The impact of farming on prehistoric culinary practices throughout Northern Europe.

To investigate changes in culinary practices associated with the arrival of farming, we analysed the organic residues of over 1,000 pottery vessels from hunter-gatherer-fisher and early agricultural sites across Northern Europe from the Lower Rhine Basin to the Northeastern Baltic. Here, pottery was widely used by hunter-gatherer-fishers prior to the introduction of domesticated animals and plants. Overall, there was surprising continuity in the way that hunter-gatherer-fishers and farmers used pottery. Both aquatic products and wild plants remained prevalent, a pattern repeated consistently across the study area. We argue that the rapid adaptation of farming communities to exploit coastal and lagoonal resources facilitated their northerly expansion, and in some cases, hunting, gathering, and fishing became the most dominant subsistence strategy. Nevertheless, dairy products frequently appear in pottery associated with the earliest farming groups often mixed with wild plants and fish. Interestingly, we also find compelling evidence of dairy products in hunter-gatherer-fisher Ertebølle pottery, which predates the arrival of domesticated animals. We propose that Ertebølle hunter-gatherer-fishers frequently acquired dairy products through exchange with adjacent farming communities prior to the transition. The continuity observed in pottery use across the transition to farming contrasts with the analysis of human remains which shows substantial demographic change through ancient DNA and, in some cases, a reduction in marine consumption through stable isotope analysis. We postulate that farmers acquired the knowledge and skills they needed to succeed from local hunter-gatherer-fishers but without substantial admixture.

The Associations of Chronotype and Shift Work With Rheumatoid Arthritis.

The circadian clock regulates multiple aspects of human physiology including immunity. People have a circadian preference termed chronotype. Those with an evening preference may be better suited to shift work, but also carry higher risk of adverse health. Shift work leads to misalignment of circadian rhythms and is associated with increased risk of inflammatory disease such as asthma and cancer. Here, we investigate the association between chronotype, shift work, and rheumatoid arthritis (RA). The associations between exposures of shift work and chronotype on risk of RA were studied in up to 444,210 U.K. Biobank participants. Multivariable logistic regression models were adjusted for covariates: age, sex, ethnicity, alcohol intake, smoking history, Townsend Deprivation Index (TDI), sleep duration, length of working week, and body mass index (BMI). After adjusting for covariates, individuals with a morning chronotype had lower odds of having rheumatoid arthritis (RA; odds ratio [OR]: 0.93, 95% confidence interval [CI]: 0.88-0.99) when compared to intermediate chronotypes. The association between morning chronotype and RA persisted with a more stringent RA case definition (covariate-adjusted OR: 0.89, 95% CI: 0.81-0.97). When adjusted for age, sex, ethnicity, and TDI, shift workers had higher odds of RA (OR: 1.22, 95% CI: 1.1-1.36) compared to day workers that attenuated to the null after further covariate adjustment (OR: 1.1, 95% CI: 0.98-1.22). Morning chronotypes working permanent night shifts had significantly higher odds of RA compared to day workers (OR: 1.89, 95% CI: 1.19-2.99). These data point to a role for circadian rhythms in RA pathogenesis. Further studies are required to determine the mechanisms underlying this association and understand the potential impact of shift work on chronic inflammatory disease and its mediating factors.

The transmission of pottery technology among prehistoric European hunter-gatherers.

Human history has been shaped by global dispersals of technologies, although understanding of what enabled these processes is limited. Here, we explore the behavioural mechanisms that led to the emergence of pottery among hunter-gatherer communities in Europe during the mid-Holocene. Through radiocarbon dating, we propose this dispersal occurred at a far faster rate than previously thought. Chemical characterization of organic residues shows that European hunter-gatherer pottery had a function structured around regional culinary practices rather than environmental factors. Analysis of the forms, decoration and technological choices suggests that knowledge of pottery spread through a process of cultural transmission. We demonstrate a correlation between the physical properties of pots and how they were used, reflecting social traditions inherited by successive generations of hunter-gatherers. Taken together the evidence supports kinship-driven, super-regional communication networks that existed long before other major innovations such as agriculture, writing, urbanism or metallurgy.

