Complex Traits Heritability is Highly Clustered in the eQTL Bipartite Network.

Single Nucleotide Polymorphisms (SNPs) associated with traits typically explain a small part of the trait genetic heritability-with the remainder thought to be distributed throughout the genome. Such SNPs are likely to alter expression levels of biologically relevant genes. Expression Quantitative Trait Locus (eQTL) networks analysis has helped to functionally characterize such variants. We systematically analyze the distribution of SNP heritability for ten traits across 29 tissue-specific eQTL networks. We find that heritability is clustered in a small number or tissue-specific, functionally relevant SNP-gene modules and that the greatest occurs in local "hubs" that are both the cornerstone of the network's modules and tissue-specific regulatory elements. The network structure could thus both amplify the genotype-phenotype connection and buffer the deleterious effect of the genetic variations on other traits. Together, these results define a conceptual framework for understanding complex trait architecture and identifying key mutations carrying most of the heritability.

Risk factors for incomplete telehealth appointments among patients with inflammatory bowel disease.

Background: The COVID-19 pandemic led to the urgent implementation of telehealth visits in inflammatory bowel disease (IBD) care; however, data assessing feasibility remain limited. Objectives: We looked to determine the completion rate of telehealth appointments for adults with IBD, as well as to evaluate demographic, clinical, and social predictors of incomplete appointments. Design: We conducted a retrospective analysis of all patients with IBD who had at least one scheduled telehealth visit at the NYU IBD Center between 1 March 2020 and 31 August 2021, with only the first scheduled telehealth appointment considered. Methods: Medical records were parsed for relevant covariables, and multivariable logistic regression was used to estimate the adjusted association between demographic factors and an incomplete telehealth appointment. Results: From 1 March 2020 to 31 August 2021, there were 2508 patients with IBD who had at least one telehealth appointment, with 1088 (43%) having Crohn's disease (CD), 1037 (41%) having ulcerative colitis (UC), and 383 (15%) having indeterminate colitis. Of the initial telehealth visits, 519 (21%) were not completed, including 435 (20%) among patients <60 years as compared to 84 (23%) among patients ⩾60 years (p = 0.22). After adjustment, patients with CD had higher odds of an incomplete appointment as compared to patients with UC [adjusted odds ratio (adjOR): 1.37, 95% confidence interval (CI): 1.10-1.69], as did females (adjOR: 1.26, 95% CI: 1.04-1.54), and patients who had a non-first-degree relative listed as an emergency contact (adjOR: 1.69, 95% CI: 1.16-2.44). While age ⩾60 years was not associated with appointment completion status, we did find that age >80 years was an independent predictor of missed telehealth appointments (adjOR: 2.92, 95% CI: 1.12-7.63) when compared to individuals aged 60-70 years. Conclusion: Patients with CD, females, and those with less social support were at higher risk for missed telehealth appointments, as were adults >80 years. Engaging older adults via telehealth, particularly those aged 60-80 years, may therefore provide an additional venue to complement in-person care.

Does Incident Cardiovascular Disease Lead to Greater Odds of Functional and Cognitive Impairment? Insights From the Health and Retirement Study.

BACKGROUND: Although studies to date have broadly shown that cardiovascular disease (CVD) increases cognitive and physical impairment risk, there is still limited understanding of the magnitude of this risk among relevant CVD subtypes or age cohorts. METHODS: We analyzed longitudinal data from 16 679 U.S. Health and Retirement Study participants who were aged ≥65 years at study entry. Primary endpoints were physical impairment (activities of daily living impairment) or cognitive impairment (Langa-Weir Classification of dementia). We compared these endpoints among participants who developed incident CVD versus those who were CVD free, both in the short term (<2-year postdiagnosis) and long term (>5 years), controlling for sociodemographic and health characteristics. We then analyzed the effects by CVD subtype (atrial fibrillation, congestive heart failure, ischemic heart disease, and stroke) and age-at-diagnosis (65-74, 75-84, and ≥85). RESULTS: Over a median follow-up of 10 years, 8 750 participants (52%) developed incident CVD. Incident CVD was associated with significantly higher adjusted odds (aOR) of short-term and long-term physical and cognitive impairment. The oldest (≥85) age-at-diagnosis subgroup had the highest risk of short-term physical (aOR 3.01, 95% confidence interval [CI]: 2.40-3.77) and cognitive impairment (aOR 1.96, 95% CI: 1.55-2.48), as well as long-term impairment. All CVD subtypes were associated with higher odds of physical and cognitive impairment, with the highest risk for patients with incident stroke. CONCLUSIONS: Incident CVD was associated with an increased risk of physical and cognitive impairment across CVD subtypes. Impairment risk after CVD was highest among the oldest patients (≥85 years) who should therefore remain a target for prevention efforts.

