Re-valuation of annual cytology using HPV self-sampling to upgrade prevention (REACH UP): A feasibility study in women living with HIV in the UK.

INTRODUCTION: Current UK guidelines for cervical cancer screening are based on the assumption that most women living with HIV (WLWH) are also high-risk (HR) human papillomavirus (HPV)-positive. We aimed to provide data on prevalence of HR-HPV in WLWH in the UK and to assess feasibility and acceptability of HR-HPV self-sampling in this group. METHODS: Women living with HIV attending six HIV services in London/south of England, with no history of cervical cancer, were enrolled. Participants self-collected a vaginal swab for the detection of HR-HPV, completed a survey about sexual/gynaecological history, attitudes towards annual screening and perception of HR-HPV self-sampling, and were asked to have their annual cervical smear. RESULTS: In all, 67 women were included: 86.5% were of black ethnicity, the median (range) age was 47 (24-60) years, median CD4 T-cell count was 683 cells/µL [interquartile range (IQR): 527-910], and 95.4% had viral load ≤ 50 copies/mL. All performed the vaginal swab. Eighteen (27%) had no cervical smear results; none of these women attended HIV services where this was routinely offered. No cervical samples were positive for HR-HPV. Three-quarters (75.8%) of participants reported adherence to annual screening, with only one woman (1.5%) attending irregularly. On visual analogue scales (from 0 to 100), median (IQR) acceptability and necessity of smear tests were 100 (75-100) and 100 (85-100), respectively. CONCLUSIONS: Our results suggest that the prevalence of HR-HPV in WLWH in the UK may be low. Self-sampling seems to be acceptable, suggesting, if validated, its potential role in supporting less frequent smear testing and improving screening uptake in WLWH.

Early menopause in acquired immunodeficiency syndrome.

Premature menopause can occur in women living with human HIV. In this study, we analyzed and reviewed published literature using the PubMed, Cochrane, and Embase databases since the year 1990 using a combination of MeSH terms such as "Early," "Premature," "Menopause," "HIV," and "Hormones." Monitoring and implementation of targeted interventions for premature or early menopause among HIV-infected women might prevent or delay complications such as osteoporosis, cardiovascular diseases, and mental health issues.

Tenofovir-associated renal and bone toxicity.

OBJECTIVES: The aims of the study were to describe the clinical presentation and renal and bone abnormalities in a case series of HIV-infected patients receiving treatment with tenofovir (TDF), and to recommend appropriate screening for toxicity related to TDF. METHODS: Patients were identified from referrals to a specialist HIV renal clinic. Patients were included if treatment with TDF was assessed as the primary cause of the renal function impairment and clinical data were available prior to and following discontinuation of TDF treatment. Data were collected from case note review and clinic databases. RESULTS: Twenty-two patients (1.6% of all those who received TDF) were identified with TDF-associated renal toxicity. All had normal serum creatinine prior to TDF therapy. All presented with proteinuria. On stopping TDF, renal function improved. Eight patients had confirmed Fanconi syndrome. Twelve patients presented with bone pain and osteomalacia was confirmed on an isotope bone scan in seven of these patients. The findings (in those patients tested) of tubular proteinuria, reduced tubular transport maximum of phosphate (TmP), and glycosuria were all consistent with the proximal tubule being the site of toxicity. CONCLUSION: Renal toxicity remains a concern in patients treated with TDF. Clinical presentation may be with renal dysfunction, Fanconi syndrome or osteomalacia. Our investigations suggest proximal tubular toxicity as a common pathogenic mechanism.

HIV-Associated Nephropathy in Africa: Pathology, Clinical Presentation and Strategy for Prevention.