Ancient Maltese genomes and the genetic geography of Neolithic Europe.

Archaeological consideration of maritime connectivity has ranged from a biogeographical perspective that considers the sea as a barrier to a view of seaways as ancient highways that facilitate exchange. Our results illustrate the former. We report three Late Neolithic human genomes from the Mediterranean island of Malta that are markedly enriched for runs of homozygosity, indicating inbreeding in their ancestry and an effective population size of only hundreds, a striking illustration of maritime isolation in this agricultural society. In the Late Neolithic, communities across mainland Europe experienced a resurgence of hunter-gatherer ancestry, pointing toward the persistence of different ancestral strands that subsequently admixed. This is absent in the Maltese genomes, giving a further indication of their genomic insularity. Imputation of genome-wide genotypes in our new and 258 published ancient individuals allowed shared identity-by-descent segment analysis, giving a fine-grained genetic geography of Neolithic Europe. This highlights the differentiating effects of seafaring Mediterranean expansion and also island colonization, including that of Ireland, Britain, and Orkney. These maritime effects contrast profoundly with a lack of migratory barriers in the establishment of Central European farming populations from Anatolia and the Balkans.

Seroprevalence of SARS-CoV-2 antibodies, associated epidemiological factors and antibody kinetics among healthcare workers in Connecticut.

BACKGROUND: Healthcare workers (HCWs) are at the front line of the ongoing coronavirus 2019 (COVID-19) pandemic. Comprehensive evaluation of the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) among HCWs in a large healthcare system could help to identify the impact of epidemiological factors and the presence of symptoms on the immune response to the infection over time. AIM: To determine the seroprevalence of SARS-CoV-2-specific antibodies among HCWs, identify associated epidemiological factors and study antibody kinetics. METHODS: A longitudinal evaluation of the seroprevalence and epidemiology of SARS-CoV-2-specific antibodies was undertaken in approximately 30,000 HCWs in the largest healthcare system in Connecticut, USA. FINDINGS: At baseline, the prevalence of SARS-CoV-2 antibody among 6863 HCWs was 6.3% [95% confidence interval (CI) 5.7-6.9%], and was highest among patient care support (16.7%), medical assistants (9.1%) and nurses (8.2%), and lower for physicians (3.8%) and advanced practice providers (4.5%). Seroprevalence was significantly higher among African Americans [odds ratio (OR) 3.26 compared with Caucasians, 95% CI 1.77-5.99], in participants with at least one symptom of COVID-19 (OR 3.00, 95% CI 1.92-4.68), and in those reporting prior quarantine (OR 3.83, 95% CI 2.57-5.70). No symptoms were reported in 24% of seropositive participants. Among the 47% of participants who returned for a follow-up serological test, the seroreversion rate was 39.5% and the seroconversion rate was 2.2%. The incidence of re-infection in the seropositive group was zero. CONCLUSION: Although there is a decline in the immunoglobulin G antibody signal over time, 60.5% of seropositive HCWs had maintained their seroconversion status after a median of 5.5 months.

Using metabolic markers to identify insulin resistance in premenopausal women with and without polycystic ovary syndrome.

