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The article discusses racial and ethnic disparities in the diagnosis of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) infections in the U.S. from 2001 through 2005. Estimates on HIV and AIDS cases reached 184,991 involving African-American adults and adolescents. Most of individuals positively-diagnosed belong to ages 22 to 44.

The WHO launched a multicentre study to explore the nature and prevalence of HIV-1-associated neurological, psychiatric, and neuropsychological abnormalities in persons living in different geographical and sociocultural contexts. The study is being conducted in Brazil, Germany, Kenya, Thailand, the United States of America, and Zaire. A comprehensive instrument for the collection of neuropsychiatric data (including a battery of neuropsychological tests suitable for cross-cultural use) has been developed, and the feasibility of the recruitment and assessment procedure designed for the main phase has now been demonstrated. [ABSTRACT FROM AUTHOR]

Although platform trials have many benefits, the complexity of these designs may result not only in increased methodological but also regulatory and ethical challenges. These aspects were addressed as part of the IMI project EU Patient-Centric Clinical Trial Platforms (EU-PEARL). We reviewed the available guidelines on platform trials in the European Union and the United States. This is supported and complemented by feedback received from regulatory interactions with the European Medicines Agency and the US Food and Drug Administration. Throughout the project we collected the needs of all relevant stakeholders including ethics committees, regulators, and health technology assessment bodies through active dialog and dedicated stakeholder workshops. Furthermore, we focused on methodological aspects and where applicable identified the corresponding guidance. Learnings from the guideline review, regulatory interactions, and workshops are provided. Based on these, a master protocol template was developed. Issues that still need harmonization or clarification in guidelines or where further methodological research is needed are also presented. These include questions around clinical trial submissions in Europe, the need for multiplicity control across the whole master protocol, the use of non-concurrent controls, and the impact of different randomization schemes. Master protocols are an efficient and patient-centered clinical trial design that can expedite drug development. However, they can also introduce additional operational and regulatory complexities. It is important to understand the different requirements of stakeholders upfront and address them in the trial. While relevant guidance is increasing, early dialog with relevant stakeholders can help to further support such designs., (© 2024 The Authors, Johnson & Johnson Innovative Medicines and Sanofi. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Osteoarthritis (OA) is a major cause of chronic pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are analgesics commonly used for musculoskeletal pain; however, NSAIDs can increase the risk of certain adverse events, such as gastrointestinal bleeding, edema, heart failure, and hypertension., Objective: The objective of this study was to characterize existing comorbidities among patients with OA. For patients with OA with and without a coexisting medical condition of interest (CMCOI), we estimated the prevalence of prescribing and dispensing NSAIDs pre-OA and post-OA diagnosis., Methods: Data from three large administrative claims databases were used to construct an OA retrospective cohort. Databases leveraged were IBM MarketScan Medicare Supplemental Database (MDCR), IBM MarketScan Commercial Database (CCAE), and Optum's de-identified Clinformatics ® Data Mart Database (Optum CDM). The OA study population was defined to be those patients who had an OA diagnosis from an inpatient or outpatient visit with at least 365 days of prior observation time in the database during January 2000 through May 2021. Asthma, cardiovascular disorders, renal impairment, and gastrointestinal bleeding risks were the CMCOI of interest. Patients with OA were then classified as having or not having evidence of a CMCOI. For both groups, NSAID dispensing patterns pre-OA and post-OA diagnosis were identified. Descriptive analysis was performed within the Observational Health Data Sciences and Informatics framework., Results: In each database, the proportion of the OA population with at least one CMCOI was nearly 50% or more (48.0% CCAE; 74.4% MDCR; 68.6% Optum CDM). Cardiovascular disease was the most commonly observed CMCOI in each database, and in two databases, nearly one in four patients with OA had two or more CMCOI (23.2% MDCR; 22.6% Optum CDM). Among the OA population with CMCOI, NSAID utilization post-OA diagnosis ranged from 33.0 to 46.2%. Following diagnosis of OA, an increase in the prescribing and dispensing of NSAIDs was observed in all databases, regardless of patient CMCOI presence., Conclusions: This study provides real-world evidence of the pattern of prescribing and dispensing of NSAIDs among patients with OA with and without CMCOI, which indicates that at least half of patients with OA in the USA have a coexisting condition. These conditions may increase the risk of side effects commonly associated with NSAIDs. Yet, at least 32% of these patients were prescribed and dispensed NSAIDs. These data support the importance of shared decision making between healthcare professionals and patients when considering NSAIDs for the treatment of OA in patients with NSAID-relevant coexisting medical conditions., (© 2024. The Author(s).)