The human immunodeficiency virus (HIV) infection can lead to progressive decline in renal function known as HIV-associated nephropathy (HIVAN). Importantly, individuals of African ancestry are more at risk of developing HIVAN than their European descent counterparts. An in-depth search on Google Scholar, Medline and PubMed was conducted using the terms "HIVAN" and "pathology and clinical presentation", in addition to "prevalence and risk factors for HIVAN", with special emphasis on African countries for any articles published between 1990 and 2017. HIVAN is characterized by progressive acute renal failure, proteinuria and enlarged kidneys. A renal biopsy is necessary to establish definitive diagnosis. Risk factors are male gender, low CD4 counts, high viral load and long use of combined antiretroviral medication (cART). There is a wide geographical variation in the prevalence of HIVAN as it ranges from 4.7% to 38% worldwide and little published literature is available about its prevalence in African nations. Microalbuminuria is a common finding in African populations and is significantly associated with severity of HIV disease progression and CD4 count less than 350 cells/µL. Other clinical presentations in African populations include acute kidney injury (AKI), nephrotic syndrome and chronic kidney disease. The main HIV-associated renal pathological lesions were focal segmental glomerulosclerosis, mainly the collapsing form, acute interstitial nephritis (AIN), and immune complex-mediated glomerulonephritis (ICGN). HIV infection-induced transcriptional program in renal tubular epithelial cells as well as genetic factors is incriminated in the pathogenesis of HIVAN. This narrative review discusses the prevalence, presentation, pathogenesis and the management of HIVAN in Africa. In low resource setting countries in Africa, dealing with HIV complications like HIVAN may add more of a burden on the health system (particularly renal units) than HIV medication itself. Therefore, the obvious recommendation is early use of cART in order to decrease risk factors that lead to HIVAN.

Metabolic clinic for individuals with HIV/AIDS: a commitment and vision to the future of HIV services.

One of the biggest current challenges in managing an ageing cohort living with the HIV is handling dyslipidaemia, diabetes, metabolic syndrome and nonalcoholic fatty liver disease. Combination antiretroviral therapy decrease mortality and morbidity in HIV patients, but lead to increase in insulin resistance, dyslipidaemia, abnormalities of fat distribution and high risk of cardiovascular disease. Therefore, a metabolic clinic was established for individuals living with HIV in the Milton Keynes University Hospital NHS Foundation Trust. The clinic meets considerable demands by service users and hence has the potential to be popular. This review focuses on the importance of the development of a metabolic clinic for the purpose of audit, research, teaching and exchange of knowledge between HIV specialists and the metabolic team in the management of complex cases. Therefore, the metabolic clinic should be an integral part of HIV services especially as the cohort of the 'older' HIV population increases.

Non-Alcoholic Fatty Liver Disease and HIV/AIDS: A New Way of Modulation of Cardiovascular Risk.

With the advent and subsequent success of antiretroviral therapy, HIV infection has largely become a chronic condition and is increasingly seen alongside metabolic disorders such as dyslipidemia and insulin resistance. Furthermore, the administration of antiretroviral therapy itself is associated with an increase in the incidence of metabolic risk factors, namely insulin resistance, lipoatrophy, dyslipidemia, and abnormalities of fat distribution, in HIV patients. Thus, further challenges in the management of HIV patients include the management of diabetes and the metabolic syndrome, non-alcoholic fatty liver disease. Importantly, HIV and non-alcoholic fatty liver disease are both associated with increased risk of cardiovascular disease. Overall, the management of non-alcoholic fatty liver disease and cardiovascular risks associated with HIV is complex and requires specialist management. Further research is needed to address the best strategies in the management of cardiovascular disease in patients with HIV. This narrative review aims to discuss non-alcoholic fatty liver disease and HIV infection, HIV and cardiovascular disease, as well as how fatty liver modulates cardiovascular disease in HIV patients.

Diabetes, metabolic syndrome and dyslipidemia in people living with HIV in Africa: re-emerging challenges not to be forgotten.

BACKGROUND: The current challenge in managing people living with human immunodeficiency virus (PLWHIV) includes the identification and monitoring for comorbid health risks associated with HIV and its treatment and longer survival. Dyslipidemia, diabetes mellitus and metabolic syndrome are increasingly seen in PLWHIV. OBJECTIVE: In this narrative review, we aimed to summarize the current knowledge about diabetes, dyslipidemia and metabolic syndrome in PLWHIV in Africa and also to discuss the challenges that patients as well as health authorities in Africa may face. METHODS: PubMed and Google scholar published-English literatures concerning earlier mentioned entities regardless of time limit were critically reviewed. RESULTS: The prevalence of metabolic disorders in HIV population in Africa was estimated to range from 2.1% to 26.5% for diabetes and 20.2% to 43.5% for pre-diabetes, 13% to 58% for metabolic syndrome and 13% to 70% for dyslipidemia. CONCLUSION: The management of metabolic disorders and cardiovascular disease risks related to HIV is complex especially in Africa due to healthcare resources, but our experience suggests that metabolic clinic is beneficial to patients and staff and should be an important part of HIV services especially as the older HIV population is increasing. In this context, cardiovascular risk assessment of HIV-infected patients will become an important component of care in developing countries in Africa and strategies are needed to deal with progressive increase in the epidemic of type 2 diabetes, dyslipidemia and metabolic syndrome.

