The HIV testing experiences of adolescents in Ndola, Zambia: do families and friends matter?

This study explored how adolescents involve their families, friends and sex partners when making decisions about seeking HIV voluntary counseling and testing (VCT) and disclosing their HIV-status. The study is based on 40 qualitative in-depth interviews with 16 to 19 year olds who knew their HIV status in Ndola, Zambia. The findings show that: a) almost half of the youth turned to family members for advice or approval prior to seeking VCT; b) a disapproving reaction from family members or friends often discouraged youth from attending VCTuntil they found someone supportive; c) informants often attended VCTalone or with a friend, but rarely with a family member; and d) disclosure was common to family and friends, infrequent to sex partners, and not linked to accessing care and support services. Family members need access to information on VCT so they can support young peoples' decisions to test for HIV and to disclose their HIV status. These results reinforce the need to provide confidential VCT services for adolescents and the need to develop and test innovative strategies to reach adolescents, their families and sex partners with VCT information and services.     

Sleep–wake regulation and hypocretin–melatonin interaction in zebrafish

In mammals, hypocretin/orexin (HCRT) neuropeptides are important sleep–wake regulators and HCRT deficiency causes narcolepsy. In addition to fragmented wakefulness, narcoleptic mammals also display sleep fragmentation, a less understood phenotype recapitulated in the zebrafish HCRT receptor mutant (hcrtr−/−). We therefore used zebrafish to study the potential mediators of HCRT-mediated sleep consolidation. Similar to mammals, zebrafish HCRT neurons express vesicular glutamate transporters indicating conservation of the excitatory phenotype. Visualization of the entire HCRT circuit in zebrafish stably expressing hcrt:EGFP revealed parallels with established mammalian HCRT neuroanatomy, including projections to the pineal gland, where hcrtr mRNA is expressed. As pineal-produced melatonin is a major sleep-inducing hormone in zebrafish, we further studied how the HCRT and melatonin systems interact functionally. mRNA level of arylalkylamine-N-acetyltransferase (AANAT2), a key enzyme of melatonin synthesis, is reduced in hcrtr−/− pineal gland during the night. Moreover, HCRT perfusion of cultured zebrafish pineal glands induces melatonin release. Together these data indicate that HCRT can modulate melatonin production at night. Furthermore, hcrtr−/− fish are hypersensitive to melatonin, but not other hypnotic compounds. Subthreshold doses of melatonin increased the amount of sleep and consolidated sleep in hcrtr−/− fish, but not in the wild-type siblings. These results demonstrate the existence of a functional HCRT neurons-pineal gland circuit able to modulate melatonin production and sleep consolidation.     

Risky Sex and HIV Acquisition Among HIV Serodiscordant Couples in Zambia, 2002–2012: What Does Alcohol Have To Do With It?

In this paper we evaluate the effects of heavy alcohol consumption on sexual behavior, HIV acquisition, and antiretroviral treatment (ART) initiation in a longitudinal open cohort of 1929 serodiscordant couples in Lusaka, Zambia from 2002 to 2012. We evaluated factors associated with baseline heavy alcohol consumption and its association with condomless sex with the study partner, sex outside of the partnership, and ART initiation using multivariable logistic regression. We estimated the effect of alcohol consumption on HIV acquisition using multivariable Cox models. Baseline factors significantly associated with women’s heavy drinking (drunk weekly or more in 12-months before enrollment) included woman’s older age (adjusted prevalence odds ratio [aPOR] = 1.04), partner heavy drinking (aPOR = 3.93), and being HIV-infected (aPOR = 2.03). Heavy drinking among men was associated with less age disparity with partner (aPOR per year disparity = 0.97) and partner heavy drinking (aPOR = 1.63). Men’s being drunk daily (aOR = 1.18), women’s being drunk less than monthly (aOR = 1.39) vs. never drunk and being in a male HIV-negative and female HIV-positive union (aOR = 1.45) were associated with condomless sex. Heavy alcohol use was associated with having 1 or more outside sex partners among men (aOR drunk daily = 1.91, drunk weekly = 1.32, drunk monthly = 2.03 vs. never), and women (aOR drunk monthly = 2.75 vs. never). Being drunk weekly or more increased men’s risk of HIV acquisition (adjusted hazard ratio [aHR] = 1.72). Men and women being drunk weekly or more was associated (p < 0.1) with women’s seroconversion (aHR = 1.42 and aHR = 3.71 respectively). HIV-positive women who were drunk monthly or more had lower odds of initiating ART (aOR = 0.83; 95% CI = 0.70–0.99) adjusting for age, months since baseline and previous pregnancies. Individuals in HIV-serodiscordant couples who reported heavy drinking had more outside sex partnerships and condomless sex with their study partner and were more likely to acquire HIV. HIV-positive women had lower odds of initiating ART if they were heavy drinkers.     