There are many challenges with rare diseases drug development and rare oncology indications are not different. To understand the regulatory landscape as it relates to application of clinical pharmacology principles in rare oncology product development, we reviewed publicly available information of 39 approvals by US FDA between January 2019 and March 2023. The objective was to understand the expected clinical pharmacology studies and knowledge base in such approvals. Model informed drug development (MIDD) applications were also reviewed, as such approaches are expected to play a critical role in filling clinical pharmacology gaps in rare oncology, where number of clinical trials and size of these trials will perhaps continue to be small. The findings highlighted how clinical pharmacology contributed to the evidence of effectiveness, dose optimization and elucidation of intrinsic and extrinsic factors affecting drug's behavior. Clinical pharmacology studies were often integrated with modeling in many of the NDAs/BLAs. Of the post marketing requirements (PMR) received, 18% were for dose optimization, 49% for DDI, 8% for QTc, 49% for specific population, and 5% for food effect. Two post marketing commitments (PMC) were issued for immunogenicity of the 11 biologics submissions. 15% (6 of 39) of the submissions used maximum tolerated dose (MTD) to advance their molecule into Phase 2 studies. Of them 3 approvals received PMR for dose optimization. 3 + 3 was the most prevalent Phase 1 design with use in 74% of the New Drug Applications (NDA)/Biologic License Applications (BLA) reviewed. Rest used innovative approaches such as BLRM, BOIN or mTPi, with BLRM being the most common. Seamless clinical pharmacology and MIDD approaches are paramount for rare oncology drug development., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Patients with advanced, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (Exon20ins) have poor prognoses, exacerbated by a previous lack of specific treatment guidelines and unmet need for targeted therapies. Amivantamab, an EGFR and MET bispecific antibody, demonstrated efficacy and tolerability in patients with advanced EGFR-mutated NSCLC with Exon20ins following platinum-based therapy in CHRYSALIS (NCT02609776; Cohort D+). Since CHRYSALIS was single-arm, individual patient data (IPD)-based adjusted analyses versus similar patients in real-world clinical practice (RWCP) were conducted to generate comparative evidence., Methods: RWCP cohorts were derived from seven European and US real-world sources, comprising patients fulfilling CHRYSALIS Cohort D+ eligibility criteria. Amivantamab was compared with a basket of RWCP treatments. Differences in prognostic characteristics were adjusted for using inverse probability weighting (IPW; average treatment effect among the treated [ATT]). Balance between cohorts was assessed using standardized mean differences (SMDs). Overall response rate (ORR; investigator- [INV] and independent review committee-assessed [IRC]), overall survival (OS), progression-free survival (PFS; INV and IRC) and time-to-next treatment (TTNT) were compared. Binary and time-to-event endpoints were analyzed using weighted logistic regression and proportional hazards regression, respectively., Results: Pre-adjustment, baseline characteristics were comparable between cohorts. IPW ATT-adjustment improved comparability, giving closely matched characteristics. ORR (INV) was 36.8% for amivantamab versus 17.0% for the adjusted EU + US cohort (response rate ratio [RR]: 2.16). Median OS, PFS (INV) and TTNT were 22.77 versus 12.52 months (hazard ratio [HR]: 0.47; p < 0.0001), 6.93 versus 4.17 months (HR: 0.55; p < 0.0001) and 12.42 versus 5.36 months (HR: 0.44; p < 0.0001) for amivantamab versus the adjusted EU + US cohort, respectively. Results were consistent versus EU- and US-only cohorts, and when using IRC assessment., Conclusion: Adjusted comparisons demonstrated significantly improved outcomes for amivantamab versus RWCP, highlighting the value of amivantamab in addressing unmet need in patients with advanced EGFR Exon20ins NSCLC following platinum-based therapy., Trial Registration: CHRYSALIS: NCT02609776., (© 2023. The Author(s).)

Therapeutic proteins (TPs) comprise a variety of modalities, including antibody-based drugs, coagulation factors, recombinant cytokines, enzymes, growth factors, and hormones. TPs usually cannot traverse cellular barriers and exert their pharmacological activity by interacting with targets on the exterior membrane of cells or with soluble ligands in the tissue interstitial fluid/blood. Due to their large size, lack of cellular permeability, variation in metabolic fate, and distinct physicochemical characteristics, TPs are subject to different absorption, distribution, metabolism, and excretion (ADME) processes as compared with small molecules. Limited regulatory guidance makes it challenging to determine the most relevant ADME data required for regulatory submissions. The TP ADME working group was sponsored by the Translational and ADME Sciences Leadership Group within the Innovation and Quality (IQ) consortium with objectives to: (1) better understand the current practices of ADME data generated for TPs across IQ member companies, (2) learn about their regulatory strategies and interaction experiences, and (3) provide recommendations on best practices for conducting ADME studies for TPs. To understand current ADME practices and regulatory strategies, an industry-wide survey was conducted within IQ member companies. In addition, ADME data submitted to the U.S. Food and Drug Administration was also collated by reviewing regulatory submission packages of TPs approved between 2011 and 2020. This article summarizes the key learnings from the survey and an overview of ADME data presented in biologics license applications along with future perspectives and recommendations for conducting ADME studies for internal decision-making as well as regulatory submissions for TPs. SIGNIFICANCE STATEMENT: This article provides comprehensive assessment of the current practices of absorption, distribution, metabolism, and excretion (ADME) data generated for therapeutic proteins (TPs) across the Innovation and Quality participating companies and the utility of the data in discovery, development, and regulatory submissions. The TP ADME working group also recommends the best practices for condu-cting ADME studies for internal decision-making and regulatory submissions., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Objectives: To compare work absenteeism and short-term disability among adults with psoriasis or psoriatic arthritis (PsA), versus controls in the USA., Methods: Adults eligible for work absenteeism and/or short-term disability benefits between 1/1/2009 and 4/30/2020 were screened in the IBM® MarketScan® Commercial and Health and Productivity Management Databases. The following groups were defined: (1) psoriasis: ≥ 2 psoriasis diagnoses ≥ 30 days apart and no PsA diagnoses; (2) PsA: ≥ 2 PsA diagnoses ≥ 30 days apart; (3) control: absence of psoriasis and PsA diagnoses. Controls were matched to psoriasis and PsA patients based on age, gender, index year, and comorbidities. Non-recreational work absences and sick leaves were evaluated in absentee-eligible patients, and short-term disability was evaluated in short-term disability-eligible patients. Costs (in 2019 USD) associated with each type of work absence were evaluated., Results: 4261 psoriasis and 616 PsA absentee-eligible and 25,213 psoriasis and 3480 PsA short-term disability-eligible patients were matched to controls. Average non-recreational work absence costs were $1681, $1657, and $1217 for the PsA, psoriasis, and control group, respectively. Compared with psoriasis patients and controls, more PsA patients had sick leaves after 1 year (56.2% versus 55.6% and 41.5%, p < 0.0001). Similarly, short-term disability was more frequent in PsA patients than psoriasis patients and controls at year one (8.8% versus 5.6% and 4.7%, p < 0.0001) and corresponding costs were higher ($605, $406, and $335 on average, p < 0.0001)., Conclusion: Annual work absenteeism and short-term disability were consistently greater among patients with PsA and psoriasis than controls, highlighting the substantial economic burden of psoriatic disease. Key points • Patients with PsA had greater short-term disability compared with patients with psoriasis and patients with neither psoriasis nor PsA. • Patients with PsA and patients with psoriasis incurred greater non-recreational work absences and sick leaves than patients with neither psoriasis nor PsA., (© 2021. The Author(s).)