Assessing positive and negative changes in the aftermath of adversity: psychometric evaluation of the changes in outlook questionnaire.

The Changes in Outlook Questionnaire (CiOQ; S. Joseph, R. Williams, & W. Yule, 1993) is a 26-item self-report measure that was designed to assess positive and negative changes in the aftermath of adversity. This article had 3 aims: 1st, to investigate the factor structure of the CiOQ; 2nd, to test for internal consistency reliability and convergent and discriminant validity; and, 3rd, to investigate the association between positive and negative changes in outlook, posttraumatic stress, and psychological distress. Three studies are reported. Study 1 provides evidence that positive and negative changes are statistically separable and that the 2-factor model is a better fit than the 1-factor model. Studies 2 and 3 provide evidence for internal consistency reliability, convergent and discriminant validity of the CiOQ, and its associations with posttraumatic stress and psychological distress. In conclusion, the CiOQ has much promise for research on responses to stressful and traumatic events.

Multivalent IDP assemblies: Unique properties of LC8-associated, IDP duplex scaffolds.

A wide variety of subcellular complexes are composed of one or more intrinsically disordered proteins (IDPs) that are multivalent, flexible, and characterized by dynamic binding of diverse partner proteins. These multivalent IDP assemblies, of broad functional diversity, are classified here into five categories distinguished by the number of IDP chains and the arrangement of partner proteins in the functional complex. Examples of each category are summarized in the context of the exceptional molecular and biological properties of IDPs. One type - IDP duplex scaffolds - is considered in detail. Its unique features include parallel alignment of two IDP chains, formation of new self-associated domains, enhanced affinity for additional bivalent ligands, and ubiquitous binding of the hub protein LC8. For two IDP duplex scaffolds, dynein intermediate chain IC and nucleoporin Nup159, these duplex features, together with the inherent flexibility of IDPs, are central to their assembly and function. A new type of IDP-LC8 interaction, distributed binding of LC8 among multiple IDP recognition sites, is described for Nup159 assembly.

BetaCore, a designed water soluble four-stranded antiparallel beta-sheet protein.

BetaCore is a designed approximately 50-residue protein in which two BPTI-derived core modules, CM I and CM II, are connected by a 22-atom cross-link. At low temperature and pH 3, homo- and heteronuclear NMR data report a dominant folded ('f') conformation with well-dispersed chemical shifts, i, i+1 periodicity, numerous long-range NOEs, and slowed amide hydrogen isotope exchange patterns that is a four-stranded antiparallel beta-sheet with nonsymmetrical and specific association of CM I and CM II. BetaCore 'f' conformations undergo reversible, global, moderately cooperative, non-two-state thermal transitions to an equilibrium ensemble of unfolded 'u' conformations. There is a significant energy barrier between 'f' and 'u' conformations. This is the first designed four-stranded antiparallel beta-sheet that folds in water.

Hydrogen exchange, core modules, and new designed proteins.

A strategy for design of new proteins that mimic folding properties of native proteins is based on peptides modeled on the slow exchange cores of natural proteins. We have synthesized peptides, called core modules, that correspond to the elements of secondary structure that carry the very slowest exchanging amides in a protein. The expectation is that, if soluble in water, core modules will form conformational ensembles that favor native-like structure. Core modules modeled on natural bovine pancreatic trypsin inhibitor have been shown by NMR studies to meet this expectation. The next step toward production of a native state mimic is to further shift the conformational bias of a core module toward more ordered structure by promoting module-module interactions that are mutually stabilizing. For this, two core modules were incorporated into a single molecule by means of a long cross-link. From a panel of several two-module peptides, one very promising lead emerged; it is called BetaCore. BetaCore is monomeric in water and forms a new fold composed of a four-stranded, antiparallel beta-sheet. The single, dominant conformation of BetaCore is characterized by various NMR experiments. Here we compare the individual core module to the two-module BetaCore and discuss the progressive stabilization of intramodule structure and the formation of new intermodule interactions.

