Relationship Among Clinically Obtained Biomarkers of Inflammation, Hypercoagulability, and Macrophage Activation, and Delirium in Critically Ill Patients With COVID-19.

Critically ill patients with COVID-19 experience high rates of delirium and coma. Whether delirium occurs through novel mechanisms in COVID-19 is not known. We analyzed the relationship among biomarkers of inflammation (C-reactive protein [CRP]), hypercoagulability (d-dimer), and lung macrophage activation (ferritin), and the primary composite outcome of delirium/coma next day. We also measured associations between biomarkers and next day delirium and coma independently, and delirium severity. DESIGN: Retrospective, observational cohort study. SETTING: ICUs at two large, urban, academic referral hospitals. PATIENTS: All consecutive adult patients admitted to the ICU from March 1, 2020, to June 7, 2020, with COVID-19 with clinical biomarkers and delirium assessments performed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Daily concentrations of CRP, d-dimer, and ferritin were obtained. Coma (assessed by Richmond Agitation-Sedation Scale) and delirium (assessed by Confusion Assessment Method for the ICU/Confusion Assessment Method for the ICU-7) were measured bid. A cohort of 197 ICU patients with COVID-19 were included. Higher d-dimer (odds ratio [OR], 1.57; 95% CI, 1.17-2.12; p < 0.01) and ferritin quartiles (OR, 1.36; 95% CI, 1.02-1.81; p < 0.01) were associated with greater odds of the composite outcome of delirium/coma next day. d-dimer was associated with greater odds of next day delirium (OR, 1.49; 95% CI, 1.14-1.94; p < 0.01) and coma independently (OR, 1.52; 95% CI, 1.08-2.14; p = 0.017). Higher ferritin quartiles were associated with greater odds of next day delirium (OR, 1.33; 95% CI, 1.04-1.70; p = 0.026) and coma independently (OR, 1.59; 95% CI, 1.14-2.23; p < 0.01). Higher CRP quartiles were associated with coma (OR, 1.36; 95% CI, 1.03-1.79; p = 0.030) and delirium severity the next day (ß = 0.30; se, 0.07; p ≤ 0.01). CONCLUSIONS: Our hypothesis-generating study found d-dimer and ferritin were associated with delirium/coma the following day, as well as delirium and coma independently. CRP was associated with next day coma and delirium severity. Larger studies to validate these results are needed.

The social construction of illness: key insights and policy implications.

The social construction of illness is a major research perspective in medical sociology. This article traces the roots of this perspective and presents three overarching constructionist findings. First, some illnesses are particularly embedded with cultural meaning--which is not directly derived from the nature of the condition--that shapes how society responds to those afflicted and influences the experience of that illness. Second, all illnesses are socially constructed at the experiential level, based on how individuals come to understand and live with their illness. Third, medical knowledge about illness and disease is not necessarily given by nature but is constructed and developed by claims-makers and interested parties. We address central policy implications of each of these findings and discuss fruitful directions for policy-relevant research in a social constructionist tradition. Social constructionism provides an important counterpoint to medicine's largely deterministic approaches to disease and illness, and it can help us broaden policy deliberations and decisions.

The culture of academic medicine: faculty perceptions of the lack of alignment between individual and institutional values.

BACKGROUND: Energized, talented faculty are essential to achieving the missions of academic medical centers (AMCs) in education, research and health care. The alignment of individuals' values with workplace experiences are linked to meaningfulness of work and productivity. OBJECTIVE: To determine faculty values and their alignment with institutional values. DESIGN: A qualitative hypothesis-generating interview study to understand the professional experiences of faculty and organizational approach in five AMCs that were nationally representative in regional and organizational characteristics. Analysis was inductive and data driven. PARTICIPANTS: Using stratified, purposeful sampling, we interviewed 96 male and female faculty at different career stages (early career, plateaued, senior faculty and those who had left academic medicine) and diverse specialties (generalists, medical and surgical subspecialists, and research scientists). APPROACH: Dominant themes that emerged from the data. RESULTS: Faculty described values relating to excellence in clinical care, community service (including care for the underserved and disadvantaged), teaching, intellectual rigor/freedom and discovery, all values that mirror the stated missions of AMCs. However, many faculty also described behaviors that led them to conclude that their AMCs, in practice, undervalued excellence in clinical care, and their social and educational missions. Themes were seen across gender, career stage, race and discipline, except that female leaders appeared more likely than male leaders to identify incongruence of individual values and organizational practices. CONCLUSIONS: In this study of five diverse medical schools, faculty values were well aligned with stated institutional missions; however, many perceived that institutional behaviors were not always aligned with individual faculty values.