Evolving immunogenicity assay performance expectations and a lack of harmonized anti-drug antibody validation testing and reporting tools have resulted in significant time spent by health authorities and sponsors on resolving filing queries. Following debate at the American Association of Pharmaceutical Sciences National Biotechnology Conference, a group was formed to address these gaps. Over the last 3 years, 44 members from 29 organizations (including 5 members from Europe and 10 members from FDA) discussed gaps in understanding immunogenicity assay requirements and have developed harmonization tools for use by industry scientists to facilitate filings to health authorities. Herein, this team provides testing and reporting strategies and tools for the following assessments: (1) pre-study validation cut point; (2) in-study cut points, including procedures for applying cut points to mixed populations; (3) system suitability control criteria for in-study plate acceptance; (4) assay sensitivity, including the selection of an appropriate low positive control; (5) specificity, including drug and target tolerance; (6) sample stability that reflects sample storage and handling conditions; (7) assay selectivity to matrix components, including hemolytic, lipemic, and disease state matrices; (8) domain specificity for multi-domain therapeutics; (9) and minimum required dilution and extraction-based sample processing for titer reporting., (© 2021. The Author(s).)

Objectives: To compare healthcare resource utilization and costs among patients with psoriasis, psoriatic arthritis (PsA), and a control group of patients without psoriasis and PsA in the USA., Methods: The IBM® MarketScan® Commercial Database was used to identify three adult patient groups from 1/1/2009 through 4/30/2020: (1) Psoriasis: ≥ 2 diagnoses ≥ 30 days apart for psoriasis (no PsA diagnoses); (2) PsA: ≥ 2 diagnoses for PsA; (3) Control: no psoriasis or PsA diagnoses in their entire claims records. Patients with comorbid rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, or ulcerative colitis were excluded from the analyses. Controls were matched 1:1 to psoriasis and PsA patients based on age, gender, index year, and number of non-rheumatological comorbidities. Healthcare resource utilization and costs (in 2019 USD) were evaluated descriptively and through mixed models for five years of follow-up., Results: A total of 142,531 psoriasis and 21,428 PsA patients were matched to the control group (N = 163,959). Annual all-cause healthcare costs per patient were $7,470, $11,062, and $29,742 for the control, psoriasis, and PsA groups, respectively. All-cause healthcare costs increased over time and were significantly greater among PsA vs. psoriasis (p < 0.0001) and the control groups (p < 0.0001). Across all categories of healthcare resources, utilization was greatest among patients with PsA and lowest in the control group., Conclusion: Annual healthcare costs and resource utilization were significantly higher with PsA compared with psoriasis and the control group, confirming the substantial economic burden of PsA. The cost disparity between these patient groups highlights a continued unmet medical need. Key Points • Patients with PsA incurred significantly greater healthcare resource utilization and costs than patients with psoriasis and patients without psoriasis and PsA. • Significantly greater costs and healthcare resource utilization were also observed among patients with psoriasis compared with patients without psoriasis and PsA., (© 2021. International League of Associations for Rheumatology (ILAR).)

The 14 th edition of the Workshop on Recent Issues in Bioanalysis (14 th WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14 th WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by LCMS were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations on Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity). Part 1 (Innovation in Small Molecules, Hybrid LBA/LCMS & Regulated Bioanalysis), Part 2A (BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation) and Part 2B (Regulatory Input) are published in volume 13 of Bioanalysis, issues 4 and 5 (2020), respectively.

Introduction: The objective of this study was to describe the treatment patterns among patients with newly diagnosed multiple myeloma (MM) who had not received autologous stem cell transplantation (ASCT). It further compares the safety and clinical outcomes across different frontline regimens as well as explores whether treatment duration predicts outcomes., Methods: Patients with MM (> 45 years) who had not received ASCT were retrospectively identified from the US SEER-Medicare (Jan 2007-Dec 2016) and Optum (Jan 2007-Sep 2018) databases. Cox proportional hazard models were used to compare overall survival (OS) among bortezomib + lenalidomide + dexamethasone regimen (VRd), lenalidomide + dexamethasone regimen (Rd), cyclophosphamide + bortezomib + dexamethasone regimen (CyBorD), bortezomib + dexamethasone regimen (Vd), and other bortezomib-containing therapies based on propensity score matching. To address immortal time bias, time-fixed and time-dependent Cox models were employed to estimate the association of longer frontline treatment exposure with outcomes., Results: Mean (standard deviation; SD) age was 71 (9.8) years; and 49.51% were women. Bortezomib and lenalidomide-based combinations were the most common treatment modalities. After matching, the HR (95% CI) of OS by frontline therapies comparing VRd with Vd was 0.76 (0.66, 0.86), CyBorD was 0.87 (0.75, 1.05), for other bortezomib-based therapies was 0.56 (0.49, 0.64), Rd was 0.83 (0.73, 0.95), and for other therapies was 0.70 (0.61, 0.80). Longer frontline treatment duration was associated with better OS for overall frontline [HR (95% CI) 0.86 (0.82, 0.90)]; Vd [0.81 (0.74, 0.89)]; CyBorD [0.79 (0.64, 0.98)] and Rd [0.86 (0.78, 0.95)]., Conclusion: Results demonstrated that the frontline therapies prescribed to most patients who did not receive ASCT for MM in the United States were consistent with the NCCN guideline recommendations. Longer frontline treatment duration was associated with improved OS.

Currently, there is a multitude of CD3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. The key safety concerns with CD3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (CRS), target organ toxicity due to redirection of T-cells to normal tissues expressing the tumor-associated antigen (TAA) (off-tumor/on-target cytotoxicity), and, in some instances, neurotoxicity. Another key challenge is to arrive at a safe clinical starting dose and an efficient escalating strategy that allows patients in early dose cohorts the potential for clinical benefit in Phase 1 trials. To expand the therapeutic index and bring more treatment options to patients, there are intense efforts to overcome these challenges through improvements in molecular design, preclinical safety assessment strategies, and clinical management practices. A recent workshop at the U.S. Food and Drug Administration (FDA) with industry, academic, and regulatory agency representation was held to discuss the challenges and explore where such improvements to the development of CD3 bispecifics can be implemented. Here, the content of the presentations and the discussion that occurred during this workshop are summarized.