BACKGROUND: Insulin resistance (IR) is associated with increased risk for type 2 diabetes mellitus and cardiovascular disease. Quantifying IR is invasive and time-consuming, and thus not routinely used in clinical practice. Simple metabolic markers to predict IR exist, but have not been validated in premenopausal women or women with polycystic ovary syndrome (PCOS). OBJECTIVE: To evaluate the ability of metabolic markers to identify premenopausal women with/without PCOS who are insulin resistant. DESIGN/SETTING: Cross-sectional analysis. PARTICIPANTS: One hundred and seventy-one non-diabetic premenopausal overweight/obese women without PCOS and 71 women with PCOS. METHODS: IR was quantified by the steady-state plasma glucose during the modified insulin-suppression test. Metabolic markers (BMI, lipid/lipoprotein concentrations, and fasting glucose) were evaluated for their discriminative ability to identify IR, using area under the receiver-operating-characteristic curve (AUROC) analysis. Optimal cut-points were evaluated for predictive power. RESULTS: In the non-PCOS group, the triglyceride/HDL cholesterol ratio (TG/HDL-C) was the best marker (AUROC 0.73). Optimal diagnostic cut-point was 1.9. In the PCOS group, the TG/HDL-C ratio, cholesterol/HDL-C ratio (TC/HDL-C), and HDL-C performed well (AUROC > 0.80), with optimal cut-points for TG/HDL-C 1.3, TC/HDL-C 3.4, and HDL-C 52 mg/dL: TG/HDL-C was more sensitive, but HDL-C had a higher PPV for IR. CONCLUSION: TG/HDL-C can identify IR in premenopausal women with and/without PCOS; diagnostic cut-points differ from those of men and postmenopausal women. HDL-C is an alternative predictor in women with PCOS. These simple metabolic markers, which are standardized between labs, inexpensive, and routinely measured, can be used to tailor lifestyle and medical interventions to improve health outcomes in insulin-resistant premenopausal women.

Late Glacial and Early Holocene human demographic responses to climatic and environmental change in Atlantic Iberia.

Successive generations of hunter-gatherers of the Late Glacial and Early Holocene in Iberia had to contend with rapidly changing environments and climatic conditions. This constrained their economic resources and capacity for demographic growth. The Atlantic façade of Iberia was occupied throughout these times and witnessed very significant environmental transformations. Archaeology offers a perspective on how past human population ecologies changed in response to this scenario. Archaeological radiocarbon data are used here to reconstruct demographics of the region over the long term. We introduce various quantitative methods that allow us to develop palaeodemographic and spatio-temporal models of population growth and density, and compare our results to independent records of palaeoenvironmental and palaeodietary change, and growth rates derived from skeletal data. Our results demonstrate that late glacial population growth was stifled by the Younger Dryas stadial, but populations grew in size and density during the Early to Middle Holocene transition. This growth was fuelled in part by an increased dependence on marine and estuarine food sources, demonstrating how the environment was linked to demographic change via the resource base, and ultimately the carrying capacity of the environment. This article is part of the theme issue 'Cross-disciplinary approaches to prehistoric demography'.

Understanding the Scientific Basis of Post-traumatic Stress Disorder (PTSD): Precision Behavioral Management Overrides Stigmatization.

Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype-phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation "Precision Behavioral Management" (PBM™) based on GARS test values and other pro-dopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.

Dietary weight loss in insulin-resistant non-obese humans: Metabolic benefits and relationship to adipose cell size.

BACKGROUND AND AIMS: Overweight and obesity increase risk for diabetes and cardiovascular disease, largely through development of insulin resistance. Benefits of dietary weight loss are documented for obese individuals with insulin resistance. Similar benefits have not been shown in overweight individuals. We sought to quantify whether dietary weight loss improves metabolic risk profile in overweight insulin-resistant individuals, and evaluated potential mediators between weight loss and metabolic response. METHODS AND RESULTS: Healthy volunteers with BMI 25-29.9 kg/m2 underwent detailed metabolic phenotyping including insulin-mediated-glucose disposal, fasting/daylong glucose, insulin, triglycerides, FFA, and cholesterol. Subcutaneous fat biopsies were performed for measurement of adipose cell size. After 14 weeks of hypocaloric diet and 2 weeks of weight maintenance, cardiometabolic measures and biopsies were repeated. Changes in weight, % body fat, waist circumference, adipose cell size and FFA were evaluated as predictors of change in insulin resistance. Weight loss (4.3 kg) yielded significant improvements in insulin resistance and all cardiovascular risk markers except glucose, HDL-C, and LDL-C. Improvement in insulin sensitivity was greater among those with <2 vs >2 cardiovascular risk factors at baseline. Decrease in adipose cell size and waist circumference, but not weight or body fat, independently predicted improvement in insulin resistance. CONCLUSIONS: Weight loss yields metabolic health benefits in insulin-resistant overweight adults, even in the absence of classic cardiovascular risk factors. Weight loss-related improvement in insulin sensitivity may be mediated through changes in adipose cell size and/or central distribution of body fat. The insulin-resistant subgroup of overweight individuals should be identified and targeted for dietary weight loss. CLINICAL TRIALS IDENTIFIER: NCT00186459.

