increased in obese as compared with nonobese subjects and declines with weight loss. To determine whether alteration of the vitamin D-endocrine system occurs in obesity and whether ensuing secondary hyperparathyroidism is associated with a reduction in urinary calcium, a study was performed in 12 obese white individuals, five men and seven women, and 14 nonobese white subjects, eight men and six women, ranging in age from 20 to 35 yr. Body weight averaged 106 +/- 6 kg in the obese and 68 +/- 2 kg in the nonobese subjects (P less than 0.01). Each of them were hospitalized on a metabolic ward and were given a constant daily diet containing 400 mg of calcium and 900 mg of phosphorus. Whereas mean serum calcium, serum ionized calcium, and serum phosphorus were the same in the two groups, mean serum immunoreactive PTH (518 +/- 48 vs. 243 +/- 33 pg/ml, P less than 0.001), mean serum 1,25-dihydroxyvitamin D [1,25(OH)2D] (37 +/- 2 vs. 29 +/- 2, P less than 0.01), and mean serum Gla protein (33 +/- 2 vs. 24 +/- 2 ng/ml, P less than 0.02) were significantly higher, and mean serum 25-hydroxyvitamin D (25-OHD) (8 +/- 1 vs. 20 +/- 2 ng/ml, P less than 0.001) was significantly lower in the obese than in the nonobese men and women. Mean urinary phosphorus was the same in the two groups, whereas mean urinary calcium (115 +/- 10 vs. 166 +/- 13 mg/d, P less than 0.01) was significantly lower, and mean urinary cyclic AMP (3.18 +/- 0.43 vs. 1.84 +/- 0.25 nM/dl GF, P less than 0.01) and creatinine clearance (216 +/- 13 vs. 173 +/- 6 liter/d, P less than 0.01) were significantly higher in the obese than in the nonobese individuals. There was a significant positive correlation between percentage of ideal body weight and urinary cyclic AMP (r = 0.524, P less than 0.01) and between percentage of ideal body weight and serum immunoreactive PTH (r = 0.717, P less than 0.01) in the two groups. The results provide evidence that alteration of the vitamin D-endocrine system in obese subjects is characterized by secondary hyperparathyroidism which is associated with enhanced renal tubular reabsorption of calcium and increased circulating 1,25(OH)2D. The reduction of serum 25-OHD in them is attributed to feedback inhibition of hepatic synthesis of the precursor by the increased serum 1,25(OH)2D.

BACKGROUND: Salvage radiation therapy is often necessary in men who have undergone radical prostatectomy and have evidence of prostate-cancer recurrence signaled by a persistently or recurrently elevated prostate-specific antigen (PSA) level. Whether antiandrogen therapy with radiation therapy will further improve cancer control and prolong overall survival is unknown. METHODS: In a double-blind, placebo-controlled trial conducted from 1998 through 2003, we assigned 760 eligible patients who had undergone prostatectomy with a lymphadenectomy and had disease, as assessed on pathological testing, with a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension beyond the prostatic capsule), no nodal involvement, and a detectable PSA level of 0.2 to 4.0 ng per milliliter to undergo radiation therapy and receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary end point was the rate of overall survival. RESULTS: The median follow-up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P=0.04). The 12-year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P<0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P=0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P<0.001). CONCLUSIONS: The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo. (Funded by the National Cancer Institute and AstraZeneca; RTOG 9601 ClinicalTrials.gov number, NCT00002874 .).

The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR-S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting.

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.

BACKGROUND: The Migraine Disability Assessment (MIDAS) score is used to quantify headache-related disability. In a previous study, we showed that the MIDAS score was highly reliable in population-based samples of migraine headache sufferers in two countries. OBJECTIVES: To examine the test-retest reliability and internal consistency of the five items comprising the MIDAS score and the overall MIDAS score in a population-based sample of both migraine and nonmigraine headache sufferers. METHODS: Using a clinically validated telephone interview, a population-based sample of migraine and nonmigraine headache sufferers was identified in Baltimore, Maryland, USA. A total of 97 migraine cases and 80 nonmigraine subjects completed the MIDAS questionnaire on two occasions an average of 3 weeks apart. The MIDAS score is derived from five questions about missed time from work (or school) and household work (one question each about missed days and days with at least 50% reduced productivity) and missed days of nonwork activities. RESULTS: Among all headache sufferers the test-retest Spearman's correlations of individual MIDAS questions ranged from 0.67 to 0.73. The Spearman's correlation for the MIDAS score (i.e., sum of lost days and reduced effectiveness days in each domain) was 0.84. Cronbach's alpha, a measure of internal consistency, was 0.83. Mean and median item values and the overall MIDAS scores differed between migraine and nonmigraine cases. Even after adjusting for differences in headache frequency, the mean MIDAS scores differed substantially (i.e., 10.3 points) between migraine cases and nonmigraine cases. CONCLUSIONS: The reliability and internal consistency of the MIDAS score are high, as tested in a population-based sample of headache sufferers. MIDAS scores are substantially higher in migraine cases than in non-migraine cases, supporting the validity of the measure.