From Lydia Pinkham to Queen Levitra: direct-to-consumer advertising and medicalisation.

The medicalisation of life problems has been occurring for well over a century and has increased over the past 30 years, with the engines of medicalisation shifting to biotechnology, managed care, and consumers. This paper examines one strand of medicalisation during the last century: direct-to-consumer advertising (DTCA) of pharmaceuticals. In particular, it examines the roles that physicians and the Food and Drug Administration (FDA) have played in regulating DTCA in the US. Two advertising exemplars, the late 19(th) century Lydia E. Pinkham's Vegetable Compound (for 'women's complaints') and contemporary Levitra (for erectile dysfunction) are used to examine the parallels between the patent medicine era and the DTCA era. DTCA re-establishes the direct and independent relationship between drug companies and consumers that existed in the late 19(th) century, encouraging self-diagnosis and requests for specific drugs. The extravagant claims of Lydia Pinkham's day are constrained by laws, but modern-day advertising is more subtle and sophisticated. DTCA has facilitated the impact of the pharmaceutical industry and consumers in becoming more important forces in medicalisation.

Light controllable siRNAs regulate gene suppression and phenotypes in cells.

Small interfering RNA (siRNA) is widely recognized as a powerful tool for targeted gene silencing. However, siRNA gene silencing occurs during transfection, limiting its use is in kinetic studies, deciphering toxic and off-target effects and phenotypic assays requiring temporal, and/or spatial regulation. We developed a novel controllable siRNA (csiRNA) that is activated by light. A single photo removable group is coupled during oligonucleotide synthesis to the 5' end of the antisense strand of the siRNA, which blocks the siRNA's activity. A low dose of light activates the siRNA, independent of transfection resulting in knock down of specific target mRNAs and proteins (GAPDH, p53, survivin, hNuf2) without stimulating non-specific effects such as regulated protein kinase PKR and induction of the interferon response. We demonstrate survivin and hNuf2 csiRNAs temporally knockdown their mRNAs causing multinucleation and cell death by mitotic arrest, respectively. Furthermore, we demonstrate a dose-dependent light regulation of hNuf2 csiRNA activity and resulting phenotype. The light controllable siRNAs are introduced into cells using commercially available reagents including the MPG peptide based delivery system. The csiRNAs are comparable to standard siRNAs in their transfection efficiency and potency of gene silencing. This technology should be of interest for phenotypic assays such as cell survival, cell cycle regulation, and cell development.

Caged substrates applied to high content screening: an introduction with an eye to the future.

The use of photoremovable protecting groups in biology affords the end user high temporal, spatial, and concentration control of reagents and substrates. High content screening and other large-scale biology applications would benefit greatly from these advantages. Herein, we report progress in this field by highlighting the recent development of controllable siRNA (csiRNA), which is a dormant siRNA that can be activated using 365 nm light. Two different experimental designs are described to highlight the temporal and concentration variables that can be controlled. First, the RNAi process is activated at two timepoints, 24- and 48-h post-transfection, to demonstrate that the action of csiRNA does not begin until activated. Second, increasing light dosage exposure to cells transfected with csiRNA that controls the concentration of active siRNA molecules. All experiments are conducted in a 96-well format with light delivered through the UCOM device.

Trends in the use of psychotropic medications among adolescents, 1994 to 2001.