Insurance Companies Fighting the Peer Review Empire without any Validity: the Case for Addiction and Pain Modalities in the face of an American Drug Epidemic.

The United States are amid an opioid overdose epidemic; we are challenged to provide non-addicting/non-pharmacological alternatives to assist in pain attenuation. There are proven strategies available to manage chronic pain effectively without opioids. Utilization review providers for insurance companies often ignore medicine based scientific peer-reviewed studies that warn against the chronic use of opioid medications, as well as the lack of evidence to support long-term use of opioids for pain. This paradigm must change if we are to indeed change the drug-embracing culture in American chronic pain management. A barrier to treatment is pushback on the part of insurance companies especially as it relates to fighting against pain relief alternatives compared to classical analgesic agents. Pain specialists in the U.S., are compelled to find alternative solutions to help pain victims without promoting unwanted tolerance to analgesics and subsequent biological induction of the "addictive brain." It is noteworthy that reward center of the brain plays a crucial role in the modulation of nociception, and that adaptations in dopaminergic circuitry may affect several sensory and affective components of chronic pain syndromes. Possibly knowing a patient's genetic addiction risk score (GARS™) could eliminate guessing as it relates to becoming addicted.

Safety and efficacy of pasireotide in dumping syndrome-results from a phase 2, multicentre study.

BACKGROUND: Dumping syndrome is a prevalent complication of oesophageal and gastric surgery characterised by early (postprandial tachycardia) and late (hypoglycaemia) postprandial symptoms. AIM: To evaluate efficacy and safety of the somatostatin analogue, pasireotide in patients with dumping syndrome after bariatric or upper gastrointestinal cancer surgery. METHODS: A single-arm, open-label, multicentre, intrapatient dose-escalation, phase 2 study with 4 phases: screening, 3-month SC (subcutaneous), 3-month IM (intramuscular) and 6-month optional extension IM phase. Primary endpoint was the proportion of patients without hypoglycaemia (plasma glucose <3.3 mmol/L [60 mg/dL] during an oral glucose tolerance test, OGTT) at the end of 3-month SC phase. A ≥50% response rate was considered clinically relevant. RESULTS: Forty-three patients with late dumping were enrolled; 33 completed the 3-month SC phase and 23 completed the 12-month study. The proportion of patients without hypoglycaemia at month 3 (primary endpoint) was 60.5% (26 of 43; 95% confidence interval, 44.4%-75.0%). Improvement in quality of life was observed during SC phase, which was maintained in the IM phase. The proportion of patients with a rise in pulse rate of ≥10 beats/min during OGTT reduced from baseline (60.5%) to month 3 (18.6%) and month 12 (27.3%). Overall (month 0-12), the most frequent (>20% of patients) adverse events were headache (34.9%); diarrhoea, hypoglycaemia (27.9% each); fatigue, nausea (23.3% each); and abdominal pain (20.9%). CONCLUSION: These results suggest that pasireotide is a promising option in patients with dumping syndrome after bariatric or upper gastrointestinal cancer surgery.

Familial clustering of systemic lupus erythematosus in the cayman islands.