Importance: Receipt of hepatitis B virus vaccine is important to prevent infection. However, adherence to the hepatitis B vaccine series among adults at risk of infection has been low., Objective: To assess whether recipients of a 2-dose hepatitis B vaccine with cytosine phosphoguanine adjuvant (HepB-CpG vaccine; Heplisav-B) are more likely to complete their series compared with recipients of a 3-dose vaccine with alum adjuvant (comparator vaccine; Engerix-B [HepB-alum])., Design, Setting, and Participants: This nested cohort study was conducted from August 7 to December 31, 2018, at Kaiser Permanente Southern California, an integrated health care system with a diverse population of approximately 4.6 million members. Adults not receiving dialysis who received a first dose of a hepatitis B vaccine series in family practice or internal medicine departments of 15 Kaiser Permanente Southern California medical centers were followed up through electronic health records for up to 1 year after receipt of the first dose. Data were analyzed from March 16 to September 23, 2020., Exposures: Receipt of a first dose of the HepB-CpG vaccine (2-dose vaccine) vs receipt of a first dose of the HepB-alum vaccine (3-dose vaccine)., Main Outcomes and Measures: Series completion within the recommended vaccine schedule plus 3 months (primary outcome) and series completion within 1 year after receipt of the first dose (secondary outcome)., Results: Of 4727 individuals who initiated the HepB-CpG vaccine series and 6161 individuals who initiated the HepB-alum vaccine series included in the study, 2876 (60.8%) and 3789 (61.5%), respectively, were ages 40 to 59 years, 2415 (51.1%) and 3113 (50.5%) were male, and 2364 (50.0%) and 2881 (46.8%) were Hispanic. The vaccine series was completed within the recommended schedule plus 3 months for 2111 (44.7%) individuals who initiated the HepB-CpG vaccine series and 1607 (26.1%) individuals who initiated the HepB-alum vaccine series, and within 1 year for 2858 (60.5%) and 1989 (32.3%) individuals, respectively. The individuals who initiated the HepB-CpG vaccine series were significantly more likely to complete the series (adjusted relative risk, 1.77; 95% CI, 1.68-1.87). Results were consistent across clinical and demographic strata., Conclusions and Relevance: In this study, use of the HepB-CpG vaccine was associated with hepatitis B vaccine series completion, but tailored strategies to increase completion of hepatitis B vaccine series are warranted.

Therapeutic proteins have the potential to induce unwanted immune responses. The potential impact of immunogenicity on pharmacokinetics, pharmacodynamics, safety and efficacy are well established. Here, we analyze key aspects of current US FDA and EMA guidelines on the development and validation of antidrug antibody assays. Although FDA and EMA guidance documents are in harmony on most points, EMA allows greater leeway for scientific judgement, while FDA recommends specific approaches that may not be appropriate in some situations. Many white papers suggest approaches different from the guidance documents, however, these can conflict with each other and are themselves only scientifically valid in certain situations. Here, we indicate when alternatives to guidance may be needed and what those approaches might be.

Background: The term medical nutrition (MN) refers to nutritional products used under medical supervision to manage disease- or condition-related dietary needs. Standardized MN definitions, aligned with regulatory definitions, are needed to facilitate outcomes research and economic evaluation of interventions with MN., Objectives: Ascertain how MN terms are defined, relevant regulations are applied, and to what extent MN is valued., Methods: ISPOR's Nutrition Economics Special Interest Group conducted a scoping review of scientific literature on European and US MN terminology and regulations, published between January 2000 and August 2015, and pertinent professional and regulatory Web sites. Data were extracted, reviewed, and reconciled using two-person teams in a two-step process. The literature search was updated before manuscript completion., Results: Of the initial 1687 literature abstracts and 222 Web sites identified, 459 records were included in the analysis, of which 308 used MN terms and 100 provided definitions. More than 13 primary disease groups as per International Classification of Disease, Revision 10 categories were included. The most frequently mentioned and defined terms were enteral nutrition and malnutrition. Less than 5% of the records referenced any MN regulation. The health economic impact of MN was rarely and insufficiently (n = 19 [4.1%]) assessed, although an increase in economic analyses was observed., Conclusions: MN terminology is not consistently defined, relevant European and US regulations are rarely cited, and economic evaluations are infrequently conducted. We recommend adopting consensus MN terms and definitions, for example, the European Society for Clinical Nutrition and Metabolism consensus guideline 2017, as a foundation for developing reliable and standardized medical nutrition economic methodologies., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

The Alzheimer's Association's Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimer's Association Research Framework. This review will summarize the "A, T, N System" (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed., (Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Purpose: To understand weight loss strategies, weight changes, goals, and behaviors in people with type 2 diabetes mellitus (T2DM) and whether these differ by ethnicity., Methods: T2DM was identified by self-reported diagnosis using the NHANES 2005-2012 data, which also included measured and self-reported current body weight and height, self-reported weight the prior year, and self-reported aspired weight. Nineteen weight loss strategies were evaluated for association with ≥5% weight loss or weight gain versus <5% weight change., Results: Among people with T2DM, 88.0% were overweight/obese (body mass index [BMI] ≥25 kg/m(2)) in the prior year and 86.1% the current year. About 60% of the overweight/obese took weight loss actions, mostly using diet-related methods with average weight lost <5%. Two most "effective" methods reported (smoking, taking laxatives/vomiting) are also potentially most harmful. Similar BMI distributions but different goals and behaviors about weight and weight loss were observed across ethnicity. Only physical activity meeting the recommended level and changing eating habits were consistently associated with favorable and statistically significant weight change., Conclusions: Weight management in T2DM is an ongoing challenge, regardless of ethnicity/race. Among overweight/obese T2DM subjects, recommended level of physical activity and changing eating habits were associated with statistically significant favorable weight change., (© 2016 The Author(s).)