Thrombomodulin and GFC levels in Legg–Calve–Perthes disease

Abstract

Legg–Calve–Perthes disease (LCPD) is a self-limited microvascular disorder leading to the occlusion of the femoral blood supply, which results in bone necrosis. Endothelial injury and hemostatic alterations may play a role in the microvascular compromise and decreased blood flow, which occur during the course of LCPD. Global fibrinolytic capacity (GFC) is a novel assay reflecting the overall fibrinolysis response resulting from the dynamic interactions of numerous stimulatory and inhibitory fibrinolytic molecules. Circulating soluble thrombomodulin (TM) reflects endothelial activation and/or injury. It is a cofactor in the clinically important protein C natural anticoagulant system. Beyond the coagulation pathway it is shown to have effects on biological events, especially inflammation. The aim of this study was to determine GFC and TM levels in LCPD patients. The study included 77 children in two groups. Group I consisted of 42 patients with LCPD and Group II (control) comprised 35 healthy children. Median (interquartile ratios) GFC and TM levels were significantly higher in the LCPD patients (Group I) (p<0·0001 and p=0·049, respectively). Circulating high levels of soluble TM may be associated with ongoing endothelial injury or ongoing inflammation during the disease course. Along with increased overall fibrinolytic response, increased TM may be a compensatory reaction to thrombosis. Further investigations are needed to elucidate the endothelial, anticoagulant, and fibrinolytic kinetics associated with the microvascular compromise and self-limiting nature of LCPD.     

Opportunistic Infections and Other AIDS-defining Illnesses in Poland in 2000–2002

Abstract Background: The introduction of highly active antiretroviral therapy (HAART) led to a decreased incidence of the most severe opportunistic infections (OIs) in HIV-infected patients. In Poland, HAART became widely used in 1998. Materials and Methods: This study was based on data from medical records data collected in the years 2000–2002 from medical centers for HIV-infected patients in Poland. The aim of the study was to determine the incidence of opportunistic infections (OIs) and other AIDS defining illnesses (ADIs). The χ² test was used to determine any significant trends. Results: The incidence of ADIs was 6.8, 6.5 and 4.8/100 persons/year in 2000–2002, respectively. The most common diagnosed OIs were: fungal infections, tuberculosis, recurrent pneumonia, PCP and toxoplasmosis. In patients receiving HAART (HAART+) the incidence of ADIs was significantly lower than in non-ARV-treated as well as in all HIV+ (p < 0.02, p < 0.001, p < 0.001, respectively). A significant decrease in the incidence of ADIs in HAART+ patients between 2000 and 2002 (p < 0.0001) was observed. From 25% to 30% of ADIs among HAART+ patients were diagnosed within the first 3 months of antiretroviral therapy. In HAART+ patients the most common ADIs were fungal infections and tuberculosis. The diagnosis of ADIs resulted in the recognition of HIV status in 8.7–8.9% of patients. Conclusions: Five years after the introduction of HAART the incidence of ADIs had declined. Fungal infections and tuberculosis were the most common OIs in HIV+ patients in Poland.     

Intimate Partner Violence (IPV) and Associated Factors in HPTN 071 (PopART) Study Communities in Zambia and South Africa—A Comparison by HIV Status

AIDS and Behavior - The HPTN 071(PopART) study was a community-randomised trial in Zambia and South Africa, examining the impact of combination-prevention including universal testing and treatment...     