OBJECTIVES: Few psychotropic medications are approved for use among children younger than 18 years. Yet previous studies have shown an increase in the use of psychotropic medications among school-age children and adolescents. Most previous studies examined data only up to 1997; therefore, the results predate any impact of changing federal policies and newly marketed medications. This study examined trends in the prescription of psychotropic medications to adolescents aged 14 to 18 years in office-based care in the United States from 1994 to 2001. METHODS: Data from the National Ambulatory Medical Care Survey (NAMCS) were used to determine visit rates and prescribing patterns from 1994 to 2001 for psychotropics that were prescribed in office-based treatment settings to adolescents aged 14 to 18 years. Rates of visits that resulted in a prescription for psychotropic medication were calculated for two-year periods. Analyses were conducted by type of medication, gender, and the prescribing physician's specialty. RESULTS: Rates of visits that resulted in a psychotropic prescription increased from 3.4 percent in 1994-1995 to 8.3 percent in 2000-2001. These trends were evident for males and females. The average annual growth rates for psychotropic prescriptions were much higher after 1999. Trends were also significant across drug classes. By 2001, one out of ten office visits by adolescent males resulted in a prescription for a psychotropic medication. CONCLUSIONS: Average annual growth rates for the prescription of psychotropics to adolescents increased from 1994 to 2001, with especially rapid acceleration after 1999. This increase may be associated with changing thresholds of diagnosis and treatment, availability of new medications, and changes in federal regulatory policies concerning promotion of medications by the pharmaceutical industry.

Illness and the Internet: From Private to Public Experience.

Illness is a ubiquitous experience in all societies. Until the past two decades, illness remained largely a private experience. With the development of the Internet, especially what has been termed Web 2.0, with interactive websites, illness has become increasingly a public experience. Vehicles like bulletin boards, chat rooms, listservs, electronic support groups, and more recently social media facilitate thousands of online communities where individuals with illness share information, interaction, experience, and advocacy. With the advent of social media, communication has increased and brought new challenges for online interaction. It is likely that the transformation of illness from a largely private to an increasingly public experience is a revolutionary change that is here to stay, with numerous social consequences.

The shifting engines of medicalization.

Social scientists and other analysts have written about medicalization since at least the 1970s. Most of these studies depict the medical profession, interprofessional or organizational contests, or social movements and interest groups as the prime movers toward medicalization. This article contends that changes in medicine in the past two decades are altering the medicalization process. Using several case examples, I argue that three major changes in medical knowledge and organization have engendered an important shift in the engines that drive medicalization: biotechnology (especially the pharmaceutical industry and genetics), consumers, and managed care. Doctors are still gatekeepers for medical treatment, but their role has become more subordinate in the expansion or contraction of medicalization. Medicalization is now more driven by commercial and market interests than by professional claims-makers. The definitional center of medicalization remains constant, but the availability of new pharmaceutical and potential genetic treatments are increasingly drivers for new medical categories. This requires a shift in the sociological focus examining medicalization for the twenty-first century.

A photoactivated diazopyruvoyl cross-linking agent for bonding tissue containing type-I collagen.

On the basis of the earlier examples of diazopyruvoyl (DAP) groups reported by Lawton for covalent binding and cross-linking of proteins and oligopeptides and our recent demonstration that a coumaryl diazopyruvamide was used to label Type-I collagen, we have extended our investigations to the synthesis and cross-linking capabilities of a bis-DAP polyethylene glycol to cross-link Type-I collagen. The new photoactivated cross-linking agent, N,N'-bis(3-diazopyruvoyl)-2,2'-(ethylenedioxy)bis(ethylamine) (DPD, 2), has been designed and synthesized specifically to "weld" collagenous tissues by cross-linking Type-I collagen. A working model for the photochemical welding studies of collagenous tissues was developed using gelatin strips (gel strips) composed of denatured Type-I collagen. Gel strips are transparent to near-UV and visible light, uniform in thickness, and have reproducible composition. Furthermore, the availability of nucleophilic amine sites in gel strips was demonstrated by reaction with o-phthalaldehyde, producing a fluorescent derivative of the protein. Gel strips were coated with a solution of DPD in chloroform 7 irradiated at 320-390 nm, and the resulting bonded gel strips were tested for the strength of the weld. The welds were generally brittle and had average tensile strengths that exceeded 100 N/cm2. Welds were not formed in the absence of light or DPD. Scanning electron microscopy studies revealed a pockmarked surface from severed welds. Welds of rabbit Achilles tendon were also obtained using the tethered diazopyruvamide. These welds were much weaker, having an average tensile strength of 11.95 N/cm2 for DPD-2,2'-ethylenedioxy(bis)ethylamine comonomers in the cross-linking reaction. In both studies the welds obtained by this method were significantly stronger than the controls.

Medicalization, markets and consumers.