Recent outbreaks of syphilis among men who have sex with men (MSM) in major cities in the United States and reported increases in sexual risk behavior have raised concerns about potential increases in human immunodeficiency virus (HIV) transmission. The majority of MSM who have early syphilis are HIV infected; in preliminary studies, rates of recent HIV infection among them are also high. Data from San Francisco, Los Angeles, and Seattle-King County, however, suggest no temporal increases in HIV incidence among MSM seeking HIV testing at select large public sites during the syphilis outbreaks. Because most HIV incidence and behavioral data are from large metropolitan areas with large gay populations and well-established HIV epidemics, we do not know whether, nationally, incidence of HIV infection among MSM has been increasing, decreasing, or stable during syphilis outbreaks. Further studies of HIV incidence in larger and smaller cities with different maturities of HIV epidemic are warranted. Comprehensive and integrated HIV/STD prevention and control efforts are also needed to halt the spread of syphilis and reduce HIV transmission among gay and bisexual men.

Context: HIV incidence measurements, which reflect recent or current transmission, are valuable for monitoring the epidemic and evaluating prevention programs., Objectives: To summarize HIV incidence patterns and trends in U.S. population groups., Data Sources: Publications in English from 1980 through mid-2000. STUDY SELECTION AND STATISTICAL METHODS: We searched the literature for reports of HIV incidence in the United States. Locally weighted scatterplot smoothing was used to generate smooth curves to estimate trends in incidence. Spearman rank correlation was used to estimate the correlation coefficient between prevalence and incidence., Data Synthesis: In 74 eligible reports, HIV incidence varied widely (0.002-19.8 per 100 person-years [py]) depending on risk group. Among men who have sex with men (MSM), HIV incidence peaked in the early 1980s (5-20/100 py) and then declined but remained high during the 1990s (2-4/100 py). Among injection drug users (IDUs), incidence decreased since the mid-1980s but differed by geographic area; in the 1990s, incidence remained high in the East (1-3/100 py) but was lower in the West (<0.5/100 py). Throughout the late 1980s and 1990s, incidence was low and stable in broader populations (blood donors: <0.01/100 py; military personnel: 0.01-0.07/100 py). The correlation between HIV incidence and prevalence was strong in populations with a prevalence less than 1% (r = 0.94, p<.0001), moderate in populations with a prevalence from 1% to less than 10% (r = 0.57, p<.0001), and weak in populations with a prevalence at least 10% (r = 0.23, p=.09)., Conclusions: HIV prevention in the United States should continue to focus on MSM and IDUs. HIV incidence measurements should be considered for monitoring HIV transmission in MSM, IDUs, and other populations in which seroprevalence is high.

In the United States, HIV prevention programs have historically tailored activities for specific groups primarily on the basis of behavioral risk factors and demographic characteristics. Through the Serostatus Approach to Fighting the Epidemic (SAFE), the Centers for Disease Control and Prevention is now expanding prevention programs, especially for individuals with HIV, to reduce the risk of transmission as a supplement to current programs that primarily focus on reducing the risk of acquisition of the virus. For individuals with HIV, SAFE comprises action steps that focus on diagnosing all HIV-infected persons, linking them to appropriate high-quality care and prevention services, helping them adhere to treatment regimens, and supporting them in adopting and sustaining HIV risk reduction behavior. SAFE couple a traditional infectious disease control focus on the infected person with behavioral interventions that have been standard for HIV prevention programs.

HIV surveillance and diagnostic testing for HIV infection share elements in common, yet differ notably in context. Clinical testing provides vital information for individual medical and behavioral decisions, whereas surveillance, which focuses on populations, provides information to develop policy, direct resources, and plan services. HIV/AIDS surveillance has evolved over the course of the epidemic, reflecting changes in scientific knowledge, populations affected, and information needs. Likewise, the benefits of early diagnosis of HIV have become increasingly apparent with advances in HIV treatment. This article examines the changing context of HIV/AIDS surveillance and discusses the potential impact of HIV surveillance practices and policies on HIV testing behaviors. Special emphasis is placed on the importance of protecting the confidentiality of HIV/AIDS surveillance data and on the role of health department in monitoring the impact of surveillance policies on test-seeking patterns and behaviors.

Context: Studies conducted in the late 1980s on human immunodeficiency virus (HIV) infection among older men who have sex with men (MSM) suggested the epidemic had peaked; however, more recent studies in younger MSM have suggested continued high HIV incidence., Objective: To investigate the current state of the HIV epidemic among adolescent and young adult MSM in the United States by assessing the prevalence of HIV infection and associated risks in this population in metropolitan areas., Design: The Young Men's Survey, a cross-sectional, multisite, venue-based survey conducted from 1994 through 1998., Setting: One hundred ninety-four public venues frequented by young MSM in Baltimore, Md; Dallas, Tex; Los Angeles, Calif; Miami, Fla; New York, NY; the San Francisco (Calif) Bay Area; and Seattle, Wash., Subjects: A total of 3492 15- to 22-year-old MSM who consented to an interview and HIV testing., Main Outcome Measures: Prevalence of HIV infection and associated characteristics and risk behaviors., Results: Prevalence of HIV infection was high (overall, 7.2%; range for the 7 areas, 2.2%-12. 1%) and increased with age, from 0% among 15-year-olds to 9.7% among 22-year-olds. Multivariate-adjusted HIV infection prevalence was higher among blacks (odds ratio [OR], 6.3; 95% confidence interval [CI], 4.1-9.8), young men of mixed or other race (OR, 4.8; 95% CI, 3. 0-7.6), and Hispanics (OR, 2.3; 95% CI, 1.5-3.4), compared with whites (referent) and Asian Americans and Pacific Islanders (OR, 1. 1; 95% CI, 0.5-2.8). Factors most strongly associated with HIV infection were being black, mixed, or other race; having ever had anal sex with a man (OR, 5.0; 95% CI, 1.8-13.8); or having had sex with 20 or more men (OR, 3.0; 95% CI, 2.0-4.7). Only 46 (18%) of the 249 HIV-positive men knew they were infected before this testing; 37 (15%) were receiving medical care for HIV, and 19 (8%) were receiving medical drug therapy for HIV. Prevalence of unprotected anal sex during the past 6 months was high (overall, 41%; range, 33%-49%)., Conclusions: Among these young MSM, HIV prevalence was high, underscoring the need to evaluate and intensify prevention efforts for young MSM, particularly blacks, men of mixed race or ethnicity, Hispanics, and adolescents. JAMA. 2000;284:198-204