The RightSTEPS initiative: Continuing education impact on clinicians' optimal medical therapy practices for chronic heart failure.

PURPOSE: Despite the existence of expert recommendations that can improve morbidity and mortality, reduce the need for hospitalization or readmission, and enhance quality of life in patients with heart failure (HF), many patients do not receive optimal medical therapy (OMT). The goal of this initiative, titled RightSTEPS, was to help physicians take the right steps to apply-evidence-based HF management strategies in clinical practice. METHODS: Using the PRECEDE-PROCEED Model aimed at improving the clinical behavior of the learner, the instructional design featured 23 online and live face-to-face activities offering up to 16 credit hours of CME/CNE credit. These activities were delivered sequentially in three phases: predisposing, enabling and reinforcing. The lessons provided concise, pragmatic, stepwise management strategies aimed at empowering clinicians to prescribe evidence-based, guideline-directed OMT for patients with HF. RESULTS: The predisposing and reinforcing online activities within the initiative reached a total of 71,510 learners with 23,902 successfully completed activities and post-tests; the enabling face-to-face activities reached a total audience of 763 clinicians. This initiative resulted in a statistically significant (p < 0.0001) increase in knowledge and competence related to HF OMT among the clinician learners. Furthermore, follow-up surveys indicated a commitment from learners to implement these guideline-directed strategies in their clinical practice. CONCLUSIONS: This initiative demonstrated that the design of the RightSTEPS curriculum, using the Precede-Proceed model with sequentially-delivered, blended learning, provides a methodological framework to help learners translate knowledge into improvements in clinical behavior with the potential to improve patient health outcomes.

The Right (Way) to Represent: The Emotional Politics of Remembering Mass Rape in Germany After 1945.

A Woman in Berlin (1954) has undoubtedly shaped global understanding of wartime rape. The present article focuses on the diarist's use of humor to process her disorientation, assert her subjectivity, and build affective links with other victims. I consider how the diary's tone influenced its reception and thus how aesthetic analysis might illuminate the conditions under which stories about sexual violence become audible, as well as the ways in which the "cultural politics of emotion" (to quote the title of Sarah Ahmed's 2004 study) can both foster and obstruct human rights projects.

Anomalously Rapid Hydration Water Diffusion Dynamics Near DNA Surfaces.

The emerging Overhauser effect dynamic nuclear polarization (ODNP) technique measures the translational mobility of water within the vicinity (5-15 Å) of preselected sites. The work presented here expands the capabilities of the ODNP technique and illuminates an important, previously unseen, property of the translational diffusion dynamics of water at the surface of DNA duplexes. We attach nitroxide radicals (i.e., spin labels) to multiple phosphate backbone positions of DNA duplexes, allowing ODNP to measure the hydration dynamics at select positions along the DNA surface. With a novel approach to ODNP analysis, we isolate the contributions of water molecules at these sites that undergo free translational diffusion from water molecules that either loosely bind to or exchange protons with the DNA. The results reveal that a significant population of water in a localized volume adjacent to the DNA surface exhibits fast, bulk-like characteristics and moves unusually rapidly compared to water found in similar probe volumes near protein and membrane surfaces. Control studies show that the observation of these characteristics are upheld even when the DNA duplex is tethered to streptavidin or the mobility of the nitroxides is altered. This implies that, as compared to protein or lipid surfaces, it is an intrinsic feature of the DNA duplex surface that it interacts only weakly with a significant fraction of the surface hydration water network. The displacement of this translationally mobile water is energetically less costly than that of more strongly bound water by up to several kBT and thus can lower the activation barrier for interactions involving the DNA surface.

Determining the oligomeric structure of proteorhodopsin by Gd3+ -based pulsed dipolar spectroscopy of multiple distances.

The structural organization of the functionally relevant, hexameric oligomer of green-absorbing proteorhodopsin (G-PR) was obtained from double electron-electron resonance (DEER) spectroscopy utilizing conventional nitroxide spin labels and recently developed Gd3+ -based spin labels. G-PR with nitroxide or Gd3+ labels was prepared using cysteine mutations at residues Trp58 and Thr177. By combining reliable measurements of multiple interprotein distances in the G-PR hexamer with computer modeling, we obtained a structural model that agrees with the recent crystal structure of the homologous blue-absorbing PR (B-PR) hexamer. These DEER results provide specific distance information in a membrane-mimetic environment and across loop regions that are unresolved in the crystal structure. In addition, the X-band DEER measurements using nitroxide spin labels suffered from multispin effects that, at times, compromised the detection of next-nearest neighbor distances. Performing measurements at high magnetic fields with Gd3+ spin labels increased the sensitivity considerably and alleviated the difficulties caused by multispin interactions.