Patient–Provider and Patient–Staff Racial Concordance and Perceptions of Mistreatment in the Health Care Setting

Objectives To determine what roles patient–provider and patient–staff racial concordance play on patients’ perceptions within the health care setting. Design, Setting, Participants Data from the Commonwealth Fund 2001 Quality of Care telephone survey. Analysis focused on the subsample of 6,066 adults who live in the continental United States and who reported having a regular provider or a usual source of care (n = 4,762). Measurements and Results We analyzed patients’ responses about perceptions of disrespect, unfair treatment because of race and language, and the belief that he/she would have received better treatment if he/she belonged to a different race. We compared these perceptions of mistreatment with provider and staff racial concordance, controlling for sociodemographic variables. Contrary to our hypothesis, Hispanics were more likely to report being treated with disrespect if in a concordant relationship with their provider than if in a nonconcordant one (odds ratio [OR] 2.42, P < .01). Asians were less likely to report being treated unfairly because of race if in racially concordant relationships with providers than if in nonconcordant ones (P < .05). Hispanics were also less likely to perceive unfair treatment because of language when in concordant relationships with staff as compared to nonconcordant relationships with staff (P < .05). Conclusions Patients’ perceptions of health care relationships may partially depend on racial concordance with providers and staff. The nature of the association between racial concordance and perceived disrespect varies by racial group, indicating that other race-specific factors may also need to be examined. The topics discussed in this paper were presented as an abstract at a conference for the Society of Academic Emergency Medicine, May 2006.     

Ageing and person–environment fit in different urban neighbourhoods

Based on the complementary-congruence model of person–environment fit, this study focuses on housing in old age as an interaction between housing needs and housing conditions in urban settings. The research aims are (1) to establish a set of housing-related person–environment (p–e) fit indices based on the relationship between environmental needs and existing conditions in different physical and social domains, and to describe housing among elders aged 51–80 years and in different urban districts with these indices; the study distinguishes between basic, higher-order and social needs relating to housing; (2) to explain outdoor place attachment as an indicator for quality of life in different urban districts with a set of predictors including these person–environment fit indices. Data were drawn from telephone-based interviews with 365 older adults (51–80 years) who were questioned about individual housing needs and housing conditions. Results revealed higher p–e fit scores in the domains of higher-order and social housing needs and conditions in the districts which were considered to be more pleasant but had poor access to the city and to public transportation. By contrast, age was more important in explaining differences in the domain of basic housing needs and conditions with higher p–e fit scores among older participants. In explaining outdoor place attachment, the fit between basic and social housing needs and conditions was important, but the higher-order fit did not play a role.     

Assessment and risk analysis of casing and cement impairment in oil and gas wells in Pennsylvania, 2000–2012