The emergence of a new infectious disease, AIDS, in the early 1980s resulted in the development of a national AIDS surveillance system. AIDS surveillance data provided an understanding of transmission risks and characterized communities affected by the epidemic. Later, these data provided the basis for allocating resources for prevention and treatment programs. New treatments have dramatically improved survival. Resulting declines in AIDS incidence and deaths offer hope that HIV disease can be successfully managed. However, to prevent and control HIV/AIDS in the coming decades, the public health community must address new challenges. These include the defining of the role of treatment in reducing infectiousness; the potential for an epidemic of treatment-resistant HIV; side effects of treatment; complacency that leads to relapses to high-risk behaviors; and inadequate surveillance and research capacity at state and local levels to guide the development of health interventions. Meeting these challenges will require reinvesting in the public health capacity of state and local health departments, restructuring HIV/AIDS surveillance programs to collect the data needed to guide the response to the epidemic, and providing timely answers to emerging epidemiologic questions.

Disease incidence (new cases of disease per person per year) is usually measured by using longitudinal data. However, several recent proposals for measuring the incidence of human immunodeficiency virus (HIV) rely on cross-sectional data only. These methods assume each person is only sampled once; however, in some instances, it is necessary to consider these cross-sectional methods when individuals are represented more than once in the survey sample. We derive an extension of the cross-sectional incidence estimator that is valid for data from repeatedly screened populations and show under what conditions our new estimator reduces to the old estimator. An example involving estimation of HIV incidence among repeat blood donors is presented.

To describe HIV infection prevalence and prevalence trends for disadvantaged out-of-school youth in the United States, we analyzed the HIV prevalence for and demographic characteristics of youth, aged 16 through 21 years, who entered the U.S. Job Corps from January 1990 through December 1996. Job Corps is a federally funded jobs training program for socially and economically disadvantaged out-of-school youth. All 357,443 entrants residing at Job Corps centers during their training were tested for HIV infection; 822 (2.3 per 1000) were HIV-positive. HIV prevalence was higher for women than for men (2.8 per 1000 versus 2.0 per 1000; relative risk [RR]=1.4; 95% confidence interval [CI]=1.2-1.6). Among racial/ethnic groups, prevalence was highest for African Americans (3.8 per 1000). Prevalence was higher for African American women (4.9 per 1000) than for any other gender and racial/ethnic group. From 1990 through 1996, standardized HIV prevalence-stratified by age, race/ethnicity, home region, population of home metropolitan statistical area, and year of entry--declined for women and for men: for women, from 4.1 per 1000 in 1990 to 2.1 per 1000 in 1996 (p=.001); and for men, from 2.8 per 1000 in 1990 to 1.4 per 1000 in 1996 (p=.001). These data suggest that HIV prevalence for disadvantaged out-of-school youth declined from 1990 through 1996. However, considering their youth, prevalence was still high, particularly for women and African Americans, most notably African American women. These data support the need for ongoing HIV prevention programs targeting such youth.

We developed a scheme using routinely available data to estimate the risk of human immunodeficiency virus (HIV) dementia in HIV-infected persons over time. We performed a longitudinal review of medical records from more than 100 medical facilities in 11 U.S. cities. A total of 19,462 HIV-infected persons without history of dementia enrolled in a multi-institution survey. The main outcome measure was the development of HIV dementia (1987 case definition) during the median follow-up period of 17 months (range, 1 to 72 months). Of 19,462 HIV-infected persons, HIV dementia developed in 880 persons (4.5%; 2.6% per person-year). The strongest predictors of HIV dementia were CD4+ T-lymphocyte count, anemia, and AIDS-defining infections or cancer. The 2-year probability of HIV dementia was highest for persons who had a CD4+ T-lymphocyte count of fewer than 100 cells/microL and an AIDS-defining illness or anemia or both (18.6 to 24.9%). Intermediate risk was observed in persons with CD4+ T-lymphocyte count of 100 to 199 cells/microL and an AIDS-defining illness or anemia or both or in persons with a CD4+ T-lymphocyte count of fewer than 100 cells/microL but without another risk factor (2-year probability, 10.4 to 15.2%). The 2-year probability that HIV dementia would develop was lowest (1.0%) for persons with CD4+ T-lymphocyte count of more than 200 cells/microL and no other risk factors. Risk stratification using routine clinical information provides information that may prove useful in patient care decisions.

To examine trends in progressive multifocal leukoencephalopathy (PML) mortality in the United States, we analyzed PML death rates and deaths for 1979 through 1994, using US multiple cause-of-death data. During the 16-year study period 3,894 PML deaths were reported. The age-adjusted death rate increased more than 20-fold, from less than 0.2 per million persons before 1984 to 3.3 per million persons in 1994. The increase was attributable to infection with human immunodeficiency virus (HIV) which was recorded on 2,267 (89.0%) of 2.546 death records from 1991 through 1994. PML age-adjusted death rates increased abruptly for all males beginning in 1984 and for black females in 1990. Only a small increase was observed for white females. In 1994, PML was reported in 2.1% of white males who died with HIV-associated disease compared with 1.2% of white females and 1.0% of black males and females who died of similar causes. The epidemic of PML deaths is increasing in parallel with the AIDS epidemic. The increase in HIV-associated PML deaths, first noted among males, has also become apparent among females and probably reflects the increasing importance of drug use and heterosexual transmission of HIV. The reason for the higher prevalence of PML among white males with HIV infection is unknown.