Structural insight into proteorhodopsin oligomers.

Oligomerization has important functional implications for many membrane proteins. However, obtaining structural insight into oligomeric assemblies is challenging, as they are large and resist crystallization. We focus on proteorhodopsin (PR), a protein with seven transmembrane α-helices that was found to assemble to hexamers in densely packed lipid membrane, or detergent-solubilized environments. Yet, the structural organization and the subunit interface of these PR oligomers were unknown. We used site-directed spin-labeling together with electron spin-resonance lineshape and Overhauser dynamic nuclear polarization analysis to construct a model for the specific orientation of PR subunits within the hexameric complex. We found intersubunit distances to average 16 Å between neighboring 55 residues and that residues 177 are >20 Å apart from each other. These distance constraints show that PR has a defined and radial orientation within a hexamer, with the 55-site of the A-B loop facing the hexamer core and the 177-site of the E-F loop facing the hexamer exterior. Dynamic nuclear polarization measurements of the local solvent dynamics complement the electron spin-resonance-based distance analysis, by resolving whether protein surfaces at positions 55, 58, and 177 are exposed to solvent, or covered by protein-protein or protein-detergent contacts.

Thermally-limited exciton delocalization in superradiant molecular aggregates.

We present two-dimensional Fourier transform optical spectroscopy measurements of two types of molecular J-aggregate thin films and show that temperature-dependent dynamical effects govern exciton delocalization at all temperatures, even in the presence of significant inhomogeneity. Our results indicate that in the tested molecular aggregates, even when the static structure disorder dominates exciton dephasing dynamics, the extent of exciton delocalization may be limited by dynamical fluctuations, mainly exciton-phonon coupling. Thus inhomogeneous dephasing may mediate the exciton coherence time whereas dynamical fluctuations mediate the exciton coherence length.

Invited article: The coherent optical laser beam recombination technique (COLBERT) spectrometer: coherent multidimensional spectroscopy made easier.

We have developed an efficient spectrometer capable of performing a wide variety of coherent multidimensional measurements at optical wavelengths. The two major components of the largely automated device are a spatial beam shaper which controls the beam geometry and a spatiotemporal pulse shaper which controls the temporal waveform of the femtosecond pulse in each beam. We describe how to construct, calibrate, and operate the device, and we discuss its limitations. We use the exciton states of a semiconductor nanostructure as a working example. A series of complex multidimensional spectra-displayed in amplitude and real parts-reveals increasingly intricate correlations among the excitons.

Pulsed electron spin resonance resolves the coordination site of Cu²(+) ions in α1-glycine receptor.

Herein, we identify the coordination environment of Cu²(+) in the human α1-glycine receptor (GlyR). GlyRs are members of the pentameric ligand-gated ion channel superfamily (pLGIC) that mediate fast signaling at synapses. Metal ions like Zn²(+) and Cu²(+) significantly modulate the activity of pLGICs, and metal ion coordination is essential for proper physiological postsynaptic inhibition by GlyR in vivo. Zn²(+) can either potentiate or inhibit GlyR activity depending on its concentration, while Cu²(+) is inhibitory. To better understand the molecular basis of the inhibitory effect we have used electron spin resonance to directly examine Cu²(+) coordination and stoichiometry. We show that Cu²(+) has one binding site per α1 subunit, and that five Cu²(+) can be coordinated per GlyR. Cu²(+) binds to E192 and H215 in each subunit of GlyR with a 40 µM apparent dissociation constant, consistent with earlier functional measurements. However, the coordination site does not include several residues of the agonist/antagonist binding site that were previously suggested to have roles in Cu²(+) coordination by functional measurements. Intriguingly, the E192/H215 site has been proposed as the potentiating Zn²(+) site. The opposing modulatory actions of these cations at a shared binding site highlight the sensitive allosteric nature of GlyR.

Consistent condom use is associated with lower prevalence of human papillomavirus infection in men.