Casing and cement impairment in oil and gas wells can lead to methane migration into the atmosphere and/or into underground sources of drinking water. An analysis of 75,505 compliance reports for 41,381 conventional and unconventional oil and gas wells in Pennsylvania drilled from January 1, 2000–December 31, 2012, was performed with the objective of determining complete and accurate statistics of casing and cement impairment. Statewide data show a sixfold higher incidence of cement and/or casing issues for shale gas wells relative to conventional wells. The Cox proportional hazards model was used to estimate risk of impairment based on existing data. The model identified both temporal and geographic differences in risk. For post-2009 drilled wells, risk of a cement/casing impairment is 1.57-fold [95% confidence interval (CI) (1.45, 1.67); P < 0.0001] higher in an unconventional gas well relative to a conventional well drilled within the same time period. Temporal differences between well types were also observed and may reflect more thorough inspections and greater emphasis on finding well leaks, more detailed note taking in the available inspection reports, or real changes in rates of structural integrity loss due to rushed development or other unknown factors. Unconventional gas wells in northeastern (NE) Pennsylvania are at a 2.7-fold higher risk relative to the conventional wells in the same area. The predicted cumulative risk for all wells (unconventional and conventional) in the NE region is 8.5-fold [95% CI (7.16, 10.18); P < 0.0001] greater than that of wells drilled in the rest of the state.Oil and natural gas production has increased substantially in the United States in recent years, predominantly due to innovations such as high-volume hydraulic fracturing and directional drilling in shale formations (1). Concurrent with this increase, concerns have mounted regarding effects of this oil and gas development process on groundwater quality, human health, public safety, and the climate, due, in part, to subsurface migration of methane and other associated hydrocarbon gases and volatile organic compounds. Economic development of gas and oil from shale formations requires a high well density, at least one well per 80 surface acres, over large continuous areas of a play. Osborn et al. (2) and Jackson et al. (3) identified a positive relationship between the concentration of thermogenic methane in private water wells in Pennsylvania and the proximity of those water wells to the nearest unconventional (i.e., Marcellus shale) gas production well. These studies also identified three possible mechanisms for explaining this relationship, and concluded that the most likely of these is subsurface migration from leaking gas wells. Other researchers have observed thermogenic and other subsurface-sourced methane in atmospheric concentrations high above background levels near conventional and unconventional gas development (4–6), suggesting that leaking wells may also contribute to fugitive methane and other associated gas emissions, with clear climatic and air quality consequences (7).Leaking oil and gas wells have long been recognized as a potential mechanism of subsurface migration of thermogenic and biogenic methane, as well as heavier n-alkanes, to the surface (7–11). A leaking well, in this context, is one in which zonal isolation along the wellbore is compromised due to a structural integrity failure of one or more of the cement and/or casing barriers. Such loss of integrity can lead to direct emissions to the atmosphere through one or more leaking annuli and/or subsurface migration of fluids (gas and/or liquid) to groundwater, surface waters, or the atmosphere. Cement barriers may fail at any time over the life of a well for a number of reasons, including hydrostatic imbalances caused by inappropriate cement density, inadequately cleaned bore holes, premature gelation of the cement, excessive fluid loss in the cement, high permeability in the cement slurry, cement shrinkage, radial cracking due to pressure fluctuations in the casings, poor interfacial bonding, and normal deterioration with age (12). Casing may fail due to failed casing joints, casing collapse, and corrosion (13). Loss of zonal isolation creates pressure differentials between the formations intersected by the wellbore and the open barrier(s). The pressure gradient thus created allows for the flow of gases or other formation fluids between geological zones (i.e., interzonal migration) and possibly to the surface (14–16), where it might manifest as sustained casing pressure (SCP) or sustained casing vent flow.Annuli are often vented, as noted in