OBJECTIVE: To describe the unusual clustering of systemic lupus erythematosus (SLE) in a family from the Cayman Islands. METHOD: An observational retrospective study of SLE was done following an index case of mixed connective tissue disease in a 51-year old West Indian woman of African descent. Her two daughters of the same father, who is of Cayman Islands origin, were also diagnosed with SLE. A family tree was subsequently drawn up to 1890 to identify other cases in the same family. RESULTS: There were 13 cases identified and all occurred between the 6th and the 8th generation. A family tree linked all cases to a man from the Cayman Islands who died in 1890. The nine cases with full medical records showed eight females and one male (8:1). The mean age at diagnosis was 29 years; polyarthritis occured in all nine patients (100%), kidney involvement in 6/9 (66.6%), skin rash in 6/9 (66.6%), pleuritis and pericarditis in 6/9 (66.6%) and anaemia in 6/9 (66.6%). The autoantibodies were mainly ANA in all patients (100%) and anti-dsDNA in 8/9 (88.8%). CONCLUSION: The unusual extensive familial clustering in this study represents the first to be described in a West Indian population where SLE is most prevalent and may suggest a genetic predisposition.

Burden of corticosteroid use in patients with systemic lupus erythematosus: results from a Delphi panel.

Corticosteroid-related adverse events (AEs) are commonly reported in systemic lupus erythematosus (SLE), but are often under-represented in claims data. The most common corticosteroid-related AEs are not necessarily the most costly. The present study aimed to examine corticosteroid-related AE rates and identify the associated cost consequences in patients with SLE from the perspective of rheumatologists treating SLE in the United States (US). A modified Delphi process and RAND Appropriateness Method was used to estimate corticosteroid-related AEs and costs based on data from SLE-treating US rheumatologists and estimates from alternative sources. The panel (n=10) participated in two web-based questionnaires, covering disease severity, corticosteroid use, corticosteroid-related AEs, and resource utilization associated with treatment of the AEs. Eight members of the panel then participated in a guided discussion by interactive teleconference, in which the costs associated with specific corticosteroid-related AEs were also discussed. Consensus was achieved in the teleconference when a single response category (consensus values from 1 to 4 [4=strongly agree, 1=strongly disagree]) accounted for ≥80% of responses. Thirteen consensus statements were developed following two Delphi rounds. Costs were estimated for eight corticosteroid-associated AEs from the panel of rheumatologists. In the patients with SLE treated by these physicians, 41.5% were considered to have mild disease, 36.5% moderate disease, and 22.0% severe disease. The number of specialist visits, corticosteroid use, and corticosteroid dose increased with disease severity. The estimated rates of all AEs (except for cataracts) were at least doubled in patients receiving corticosteroid doses>20 mg/day compared with ≤20 mg/day. The highest estimated mean total costs of an event (for the required treatment duration for one patient) were for avascular necrosis ($14,460) and serious infection ($11,660). The costs of more common AEs, such as osteoporosis, obesity, diabetes, and fractures, ranged from $1190 to $8220. Ten rheumatologists concluded that as disease severity increases, corticosteroid doses increased. Greater utilization of resources is needed to manage patients and corticosteroid-related AEs.

Subcutaneous adipose cell size and distribution: relationship to insulin resistance and body fat.

OBJECTIVE: Metabolic heterogeneity among obese individuals may be attributable to differences in adipose cell size. We sought to clarify this by quantifying adipose cell size distribution, body fat, and insulin-mediated glucose uptake in overweight to moderately-obese individuals. METHODS: A total of 148 healthy nondiabetic subjects with BMI 25-38 kg/m2 underwent subcutaneous adipose tissue biopsies and quantification of insulin-mediated glucose uptake with steady-state plasma glucose (SSPG) concentrations during the modified insulin suppression test. Cell size distributions were obtained with Beckman Coulter Multisizer. Primary endpoints included % small adipose cells and diameter of large adipose cells. Cell-size and metabolic parameters were compared by regression for the whole group, according to insulin-resistant (IR) and insulin-sensitive (IS) subgroups, and by body fat quintile. RESULTS: Both large and small adipose cells were present in nearly equal proportions. Percent small cells was associated with SSPG (r = 0.26, P = 0.003). Compared to BMI-matched IS individuals, IR counterparts demonstrated fewer, but larger large adipose cells, and a greater proportion of small-to-large adipose cells. Diameter of the large adipose cells was associated with % body fat (r = 0.26, P = 0.014), female sex (r = 0.21, P = 0.036), and SSPG (r = 0.20, P = 0.012). In the highest versus lowest % body fat quintile, adipose cell size increased by only 7%, whereas adipose cell number increased by 74%. CONCLUSIONS: Recruitment of adipose cells is required for expansion of body fat mass beyond BMI of 25 kg/m2 . Insulin resistance is associated with accumulation of small adipose cells and enlargement of large adipose cells. These data support the notion that impaired adipogenesis may underlie insulin resistance.