Traditional sampling methods are unsuitable for determining the levels of human immunodeficiency virus type I infection and related behavioral risk factors among young men who have sex with men. Most surveys of this hard-to-reach population have used nonprobability samples of young men in clinical or public settings. While these studies have revealed high rates of HIV infection and risk behaviors, their findings are not generalizable to broader populations of young men who have sex with men. To better understand the epidemiology of HIV within this population, the Centers for Disease Control and Prevention, in collaboration with state and local health departments, has developed a venue-based probability survey of young men who have sex with men. Conducted in seven metropolitan areas in the United States, the Young Men's Survey combines outreach techniques with standard methods of sample surveys to enumerate, sample, and estimate prevalence outcomes of a population of young men who frequent public venues and who have sex with other men. Venues where young men who have sex with men are sampled include dance clubs, bars, and street locations. At sampled venues, young men are enumerated, consecutively approached, and offered enrollment if they are determined eligible. Young men who agree to participate in the Young Men's Survey are interviewed, counseled, and tested for human immunodeficiency virus, hepatitis B, and syphilis in vans parked near sampled venues. The Young Men's Survey provides data on the locations and times at which demographic and behavioral subgroups of young men who have sex with men may be targeted for prevention activities. Behaviors and psychosocial factors associated with human immunodeficiency virus infection can be used to design culturally relevant and age-specific prevention activities for young men who have sex with men.

Objective: To describe the seroprevalence of human immunodeficiency virus type 1 (HIV-1) and risk factors for HIV-1 infection among teenagers attending selected clinics., Design: Anonymous, cross-sectional serosurveys conducted in 130 clinics in 24 cities., Settings: Adolescent medicine clinics, sexually transmitted disease clinics, clinics in juvenile detention and correctional facilities, and homeless and runaway youth centers., Patients: Teenagers in whom serum samples were drawn as part of routine medical services., Main Outcome Measures: Prevalence of HIV-1 infection and reported HIV risk behaviors., Results: From January 1, 1990 through December 31, 1992, serum specimens were collected from 79,802 teenagers; 591 of these specimens were positive for HIV-1 antibody. Seropositive test results were found in all 24 cities surveyed, and in 95 (73%) of the 130 clinics surveyed. The median clinic-specific prevalence was 0.2% (range, 0% to 1.4%) in 22 adolescent medicine clinics, 0.3% (range, 0% to 6.8%) in 33 correctional facilities, 0.5% (range, 0% to 3.5%) in 70 sexually transmitted disease clinics, and 1.1% (range, 0% to 4.1%) in five homeless youth centers. Rates exceeded 1% in 37 sites (28%). Excluding sites with many men reporting sex with men, rates in women were similar or somewhat higher than rates in men. Rates were highest among young men reporting sex with men, with clinic rates ranging from 16% to 17% in two homeless youth sites and 13% to 17% in two sexually transmitted disease clinics. Most teenagers with risk information reported heterosexual activity as their only potential risk exposure to HIV-1., Conclusions: Seroprevalence of HIV was generally low but varied by type of clinic and geographic area. The highest rates were observed among young women and gay men in some settings, suggesting that targeted prevention messages are needed.

In a hospital-based seroprevalence survey for human immunodeficiency virus type 1 (HIV-1) infection, a stratified sampling method based on age and gender was used to collect 5429 blood samples at an inner-city hospital. Sentinel Hospital Surveillance System (SHSS) criteria developed by the Centers for Disease Control and Prevention were used to classify patient diagnoses into two categories by the likelihood of being associated with HIV-1 infection. The two categories were those with high likelihood of association with HIV-1 (SHSS-ineligible) and those with low likelihood of association with HIV-1 infection (SHSS-eligible). Of the 5429 blood samples, 4262 were SHSS-eligible and 1167 were SHSS-ineligible. After personal identifies were removed, specimens were tested by ELISA and confirmed by Western blot analysis. The overall prevalence rate of HIV-1 infection was 0.98%. The seroprevalence rate was almost 2.6 times higher in high-association patients compared with low-association patients (1.89% versus 0.73%, P < .001). Results from this study indicate a high unsuspected HIV-1 seroprevalence rate in a subpopulation (SHSS-eligible) considered to have diagnoses with low likelihood of association with HIV-1 infection. These patients may better approximate HIV-1 seroprevalence in the general population of the area served by the hospital than would a sample of all patients. Monitoring HIV-1 seroprevalence in the SHSS-eligible group will be a useful measure for community serosurveillance for HIV-1 infection.

The Centers for Disease Control and Prevention has developed guidelines for determining HIV seroprevalence among patients seeking medical care at acute-care hospitals. The guidelines enable hospital staff members to perform a simple, rapid, and inexpensive survey to determine seroprevalence among the patient population, protecting the anonymity of those who are tested. The guidelines are based on national experience with large-scale anonymous, unlinked HIV serosurveys. The data from a rapid assessment survey are particularly useful for evaluating the need to provide routine, voluntary HIV counseling and testing and treatment for HIV infection. Beyond that, such data can be used in targeting education efforts, in reinforcing the use of appropriate universal precautions, in resource allocation, and in determining the need for further studies of HIV infection among the population in the hospital catchment area.

This paper presents the results of a ten-country comparative study of health care financing systems and their progressivity characteristics. It distinguishes between the tax-financed systems of Denmark, Portugal and the U.K., the social insurance systems of France, the Netherlands and Spain, and the predominantly private systems of Switzerland and the U.S. It concludes that tax-financed systems tend to be proportional or mildly progressive, that social insurance systems are regressive and that private systems are even more regressive. Out-of-pocket payments are in most countries an especially regressive means of raising health care revenues.

This paper presents the results of an eight-country comparative study of equity in the delivery of health care. Equity is taken to mean that persons in equal need of health care should be treated the same, irrespective of their income. Two methods are used to investigate inequity: an index of inequity based on standardized expenditure shares, and a regression-based test. The results suggest that inequity exists in most of the eight countries, but there is no simple one-to-one correspondence between a country's delivery system and the degree to which persons in equal need are treated the same.