INTRODUCTION: Reported associations between condom use and human papillomavirus (HPV) infection in men have been inconsistent. METHODS: We tested 463 men, ages 18-40 years, in 2 cities in the United States for 37 HPV types in samples from 5 anogenital sites. Men answered questionnaires regarding number of partners and frequency of condom use during vaginal sex in the past 3 months (5 categories, from "always" to "never"). Among 393 men who reported > or =1 female partner in the past 3 months, the proportions of men with HPV detected overall and at each anatomic site by frequency of condom use were calculated. Logistic regression was used to examine associations between frequency of condom use and HPV detection. Effect modification by number of recent partners (1 vs >1) was evaluated. RESULTS: The proportion of men positive for HPV ranged from 37.9% among men who reported they "always" used condoms to 53.9% among those who reported they "never" used condoms (P for trend = .008). Always using condoms (vs using them less frequently) was associated with lower odds of HPV detection (adjusted odds ratio, 0.50 [95% confidence interval, 0.30-0.83]). This association was stronger among men with >1 partner than among men with only 1 partner (P for interaction = .05). CONCLUSIONS: Consistent condom use was strongly associated with lower HPV prevalence in men.

Three-dimensional electronic spectroscopy of excitons in GaAs quantum wells.

We demonstrate three-dimensional (3D) electronic Fourier transform spectroscopy of GaAs quantum wells using four fully phase-coherent, noncollinear optical fields. Since the full complex signal field is measured as a function of all three time intervals, nearly every peak in the resulting 3D spectral solid arises from a distinguishable sequence of transitions represented by a single Feynman pathway. We use the 3D spectral peaks to separate two pathways involving weakly bound mixed biexcitons generated in different time orders. In the process, we reveal a peak that was previously obscured by a correlated but unbound exciton pair coherence. We also demonstrate a calibration procedure for the carrier frequency which yields biexciton binding energy values with high accuracy.

Exciton-exciton correlations revealed by two-quantum, two-dimensional fourier transform optical spectroscopy.

The Coulomb correlations between photoexcited charged particles in materials such as photosynthetic complexes, conjugated polymer systems, J-aggregates, and bulk or nanostructured semiconductors produce a hierarchy of collective electronic excitations, for example, excitons, and biexcitons, which may be harnessed for applications in quantum optics, light-harvesting, or quantum information technologies. These excitations represent correlations among successively greater numbers of electrons and holes, and their associated multiple-quantum coherences could reveal detailed information about complex many-body interactions and dynamics. However, unlike single-quantum coherences involving excitons, multiple-quantum coherences do not radiate; consequently, they have largely eluded direct observation and characterization. In this Account, we present a novel optical technique, two-quantum, two-dimensional Fourier transform optical spectroscopy (2Q 2D FTOPT), which allows direct observation of the dynamics of multiple exciton states that reflect the correlations of their constituent electrons and holes. The approach is based on closely analogous methods in NMR, in which multiple phase-coherent fields are used to drive successive transitions such that multiple-quantum coherences can be accessed and probed. In 2Q 2D FTOPT, a spatiotemporal femtosecond pulse-shaping technique has been used to overcome the challenge of control over multiple, noncollinear, phase-coherent optical fields in experimental geometries used to isolate selected signal contributions through wavevector matching. We present results from a prototype GaAs quantum well system, which reveal distinct coherences of biexcitons that are formed from two identical excitons or from two excitons that have holes in different spin sublevels ("heavy-hole" and "light-hole" excitons). The biexciton binding energies and dephasing dynamics are determined, and changes in the dephasing rates as a function of the excitation density are observed, revealing still higher order correlations due to exciton-biexciton interactions. Two-quantum coherences due to four-particle correlations that do not involve bound biexciton states but that influence the exciton properties are also observed and characterized. The 2Q 2D FTOPT technique allows many-body interactions that cannot be treated with a mean-field approximation to be studied in detail; the pulse-shaping approach simplifies greatly what would have otherwise been daunting measurements. This spectroscopic tool might soon offer insight into specific applications, for example, in detailing the interactions that affect how electronic energy moves within the strata of organic photovoltaic cells.

Two-quantum 2D FT electronic spectroscopy of biexcitons in GaAs quantum wells.

The motions of electrons in solids may be highly correlated by strong, long-range Coulomb interactions. Correlated electron-hole pairs (excitons) are accessed spectroscopically through their allowed single-quantum transitions, but higher-order correlations that may strongly influence electronic and optical properties have been far more elusive to study. Here we report direct observation of bound exciton pairs (biexcitons) that provide incisive signatures of four-body correlations among electrons and holes in gallium arsenide (GaAs) quantum wells. Four distinct, mutually coherent, ultrashort optical pulses were used to create coherent exciton states, transform these successively into coherent biexciton states and then new radiative exciton states, and finally to read out the radiated signals, yielding biexciton binding energies through a technique closely analogous to multiple-quantum two-dimensional Fourier transform (2D FT) nuclear magnetic resonance spectroscopy. A measured variation of the biexciton dephasing rate indicated still higher-order correlations.