This paper examines the impact of changes in the medical marketplace on medicalization in U.S. society. Using four cases (Viagra, Paxil, human growth hormone and in vitro fertilization), we focus on two aspects of the changing medical marketplace: the role of direct-to-consumer advertising of prescription drugs and the emergence of private medical markets. We demonstrate how consumers and pharmaceutical corporations contribute to medicalization, with physicians, insurance coverage, and changes in regulatory practices playing facilitating roles. In some cases, insurers attempt to counteract medicalization by restricting access. We distinguish mediated and private medical markets, each characterized by differing relationships with corporations, insurers, consumers, and physicians. In the changing medical environment, with medical markets as intervening factors, corporations and insurers are becoming more significant determinants in the medicalization process.

The impending globalization of ADHD: notes on the expansion and growth of a medicalized disorder.

Attention Deficit Hyperactivity Disorder (ADHD) has been medicalized in the United States since the 1960s. Primarily used in North America until the 1990s, ADHD diagnosis and treatment have increasingly been applied internationally. After documenting the expansion of ADHD in a global context, this paper presents five brief international examples examining ADHD usage and expansion: the United Kingdom, Germany, France, Italy and Brazil. We then identify and describe several vehicles that facilitate the migration of the ADHD diagnosis: the transnational pharmaceutical industry; the influence of western psychiatry; moving from ICD to DSM diagnostic criteria; the role of the Internet including the related advent of easily accessible online screening checklists; and advocacy groups. Finally, we discuss what this globalization of a diagnosis reflects about the potential global medicalization of other conditions.

p-Hydroxyphenacyl photoremovable protecting groups - Robust photochemistry despite substituent diversity.

A broadly based investigation of the effects of a diverse array of substituents on the photochemical rearrangement of p-hydroxyphenacyl esters has demonstrated that common substituents such as F, MeO, CN, CO2R, CONH2, and CH3 have little effect on the rate and quantum efficiencies for the photo-Favorskii rearrangement and the release of the acid leaving group or on the lifetimes of the reactive triplet state. A decrease in the quantum yields across all substituents was observed for the release and rearrangement when the photolyses were carried out in buffered aqueous media at pHs that exceeded the ground-state pKa of the chromophore where the conjugate base is the predominant form. Otherwise, substituents have only a very modest effect on the photoreaction of these robust chromophores.

Estimating the costs of medicalization.

Medicalization is the process by which non-medical problems become defined and treated as medical problems, usually as illnesses or disorders. There has been growing concern with the possibility that medicalization is driving increased health care costs. In this paper we estimate the medical spending in the U.S. of identified medicalized conditions at approximately $77 billion in 2005, 3.9% of total domestic expenditures on health care. This estimate is based on the direct costs associated with twelve medicalized conditions. Although due to data limitations this estimate does not include all medicalized conditions, it can inform future debates about health care spending and medicalization.

Hierarchy as a barrier to advancement for women in academic medicine.

BACKGROUND: Research on barriers to professional advancement for women in academic medicine has not adequately considered the role of environmental factors and how the structure of organizations affects professional advancement and work experiences. This article examines the impact of the hierarchy, including both the organization's hierarchical structure and professionals' perceptions of this structure, in medical school organization on faculty members' experience and advancement in academic medicine. METHODS: As part of an inductive qualitative study of faculty in five disparate U.S. medical schools, we interviewed 96 medical faculty at different career stages and in diverse specialties, using in-depth semistructured interviews, about their perceptions about and experiences in academic medicine. Data were coded and analysis was conducted in the grounded theory tradition. RESULTS: Our respondents saw the hierarchy of chairs, based on the indeterminate tenure of department chairs, as a central characteristic of the structure of academic medicine. Many faculty saw this hierarchy as affecting inclusion, reducing transparency in decision making, and impeding advancement. Indeterminate chair terms lessen turnover and may create a bottleneck for advancement. Both men and women faculty perceived this hierarchy, but women saw it as more consequential. CONCLUSIONS: The hierarchical structure of academic medicine has a significant impact on faculty work experiences, including advancement, especially for women. We suggest that medical schools consider alternative models of leadership and managerial styles, including fixed terms for chairs with a greater emphasis on inclusion. This is a structural reform that could increase opportunities for advancement especially for women in academic medicine.