Background: Routine, voluntary testing of hospital patients for the human immunodeficiency virus (HIV) has been proposed in order to identify those with early HIV infection in a setting where there is ready access to counseling, appropriate clinical referral, evaluation, and therapy. We studied the pattern of HIV infection among patients in 20 U.S. hospitals, in order to evaluate possible national strategies for the routine, voluntary HIV counseling and testing of hospital patients., Methods: Blood specimens remaining after clinical use from a systematically selected sample of patients at 20 hospitals in 15 U.S. cities were tested anonymously for antibody to HIV type 1 (HIV-1). Multivariate regression was used to determine which variables best predicted HIV seroprevalence in individual hospitals. Using these data, we estimated the number of HIV-positive patients in all U.S. hospitals and considered the efficiency of routine counseling and testing in different subgroups of patients and hospitals., Results: From September 1989 through October 1991, 9286 of 195,829 specimens (4.7 percent) were positive for HIV-1 in the 20 hospitals. The seroprevalence of HIV at these institutions ranged from 0.2 percent to 14.2 percent. Among HIV-positive patients, 32 percent had symptomatic HIV infection or the acquired immunodeficiency syndrome (AIDS) at the time of admission or evaluation. In the 20 hospitals, HIV seroprevalence was 10.4 times (95 percent confidence interval, 8.8 to 12.0) the AIDS-diagnosis rate (the annual number of patients with new diagnoses of AIDS per 1000 discharges in 1990). In a multivariate model that included 13 hospital-specific variables, only the AIDS-diagnosis rate was associated with the hospital-specific HIV-seroprevalence rate (P less than 0.001). Using these data and the AIDS-diagnosis rates for all U.S. acute care hospitals, we estimated that 225,000 HIV-positive persons were hospitalized (95 percent confidence interval, 190,000 to 260,000) in all 5558 such hospitals in 1990, including 163,000 persons presenting with conditions other than HIV or AIDS (95 percent confidence interval, 130,000 to 196,000). In 1990, in 593 U.S. hospitals with AIDS-diagnosis rates of 1.0 or more per 1000 discharges, HIV testing of patients 15 to 54 years old (3 million patients, or 12.0 percent of all patients in U.S. acute care hospitals) would have identified an estimated 68 percent of all HIV-positive patients (110,000 patients) who were admitted with conditions other than symptomatic HIV infection or AIDS., Conclusions: We estimate that about 225,000 HIV-positive persons were hospitalized in 1990, of whom only one third were admitted for symptomatic HIV infection or AIDS. Routine, voluntary HIV testing of patients 15 to 54 years old in hospitals with 1 or more patients with newly diagnosed AIDS per 1000 discharges per year could potentially have identified as many as 110,000 patients with HIV infection that was previously unrecognized.

Previous studies of the insulin gene--utilized restriction-fragment--length polymorphisms as markers for potential mutations at this locus. This indirect type of analysis could not define the number of variants that might exist within the structural portions and regulatory regions of the gene in non-insulin-dependent diabetes mellitus (NIDDM) patients. New technology has allowed us to examine insulin genes at the single nucleotide level from 100 American black NIDDM patients. Genomic DNA from patients was amplified by the polymerase chain reaction with primers flanking four regions of the gene: 1) the proximal promoter from positions -182 to 42 (including most of exon 1); 2) exon 1 from 14 to 259, which included the rest of exon 1 and all of the 1st intron; 3) exon 2 from 216 to 452; and 4) exon 3 from 1188 to 1433. One of the primers in each reaction was 32P-end labeled and the resulting products denatured into single strands and electrophoresed on nondenaturing sequencing gels such that mobility was a function of composition and size (single-strand conformational polymorphism or SSCP). Under these conditions, single-base changes in fragments up to 245 nucleotides were detected. Analysis of the proximal promoter region revealed several SSCP patterns in individuals. Direct genomic sequencing of DNA representative of these patterns showed the presence of a common C to G change at position -56 and a C deletion at position -90 in three patients.(ABSTRACT TRUNCATED AT 250 WORDS)

We analyzed progressive multifocal leukoencephalopathy (PML) mortality data from 1979 to 1987 and data on persons with acquired immunodeficiency syndrome (AIDS) reported to the Centers for Disease Control (CDC). Based on analyses of multiple-cause-of-death vital statistics, deaths related to PML have increased fourfold from 1.5/10,000,000 persons in 1979 to 6.1/10,000,000 persons in 1987. The increase in the PML annual death rate began in 1984, occurred primarily in men 20 to 49 years of age, and was greatest in states known to have a high incidence of AIDS. In 1987, 56% of death certificates that listed PML as a cause of death also listed human immunodeficiency virus (HIV) infection. Analysis of AIDS case reports to the CDC from 1981 through June 1990 demonstrated that 0.72% of persons with AIDS were reported as having PML. Although most persons with AIDS who had PML were 20 to 49 years of age (84.6%), PML was reported more frequently among persons with AIDS greater than or equal to 50 years old than less than 50 years old. In addition, PML was reported more frequently among persons with AIDS who were exposed to HIV by blood transfusion than those in all other exposure categories. These data demonstrate that the increase in PML mortality from 1979 to 1987 was associated with the large increase in immunosuppressed persons with AIDS.

HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is endemic in the Caribbean basin and Japan. Because of the close proximity of the United States to the Caribbean and the presence of HTLV-I-seropositive persons in the United States, we sought reports of patients who were HTLV-I seropositive and had a slowly progressive myelopathy. Over a 2-year period, there were 25 patients reported, 19 of whom were black and 12 of whom had been born in the United States. All patients except two had become symptomatic while living in the United States. Six patients had no apparent risk factor for acquiring HTLV-I. These data demonstrate that HAM/TSP is occurring in the United States and that the diagnosis of HAM/TSP should be considered in patients with a slowly progressive myelopathy regardless of risk factors for acquiring HTLV-I.