A collaborative care model to improve access to pediatric mental health services.

To examine if an innovative collaborative care model known as Targeted Child Psychiatric Services designed for primary care pediatricians (PCPs) and child psychiatrists (1) was associated with improved access to child psychiatry services, (2) had the potential to identify optimal care settings for pediatric mental health care and (3) examined if pediatricians appeared as likely to accept children back into their practices at discharge from TCPS depending upon diagnostic category, controlling for severity of illness and function. The diagnostic classes examined were ADHD (39%), depression (31%) and anxiety (13%). This prospective cohort design study collected medical records of 329 children referred to TCPS by 139 PCPs. To detect the likelihood of return to referring pediatricians for follow-up care at discharge from TCPS, we employed logistic regression models. Mean age was 12.3 (SD = 4.0); 43% were female. Ninety-three percent of parents complied with pediatricians' recommendations to have their child assessed by a child psychiatrist. A total of 28.0% of referrals returned to PCPs for follow-up care; the remainder were followed in mental health. Regression findings indicated that children with major depression (OR = 7.5) or anxiety disorders (OR = 5.1) were less likely to return to PCPs compared to ADHD even though severity of psychiatric illness and functional levels did not differ across diagnostic groups. Families widely accepted pediatricians' recommendations for referral to child psychiatrists. Depression and anxiety were strong correlates of retention in mental health settings at discharge from TCPS though children with these disorders appeared to be no more severely ill or functionally limited than peers with ADHD. These children possibly could be managed in a less intensive and expensive primary care treatment setting that could access mental health specialty services as needed in a collaborative model of care. TCPS is contrasted with the well-known collaborative model for adult depression in primary care. TCPS could serve as a feasible model of care that addresses the daunting barriers in accessing pediatric mental health services.

Variation of health-care resource utilization according to GERD-associated complications.

Complications associated with gastroesophageal reflux disease (GERD) can include esophageal stricture, Barrett's esophagus, gastrointestinal hemorrhage, and extraesophageal symptoms. The impact of GERD-associated complications on health-care utilization deserves further evaluation. We identified commercial enrollees 18-75 years old with claims for GERD (International Classification of Diseases, Ninth Revision, Clinical Modification Codes: 530.81 or 530.11) and subsequent usage of proton pump inhibitors from 01/01/05 to 06/30/09. The initial GERD diagnosis date was designated as the index date, and patients were studied for 6 months preindex and postindex. Eligible patients were subsequently stratified based on medical claims for GERD-associated complications as follows: stage A (GERD diagnosis, no other symptoms), stage B (GERD + extraesophageal symptoms), stage C (GERD + Barrett's esophagus), stage D (GERD + esophageal stricture), and stage E (GERD + iron-deficiency anemia or acute upper gastrointestinal hemorrhage). Patient characteristics, health-care utilization, and costs were compared between stage A and each stage with complicated GERD (B-D). Of the 174,597 patients who were eligible for analysis, 74% were classified as stage A, 20% stage B, 1% stage C, 2% stage D, and 3% stage E. Relative to stage A, patients in stages C, D, and E were significantly more likely to visit a gastroenterologist (13% vs. 68%, 71%, and 38%, respectively) and had higher rates of esophageal ulcers (0.3% vs. 8%, 5%, and 3%, respectively) and Nissen fundoplication (0.05% vs. 0.6%, 0.3%, and 0.2%, respectively). Six-month GERD-related costs ranged from $615/patient (stage A) to $1714/patient (stage D); all-cause costs ranged from $4195/patient (stage A) to $11,340/patient (stage E). Compared with stage A, all other cohorts had significantly higher all-cause and GERD-related costs (P < 0.0001 for all comparisons). While patients with more severe GERD represented a relatively small portion of the GERD cohort, they demonstrated significantly greater health-care costs and overall utilization than patients with uncomplicated GERD.