inspection records, and may contribute to fugitive emissions from the well site. Low-pressure leaks may continue to be periodically bled off and monitored, although recent studies warn that bleeding pressure to zero may actually lead to gas migration (17). High-risk (e.g., rapid repressuring of the annulus following bleed down) leaks must be structurally remedied (i.e., cement squeeze, gel squeeze, use of packers, topping off cement). State regulations (Pennsylvania code 25 §78.86) mandate that wells with leaks that cannot be vented or adequately repaired be permanently plugged, which may reduce but not eliminate the interzonal flow of gases and liquids. Leaks that continue undetected or inadequately remedied may lead to the contamination of shallow aquifers, accumulation of explosive gases within and around residences and other structures, and emission of methane and other associated gases to the atmosphere.Although not every instance of loss of zonal isolation will lead to such events, the incidence rate of cement/casing impairments and failures can provide some insight into the scale of current and future problems. However, the structural integrity failure rate of oil and gas well barriers continues to be a subject of debate. The rates most commonly cited (from 2 to >50%) are based upon industry reporting for offshore wells in the Gulf of Mexico (13, 14) and Canadian onshore (mostly conventional) wells (16). Watson and Bachu (16) note that wells drilled during periods of rapid development activity and/or wellbores deviated from vertical (e.g., horizontal wellbores) may be more prone to casing vent flow and/or gas migration away from the wellhead.Due to the lack of publicly available structural integrity monitoring records for onshore wells from industry, more recent studies have used data from state well inspection records to estimate the proportion of unconventional wells drilled that develop cement and/or casing structural integrity issues. For instance, Considine et al. (18) analyzed Pennsylvania Department of Environmental Protection (PADEP) notice of violation (NOV) records for 2008–2011 and found that between 1% and 2% of wells had one or more potential structural integrity issues during that time period. Vidic et al. (19), using the 2008–2013 data from the PADEP database, found that 3.4% of all monitored unconventional wells drilled to date in Pennsylvania might have structural integrity failures based on NOVs related to cement/casing integrity. However, neither study adequately accounts for non-NOV indicators of cement/casing integrity impairment or temporal or spatial dimensions of such impairments.Earlier work found that the NOV count alone does not account for all incidences of cement/casing failure (20). State regulatory agencies and the oil and gas industry monitor many of the wells showing signs of SCP or other indicators of cement and/or casing impairment. Remedial action is often attempted once or many times on a monitored well, but a NOV is not issued by the agency. Additionally, violation codes are sometimes entered incorrectly as non-cement/casing issues and later corrected in violation comments. By not accounting for these, previous assessments based on PADEP inspection records (18, 19) may underestimate the actual proportion of wells with cement and/or casing problems in Pennsylvania.Failure to account for temporal dimensions of the data may also skew results. Previous studies on cement/casing impairment have noted that wells drilled during boom periods may be more susceptible to loss of zonal isolation because operators might cut corners in an attempt to increase the number of wells drilled over a short period (16). The increased risk of zonal isolation problems as wells age and the increased probability of identifying these issues with more inspections may also create a time lag between the date that drilling of the well commences (i.e., the spud date) and the entry of a cement/casing issue in the inspection records. This time lag is due to the fact that wells drilled in recent years have not been subject to the same duration of analysis or number of inspections as older wells. Thus, inspection records on newer wells are incomplete relative to those of older wells.Here, we offer an in-depth analysis of the complete inspection records, including NOVs, observations and corrections noted in the inspector comments, for 32,678 oil and gas production wells drilled in Pennsylvania between 2000 and 2012. We use a time-dependent risk analysis model to assess the cumulative risk of cement/casing problems for wells based on the historical occurrence of cementing/casing impairment events.     