BACKGROUND: For women with ductal carcinoma in situ (DCIS) of the breast, the risk of developing an ipsilateral breast event (IBE; defined as local recurrence of DCIS or invasive carcinoma) after surgical excision without radiation is not well defined by clinical and pathologic characteristics. METHODS: The Oncotype DX breast cancer assay was performed for patients with DCIS treated with surgical excision without radiation in the Eastern Cooperative Oncology Group (ECOG) E5194 study. The association of the prospectively defined DCIS Score (calculated from seven cancer-related genes and five reference genes) with the risk of developing an IBE was analyzed using Cox regression. All statistical tests were two-sided. RESULTS: There were 327 patients with adequate tissue for analysis. The continuous DCIS Score was statistically significantly associated with the risk of developing an IBE (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.15 to 4.49; P = .02) when adjusted for tamoxifen use (prespecified primary analysis) and with invasive IBE (unadjusted HR = 3.68, 95% CI = 1.34 to 9.62; P = .01). For the prespecified DCIS risk groups of low, intermediate, and high, the 10-year risks of developing an IBE were 10.6%, 26.7%, and 25.9%, respectively, and for an invasive IBE, 3.7%, 12.3%, and 19.2%, respectively (both log rank P ≤ .006). In multivariable analyses, factors associated with IBE risk were DCIS Score, tumor size, and menopausal status (all P ≤ .02). CONCLUSIONS: The DCIS Score quantifies IBE risk and invasive IBE risk, complements traditional clinical and pathologic factors, and provides a new clinical tool to improve selecting individualized treatment for women with DCIS who meet the ECOG E5194 criteria.

To test the hypothesis that adult respiratory-distress syndrome (ARDS) is related to increased activity of the proteolytic enzyme elastase released from neutrophils in the lung, we determined the differential white-cell count, the elastolytic activity, the source of elastase, and the concentration and activity of the endogenous protease inhibitor alpha-1-antiprotease (alpha-1-AP) in bronchoalveolar lavage fluid from 23 patients with ARDS and from 55 patients without this syndrome. Neutrophil predominance (> 80 per cent) was observed in 18 of 23 patients with ARDS. High elastolytic activity of neutrophil origin was found in 12 of 23 patients with ARDS (52 per cent), in none of 16 normal nonsmokers (P < 0.01), in two of 17 normal smokers, and in three of 22 patients with chronic obstructive pulmonary disease. Although there were no significant differences in alpha-1-AP concentrations, its activity was reduced in eight of nine patients with ARDS and high elastolytic activity. We conclude that in many patients with ARDS, high levels of neutrophil elastolytic activity in the lungs are associated with reduced alpha-1-AP function.

BACKGROUND: While artificial intelligence (AI) offers possibilities of advanced clinical prediction and decision-making in healthcare, models trained on relatively homogeneous datasets, and populations poorly-representative of underlying diversity, limits generalisability and risks biased AI-based decisions. Here, we describe the landscape of AI in clinical medicine to delineate population and data-source disparities. METHODS: We performed a scoping review of clinical papers published in PubMed in 2019 using AI techniques. We assessed differences in dataset country source, clinical specialty, and author nationality, sex, and expertise. A manually tagged subsample of PubMed articles was used to train a model, leveraging transfer-learning techniques (building upon an existing BioBERT model) to predict eligibility for inclusion (original, human, clinical AI literature). Of all eligible articles, database country source and clinical specialty were manually labelled. A BioBERT-based model predicted first/last author expertise. Author nationality was determined using corresponding affiliated institution information using Entrez Direct. And first/last author sex was evaluated using the Gendarize.io API. RESULTS: Our search yielded 30,576 articles, of which 7,314 (23.9%) were eligible for further analysis. Most databases came from the US (40.8%) and China (13.7%). Radiology was the most represented clinical specialty (40.4%), followed by pathology (9.1%). Authors were primarily from either China (24.0%) or the US (18.4%). First and last authors were predominately data experts (i.e., statisticians) (59.6% and 53.9% respectively) rather than clinicians. And the majority of first/last authors were male (74.1%). INTERPRETATION: U.S. and Chinese datasets and authors were disproportionately overrepresented in clinical AI, and almost all of the top 10 databases and author nationalities were from high income countries (HICs). AI techniques were most commonly employed for image-rich specialties, and authors were predominantly male, with non-clinical backgrounds. Development of technological infrastructure in data-poor regions, and diligence in external validation and model re-calibration prior to clinical implementation in the short-term, are crucial in ensuring clinical AI is meaningful for broader populations, and to avoid perpetuating global health inequity.