Metabolic heterogeneity of obesity: role of adipose tissue.

Obesity is not synonymous with insulin resistance. Why some but not all individuals develop insulin resistance with weight excess is not clear, but a number of plausible hypotheses with ample support now exist. This article reviews regional fat distribution, inflammation, lipotoxicity/ectopic fat and impaired adipogenesis as leading theories as to why excess body weight has the potential to promote insulin resistance.

Novel approaches to incorporating pharmacoeconomic studies into phase III clinical trials for Alzheimer's disease.

The societal and individual costs of Alzheimer's disease are significant, worldwide. As the world ages, these costs are increasing rapidly, while health systems face finite budgets. As a result, many regulators and payers will require or at least consider phase III cost-effectiveness data (in addition to safety and efficacy data) for drug approval and reimbursement, increasing the risks and costs of drug development. Incorporating pharmacoeconomic studies in phase III clinical trials for Alzheimer's disease presents a number of challenges. We propose several specific suggestions to improve the design of pharmacoeconomic studies in phase III clinical trials. We propose that acute episodes of care are key outcome measures for pharmacoeconomic studies. To improve the possibility of detecting a pharmacoeconomic impact in phase III, we suggest several strategies including; study designs for enrichment of pharmacoeconomic outcomes that include co-morbidity of patients; reducing variability of care that can affect pharmacoeconomic outcomes through standardized care management; employing administrative claims data to better capture meaningful pharmacoeconomic data; and extending clinical trials in open label follow-up periods in which pharmacoeconomic data are captured electronically by administrative claims. Specific aspects of power analysis for pharmacoeconomic studies are presented. The particular pharmacoeconomic challenges caused by the use of biomarkers in clinical trials, the increasing use of multinational studies, and the pharmacoeconomic challenges presented by biologicals in development for Alzheimer's disease are discussed. In summary, since we are entering an era in which pharmacoeconomic studies will be essential in drug development for supporting regulatory approval, payor reimbursement and integration of new therapies into clinical care, we must consider the design and incorporation of pharmacoeconomic studies in phase III clinical trials more seriously and more creatively.

Assessment of potential measures in models of progression in Alzheimer disease.

BACKGROUND: In estimating the potential benefits of treatment, it is often necessary to extrapolate beyond clinical trial results using economic modeling. Previous attempts in Alzheimer disease (AD) were primarily based on the Mini-Mental State Examination (MMSE) due to its widespread use. These models were criticized as not accurately reflecting the total impact of the disease, providing untrustworthy estimates of treatment benefit. We compared 3 alternatives to the MMSE with respect to bridging between clinical outcomes needed for regulatory approval and economic and quality of life (QOL) outcomes important to reimbursement agencies. METHODS: The MMSE, Disability Assessment in Dementia (DAD) scale, Clinical Dementia Rating (CDR) scale, and Dependence Scale (DS) were compared in their ability to explain variation in cognitive, functional, and behavioral measures as well as economic and QOL outcomes using univariate (Pearson correlations) and multivariate (linear regression) analyses of data from research sites in the United States and Europe. RESULTS: Subjects with mild to moderate AD (n = 196; mean 75.9 years; 56% female) were evaluated. The DS, DAD, and CDR were moderately correlated with the MMSE (Pearson correlations, range 0.54-0.58) but performed better (higher adjusted R(2)) than the MMSE in explaining variations in subject behavior, QOL, and health status. The DS and DAD performed better in explaining variation in medical costs, caregiver QOL, and caregiver time. CONCLUSIONS: Measures of function (DAD) or dependence on others (DS), or global measures (CDR), appear to be better candidates than the MMSE for modeling AD progression.