Systemic inflammation and blood–brain barrier abnormality in relapsing–remitting multiple sclerosis

Background

Systemic inflammation can affect disease expression in multiple sclerosis. The mechanism might involve blood–brain barrier disruption. We aimed to assess the effects of systemic inflammation on disease progression in multiple sclerosis and the role of blood–brain barrier disruption.

Origins of specificity and affinity in antibody–protein interactions

Natural antibodies are frequently elicited to recognize diverse protein surfaces, where the sequence features of the epitopes are frequently indistinguishable from those of nonepitope protein surfaces. It is not clearly understood how the paratopes are able to recognize sequence-wise featureless epitopes and how a natural antibody repertoire with limited variants can recognize seemingly unlimited protein antigens foreign to the host immune system. In this work, computational methods were used to predict the functional paratopes with the 3D antibody variable domain structure as input. The predicted functional paratopes were reasonably validated by the hot spot residues known from experimental alanine scanning measurements. The functional paratope (hot spot) predictions on a set of 111 antibody–antigen complex structures indicate that aromatic, mostly tyrosyl, side chains constitute the major part of the predicted functional paratopes, with short-chain hydrophilic residues forming the minor portion of the predicted functional paratopes. These aromatic side chains interact mostly with the epitope main chain atoms and side-chain carbons. The functional paratopes are surrounded by favorable polar atomistic contacts in the structural paratope–epitope interfaces; more that 80% these polar contacts are electrostatically favorable and about 40% of these polar contacts form direct hydrogen bonds across the interfaces. These results indicate that a limited repertoire of antibodies bearing paratopes with diverse structural contours enriched with aromatic side chains among short-chain hydrophilic residues can recognize all sorts of protein surfaces, because the determinants for antibody recognition are common physicochemical features ubiquitously distributed over all protein surfaces.It is incompletely understood as to how functional antibodies can almost always be elicited against unlimited possibilities of protein antigens from a limited repertoire of antibodies. Antibodies provide protection against foreign protein antigens by recognizing the antigen proteins with exquisite specificity and remarkable affinity, but the principles underlying the antibody affinity and specificity remain elusive. Consequently, current antibody discoveries are by and large limited by the uncontrollable animal immune systems (1) or by the recombinant antibody libraries with relatively infinitesimal coverage of the vast combinatorial sequence space in antibody–antigen interaction interfaces (2). In developing the efficacy of a therapeutic antibody, optimizing the affinity and specificity of the antibody–antigen interaction mostly relies on selecting and screening from a large pool of random candidates. As antibodies are becoming the most prominent class of protein therapeutics (3), a better understanding of the principles governing antibody affinity and specificity will facilitate in understanding humoral immunity and in developing novel antibody-based therapeutics.Antibody paratopes are enriched with aromatic residues. Tyrosyl side chains are overpopulated on the paratopes, noticeable on solving the first structures of antibody–antigen complexes (4). Surveys thereafter showed that Tyr and Trp frequently occur in the putative binding regions of antibodies as determined from structural and sequence data (5). Recent analyses of more than 100 high-resolution antibody–antigen complexes in the Protein Data Bank (PDB) confirm a similar conclusion that aromatic residues (Tyr, Trp, and Phe) are substantially enriched in antibody paratopes (6, 7). The fundamental role of the tyrosyl side chains in antibody–antigen recognition has been demonstrated (8), with the functional antibodies selected and screened from the minimalist designs of antibody complementarity determining region (CDR) libraries with only a small subset of amino acid types (Tyr, Ala, Asp, and Ser) (9) or with binary code (Tyr and Ser) (10).Interactions involving aromatic side chains on the CDRs of antibodies with epitope residues on protein antigens have been demonstrated to contribute energetically to antibody–antigen recognition. Alanine scanning of the antibody paratope residues of the FvD1.3-hen egg white lysozyme (HEL) and FvD1.3-FvE5.2 (anti-idiotype antibody) complexes and shotgun alanine scanning assessing the energetic contributions of paratope residues to VEGF and human epidermal growth factor receptor 2 (HER2) binding indicated that around half of the hot spots (ΔΔG ≥ 1 kcal/mol) are aromatic residues (20/40) (11, 12). Double-mutant cycle experiments dissecting the residue-pair coupling energies between the epitope and paratope for the two antibody–antigen complexes also indicated the predominant energetic contribution of the aromatic side chains (9/11) in the antibody–antigen interactions (13). These energetic assessments suggest that aromatic side chains contribute a substantial portion of the affinity of the antibody–antigen complexes in general. These results are consistent with the survey indicating that aromatic residues, in particular Tyr and Trp, account for a large portion of the hot spot residues in protein–protein interactions (14, 15).Aromatic side chains interact favorably with diverse functional groups in natural amino acids, underlying the affinity and specificity of the antibody–antigen recognition through a cumulative collection of relatively weak noncovalent interactions. The aromatic side chains interact with other aromatic side chains through face-to-edge or parallel π-stacking, with positively charged side chains through the cation–π interaction, with backbone and side-chain hydrogen bond donors through hydrogen bonding to aromatic π-systems (X–H–π interaction, X = N, O, S), with alkyl carbons through the C–H–π interaction, with sulfur-containing side chains through sulfur–arene interactions, and with negative charged side chains through anion–π interactions (16, 17). Although each of the above mentioned interactions is relatively weak, on the order of a few kilocalories per mole in model systems (16, 17), the cumulative sum of the interactions involving the aromatic side chains can reasonably account for the binding energy of 12 kcal/mol for a typical antibody–antigen interaction of K_d ∼1 nM at room temperature aqueous environment. Moreover, the