Positive change processes and post-traumatic growth in people who have experienced childhood abuse: understanding vehicles of change.

Post-traumatic growth is an emerging area of research concerned with the positive psychological changes that can follow the experience of traumatic events. The aim of this study is to explore themes of post-traumatic growth within personal experience narratives of individuals who have experienced some form of early emotional, physical, or sexual abuse. Using thematic analysis, we identified three domains of themes related to positive change processes: inner drive toward growth, vehicles of change, and psychological changes. Understanding the different vehicles of change has implications for facilitating post-traumatic growth in clients who have experienced traumatic events.

Computer-assisted survey of attitudes to HIV and sexually transmissible infection partner notification in HIV-positive men who have sex with men.

BACKGROUND: HIV infection continues to rise in men who have sex with men (MSM) in the UK. Of concern are the high rates of sexually transmissible infections (STI) among HIV-positive MSM, as this is associated with onward HIV transmission. Conventional partner notification (PN) may be limited in this group by the presence of multiple non-contactable partners and the fear of breach of HIV status. METHODS: We explored attitudes to PN in HIV-positive MSM having an STI screen using a computer-assisted self interview. RESULTS AND CONCLUSION: Our study shows HIV+ MSM, rate conventional methods of PN highly (median rating 8/10) but are also supportive of new approaches to PN particularly anonymous email when linked to website information. They would also be open to targeted interventions such as peer recruitment.

Partially folded bovine pancreatic trypsin inhibitor analogues attain fully native structures when co-crystallized with S195A rat trypsin.

Crystal structures, at 1.7 A resolution, were solved for complexes between each of two chemically synthesized partially folded analogues of bovine pancreatic trypsin inhibitor (BPTI) with the proteolytically inactive rat trypsin mutant S195A. The BPTI analogue termed [14-38](Abu) retains only the disulfide bond between Cys14 and Cys38, while Cys5, Cys30, Cys51, and Cys55 are replaced by isosteric alpha-amino-n-butyric acid residues. The analogue K26P,A27D[14-38](Abu) contains two further replacements, by statistically favored residues, in the type I beta-turn that has been suggested to be a main site for initiation of BPTI folding. As a control, the structure of the complex between S195A trypsin and wild-type BPTI was also solved. Despite significant differences in the degree of structure detected among these three BPTIs in solution by several biophysical techniques, their tertiary folds once bound to S195A trypsin in a crystalline lattice are essentially superimposable.

A highly destabilizing mutation, G37A, of the bovine pancreatic trypsin inhibitor retains the average native conformation but greatly increases local flexibility.

A point mutation, G37A, on the surface of bovine pancreatic trypsin inhibitor (BPTI) destabilizes the protein by approximately 5 kcal/mol, which is very high for addition of one methyl group. In wild-type (WT) BPTI, Gly 37 HN is in an unusual NH-aromatic-NH network of interactions with the ring of Tyr 35 and the side chain HN of Asn 44. G37A was designed to disrupt this interaction, since the phi and psi backbone angles of G37 are not favorable for an amino acid containing a beta-carbon. Investigations of the structure and dynamics by NMR methods show that G37A retains the average WT structure. The NH-aromatic-NH interactions remain intact, as indicated by NOEs and the large upfield ring current shift (approximately 4 ppm) of A37 HN. The NMR structure, confirmed by molecular modeling calculations, requires phi and psi backbone angles that are highly destabilizing when alanine is in position 37. Although the average structure is essentially unchanged, the dynamics are altered dramatically. Many residues in the region of the mutation have increased flexibility, as probed by aromatic ring flip rates and native state hydrogen exchange. We conclude that a large fraction of the destabilization arises from maintaining A37 in a high-energy conformation. This suggests that disruption of the NH-aromatic-NH network is energetically very costly, and may involve other cooperatively linked interactions. The results illustrate the importance of the Gly-Gly sequence at positions 36 and 37 and the 37 HN-35 aromatic interaction to the stability, folding, and dynamics of the BPTI.