Risk factors for incident herpes simplex type 2 virus infection among women attending a sexually transmitted disease clinic.

OBJECTIVES: To estimate the incidence of herpes simplex type 2 virus (HSV-2) infection, to identify risk factors for its acquisition, and to assess the protective effect of condoms. STUDY DESIGN: Prospective study of 293 HSV-2 seronegative women, aged 18 to 35 years, attending a sexually transmitted disease clinic in Alabama from 1992 to 1995. RESULTS: Incidence of HSV-2 infection was 20.5 per 100 woman-years [95% confidence interval (CI), 13.1-30.5]. Young women (18-20 years) had a significantly higher risk of incident HSV-2 infection [adjusted hazard ratio (HR), 2.8; 95% CI, 1.3-6.4] than older women. Women diagnosed with prevalent or incident bacterial vaginosis had a higher incidence of HSV-2 infection than those who were not so diagnosed (adjusted HR, 2.4; 95% CI, 1.1-5.6). No significant protective effect was observed for consistent (100%) condom use without breakage and slippage against HSV-2 acquisition (adjusted HR, 0.8; 95% CI, 0.2-2.3). CONCLUSION: Acquisition of HSV-2 infection among study participants was higher than previous estimates for adult female sexually transmitted disease clinic attendees, and no protective effect for condoms was demonstrated. The high incidence of HSV-2 infection with its potential for adverse health consequences emphasizes the need for better prevention strategies.

Testing for sexually transmitted diseases in U.S. Public health laboratories in 2004.

OBJECTIVE: Appropriate laboratory testing practices are a critical part of sexually transmitted disease (STD) control. GOAL: The goal of this study was to describe the type and volume of STD tests performed in public health laboratories in the United States in 2004. STUDY DESIGN: A web-based survey was made available to 144 members of the Association of Public Health Laboratories. RESULTS: One hundred fourteen laboratories responded (79%). Overall, 3,553,196 chlamydia tests and 3,461,151 gonorrhea tests were performed; 64.4% of chlamydia tests and 60.8% of gonorrhea tests were nucleic acid amplification tests. Ninety-four percent of laboratories performed syphilis testing. Few laboratories used type-specific tests for herpes simplex virus or used new tests for trichomoniasis, bacterial vaginosis, or human papillomavirus. CONCLUSIONS: This survey collected important data that can be used to monitor trends in STD testing practices in public health laboratories.

Prevalence of HPV infection among men: A systematic review of the literature.

BACKGROUND: Human papillomavirus (HPV) infection is estimated to be the most common sexually transmitted infection; an estimated 6.2 million persons are newly infected every year in the United States. There are limited data on HPV infection in heterosexual men. METHODS: We conducted a systematic review of the literature by searching MEDLINE using the terms "human papillomavirus," "HPV," "male," "seroprevalence," and "serology" to retrieve articles published from 1 January 1990 to 1 February 2006. We included studies that had data on population characteristics and that evaluated male genital anatomic sites or specimens for HPV DNA or included assessments of seropositivity to HPV type 6, 11, 16, or 18 in men. We excluded studies that had been conducted only in children or immunocompromised persons (HIV infected, transplant recipients, or elderly). RESULTS: We included a total of 40 publications on HPV DNA detection and risk factors for HPV in men; 27 evaluated multiple anatomic sites or specimens, 10 evaluated a single site or specimen, and 3 evaluated risk factors or optimal anatomic sites/specimens for HPV detection. Twelve studies assessed site- or specimen-specific HPV DNA detection. HPV prevalence in men was 1.3%-72.9% in studies in which multiple anatomic sites or specimens were evaluated; 15 (56%) of these studies reported > or =20% HPV prevalence. HPV prevalence varied on the basis of sampling, processing methods, and the anatomic site(s) or specimen(s) sampled. We included 15 publications reporting HPV seroprevalence. Rates of seropositivity depended on the population, HPV type, and methods used. In 9 studies that evaluated both men and women, all but 1 demonstrated that HPV seroprevalence was lower in men than in women. CONCLUSION: HPV infection is highly prevalent in sexually active men and can be detected by use of a variety of specimens and methods. There have been few natural-history studies and no transmission studies of HPV in men. The information that we have reviewed may be useful for future natural-history studies and for modeling the potential impact of a prophylactic HPV vaccine.