specific preferences of the spatial geometries for the interacting functional groups involving aromatic side chains (see refs. 16–18 and references therein) also underlie the specificity of antibody–antigen recognitions. Direct hydrogen bonds bridging across the antibody–antigen interaction interface are expected to contribute to both the binding affinity and specificity, but the removal of an interface hydrogen bond is frequently inconsequential to the binding specificity and affinity due to compensating water-mediated interactions (13). These results suggest that the 3D distribution of the paratope aromatic side chains by and large determines the affinity and specificity of the antibody–antigen interaction.Known epitopes on antigens, on the other hand, are not easily distinguishable from the solvent accessible surfaces of protein structures. A recent review of the public domain conformational epitope prediction algorithms, for which the performances were compared with an independent test set for benchmarking, shows that the conformational epitope prediction problem remain challenging, with an area under the curve (AUC) ranging from 0.567 to 0.638 and accuracy from 15.5% to 25.6% (19). This moderate success rate was attributed to incomplete understanding of the essence of the epitopes (6). It has been well accepted that the solvent accessible and protruding surface regions are more likely to be conformational epitopes (20–23) and that the epitopes encompass substantially more loop residues than α-helix and β-strand residues (23, 24). By contrast, the conclusions from various studies on the amino acid composition of conformational epitopes are not consistent (6), in large part due to the fact that the epitope amino acid composition is not particularly distinguishable from the nonantigenic solvent accessible surface area (6, 7, 22, 23, 25). The contradiction has been discussed recently (25), indicating that the physicochemical complementarity between the paratopes and the epitopes are strikingly incomparable, with overwhelmingly emphasized tyrosyl side chains in all CDR loops (25).The goal of this work is to understand how a natural repertoire of antibodies, for which the sequence and structure are relatively limited in variation, can recognize protein antigens with seemly unlimited structural and sequence diversities. An extensive examination on the monoclonal antibodies elicited with a set of model antigens has concluded that a protein antigen surface consists of overlapping conformational epitopes forming a continuum; that is, no inherent property of the protein molecule could restrict antigenic site locations on the protein surface (26). It would be conceivable that antibodies recognize a common feature shared by all protein surface sites, and as such, a relatively limited population of antibodies could recognize limitless protein antigen surfaces. That is, protein surfaces are not as diverse as one would expect by looking at the protein sequences. However, this common feature on protein surface recognizable by antibodies is not known. Although aromatic side chains are known, in principle, to be able to interact favorably with wide varieties of functional groups in natural amino acids (see above), atomic details of the paratope aromatic side chains interacting favorably with diverse epitope surfaces have not been systematically analyzed. In addition, residues with short hydrophilic side chains (Ser, Thr, Asp, and Asn) are known to be enriched alongside the aromatic side chains in the paratopes (5, 24, 27), but the roles of these short hydrophilic side chains in antibody–antigen interactions have not been systematically investigated. More importantly, it has been well accepted that only hot spot residues in an antigen combining site of an antibody, i.e., the residues in the functional paratopes, are indispensable for the antibody–antigen interaction; side chains contacting the antigen (i.e., structural paratope residues) outside the functional paratope can frequently be truncated to Cβ carbon without affecting the antibody–antigen interaction (11, 13, 15, 28). To search for the relevant protein surface features recognizable by antibodies, it is desirable to first elucidate the principles governing the interactions for the functional paratopes with the corresponding functional epitopes. Such studies require a large number of well-defined functional paratopes and functional epitopes, but only a small number have been determined with the labor-intensive alanine scanning experiment (11–13, 29). To circumvent the scarcity of the experimental data, we use computational methods to predict the functional paratopes/epitopes in antibody–protein complex structures so that the key interactions involving the hot spots in the antibody–protein interactions can be elucidated, at least to the reliable extent depending on the functional paratope prediction accuracy.In this work, we applied computational methods to predict functional paratopes on antibody variable domains and analyzed the key atomistic contact pairs in the functional paratope–epitope interfaces. Although the structural paratope–epitope interfaces can be defined from the known complex structures, the functional binding interfaces involving hot spot residues are unknown experimentally and need to be defined with computational predictions. One set of predictions was carried out with our previously published computational method [In-silico Molecular Biology Lab–protein-protein interaction (ISMBLab-PPI)], where the protein–protein interaction confidence level (PPI_CL) for protein surface atoms to participate in protein–protein interaction is strongly correlated (r² = 0.99) with the averaged burial level of the atoms in the PPI interfaces (30). Another set of predictions was carried out with a recently published random forest algorithm, prediction of antibody contacts (proABC) (31), which was trained specifically with antibody–antigen complex structures in PDB with additional information from antibody germ-line family sequences, CDR residue positions, multiple antibody sequence alignments, CDR lengths and canonical structures, and antigen volume. Both sets of predicted functional paratope–epitope interfaces consistently led to the conclusion that antibodies, with relatively limited sequence and structural diversities in the antigen binding sites, can recognize unlimited protein antigens through recognizing the common and ubiquitous physicochemical features on all protein surfaces. The implication is that a limited repertoire of antibodies bearing paratopes with diverse structural contours enriched with aromatic side chains among short-chain hydrophilic residues can recognize all sorts of protein surfaces.     