Native-like interactions favored in the unfolded bovine pancreatic trypsin inhibitor have different roles in folding.

Folding kinetics of a series of bovine pancreatic trypsin inhibitor (BPTI) variants with similar stabilities and structures have been measured. All are strongly destabilized relative to WT. In Y21A, F22A, Y23A, G37A, and F45A, the three native disulfide bonds are retained. In RM(14-38), Cys14 and Cys38 thiols are methylated while C30-C51 and C5-C55 disulfides remain intact. At pH 2 and 20 degrees C, relaxation rate constants of the major kinetic phase range from approximately 10 ms to 0.71 s in the absence of denaturant. All mutants except G37A exhibit standard two-state behavior. Y21A, F22A, and Y23A fold much more slowly than other mutants. The experiments were designed to test the hypothesis that native-like structure detected in the unfolded BPTI is important in folding. Two native-like contacts are implied by NOEs in reduced and unfolded BPTI, between residues Tyr23 and Ala25, and between Gly37 NH and the Tyr35 ring. The results support an earlier hypothesis that formation of the central beta-hairpin, monitored by a local native interaction between Tyr23 and Ala25, is crucial to initiation of BPTI folding. The second native-like contact is important, not in folding initiation, but in preventing a kinetic trap later in the process. Evidence for this comes from mutant G37A, which behaves very differently from the others in displaying a phenomenon called rollover. G37A is, to our knowledge, the first reported case in which a single-site replacement causes rollover, while the wild type and all other known mutants of the same protein show typical two-state chevron plots. The best explanation is that the G37A mutation introduces a kinetic trap of the type described by Chan and Dill [(1998) Proteins 30, 2-33]. In native BPTI, there is an unusual polar interaction between the ring of Tyr35 and the backbone NH of Gly37. Our results suggest that the NH-aromatic interaction between residues 37 and 35 is important throughout folding in stabilizing native-like loop conformations and in preventing the flexible loops from being trapped in nonfunctional conformations during later stages of folding.

Native-like conformations are sampled by partially folded and disordered variants of bovine pancreatic trypsin inhibitor.

Partially folded conformational ensembles of bovine pancreatic trypsin inhibitor (BPTI) are accessed by replacing Cys 5, 30, 51, and 55 by alpha-amino-n-butyric acid (Abu) while retaining the disulfide between Cys 14 and 38; the resultant variant is termed [14-38](Abu). Two new analogues with modifications in the beta-turn, P26D27[14-38](Abu) and N26G27K28[14-38](Abu), are compared to partially folded [14-38](Abu), as well as to [R](Abu), the unfolded protein with all six Cys residues replaced by Abu. Structural features of the new analogues of [14-38](Abu) have been determined by circular dichroism (CD), one-dimensional (1)H NMR, and 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence experiments. Both analogues are more disordered than the parent [14-38](Abu), but while P26D27[14-38](Abu) has a small population of native-like conformations observed by NMR, no ordered structure is detected for N26G27K28[14-38](Abu). Trypsin inhibition assays were carried out using a modified rat trypsin, C191A/C220A, that minimizes cleavage of unfolded peptides. Both [14-38](Abu) and P26D27[14-38](Abu) significantly inhibit modified trypsin. N26G27K28[14-38](Abu) has low but measurable inhibitor activity, while [R](Abu) has no activity even when in very high molar excess relative to trypsin. ANS fluorescence is enhanced by [14-38](Abu) and by both variants but not by [R](Abu). We conclude that partially folded ensembles of BPTI, even those with little or no CD- or NMR-detectable structure, contain minor populations of native-like conformations. Partially folded [14-38](Abu) and both variants, as well as [R](Abu), have enhanced negative ellipticity in CD spectra acquired in the presence of the osmolyte trimethylamine N-oxide (TMAO). TMAO-induced structure is formed cooperatively, as indicated by thermal unfolding curves. Inhibitor activity as a function of TMAO concentration implies that the osmolyte-induced structure is native-like for [14-38](Abu) and P26D27[14-38](Abu) and is probably native-like for N26G27K28[14-38](Abu). [R](Abu) also shows increased CD-detected structure in the presence of TMAO, but such structure is likely to be collapsed and non-native.