Neuropsychological–Neurophysiological Alterations and Brain Atrophy in Cirrhotic Patients

Psychometric performance has been reported to be related to brain atrophy in cirrhotics, but the relationship between brain atrophy and EEG findings is still unknown. The aim of this study was to ascertain the relationship among brain atrophy, EEG, and cognitive performance in cirrhotics. Sixty-eight cirrhotics (age = 55 ± 10 years; males-66%) underwent psychometric evaluation (Symbol Digit Test, Trail Making Test—Part A, Scan test), EEG recording and spectral analysis (S-EEG), and brain CT scan. Central brain atrophy was ascertained by the following indexes of brain atrophy: the Evans' index, the bicaudate index, the cella media index, the bifrontal index, and the ventricular index; cortical brain atrophy by the sulci index. The severity of liver failure was assessed by the Child–Pugh score: 18% of patients were Child–Pugh Class A, 50% Class B, and 32% Class C. Central and cortical atrophies were found to be correlated with age, but not with the Child–Pugh score. Psychometric performance and the EEG mean dominant frequency (MDF) were found to be correlated with brain atrophy. Multivariate analysis showed that a poor psychometric performance was independently predicted by EEG slowing (MDF: p < 0.01) and by central brain atrophy (cella media index: p < 0.01). In conclusion, brain atrophy was associated with a poor psychometric performance and EEG alterations in cirrhosis. Both brain atrophy and EEG alterations independently predicted cognitive dysfunction in cirrhotic patients.     

Direct photonic–plasmonic coupling and routing in single nanowires

Metallic nanoscale structures are capable of supporting surface plasmon polaritons (SPPs), propagating collective electron oscillations with tight spatial confinement at the metal surface. SPPs represent one of the most promising structures to beat the diffraction limit imposed by conventional dielectric optics. Ag nano wires have drawn increasing research attention due to 2D sub-100 nm mode confinement and lower losses as compared with fabricated metal structures. However, rational and versatile integration of Ag nanowires with other active and passive optical components, as well as Ag nanowire based optical routing networks, has yet to be achieved. Here, we demonstrate that SPPs can be excited simply by contacting a silver nanowire with a SnO₂ nanoribbon that serves both as an unpolarized light source and a dielectric waveguide. The efficient coupling makes it possible to measure the propagation-distance-dependent waveguide spectra and frequency-dependent propagation length on a single Ag nanowire. Furthermore, we have demonstrated prototypical photonic-plasmonic routing devices, which are essential for incorporating low-loss Ag nanowire waveguides as practical components into high-capacity photonic circuits.     

Clinician Stress and Patient–Clinician Communication in HIV Care

BACKGROUND

Clinician stress is common, but few studies have examined its relationship with communication behaviors.

OBJECTIVE

To investigate associations between clinician stress and patient?Cclinician communication in primary HIV care.

DESIGN

Observational study.

PARTICIPANTS

Thirty-three primary HIV clinicians and 350 HIV-infected adult, English-speaking patients at three U.S. HIV specialty clinic sites.

MAIN MEASURES

Clinicians completed the Perceived Stress Scale, and we categorized scores in tertiles. Audio-recordings of patient??clinician encounters were coded using the Roter Interaction Analysis System. Patients rated the quality of their clinician??s communication and overall quality of medical care. We used regression with generalized estimating equations to examine associations between clinician stress and communication outcomes, controlling for clinician gender, clinic site, and visit length.

KEY RESULTS

Among the 33 clinicians, 70?% were physicians, 64?% were women, 67?% were non-Hispanic white, and the mean stress score was 3.9 (SD 2.4, range 0?C8). Among the 350 patients, 34?% were women, 55?% were African American, 23?% were non-Hispanic white, 16?% were Hispanic, and 30?% had been with their clinicians >5?years. Verbal dominance was higher for moderate-stress clinicians (ratio?=?1.93, p?<?0.01) and high-stress clinicians (ratio?=?1.76, p?=?0.01), compared with low-stress clinicians (ratio 1.45). More medical information was offered by moderate-stress clinicians (145.5 statements, p <0.01) and high-stress clinicians (125.9 statements, p?=?0.02), compared with low-stress clinicians (97.8 statements). High-stress clinicians offered less psychosocial information (17.1 vs. 19.3, p?=?0.02), and patients of high-stress clinicians rated their quality of care as excellent less frequently than patients of low-stress clinicians (49.5?% vs. 66.9?%, p?<?0.01). However, moderate-stress clinicians offered more partnering statements (27.7 vs. 18.2, p?=?0.04) and positive affect (3.88 vs. 3.78 score, p?=?0.02) than low-stress clinicians, and their patients?? ratings did not differ.

CONCLUSIONS

Although higher stress was associated with verbal dominance and lower patient ratings, moderate stress was associated with some positive communication behaviors. Prospective mixed methods studies should examine the complex relationships across the continuum of clinician well-being and health communication.