Bicyclic Peptide Library Screening for the Identification of Gαi Protein Modulators.

Noncanonical G protein activation and inactivation, particularly for the Gαi/s protein subfamilies, have long been a focus of chemical research. Combinatorial libraries were already effectively applied to identify modulators of the guanine-nucleotide exchange, as can be exemplified with peptides such as KB-752 and GPM-1c/d, the so-called guanine-nucleotide exchange modulators. In this study, we identified novel bicyclic peptides from a combinatorial library screening that show prominent properties as molecular switch-on/off modulators of Gαi signaling. Among the series of hits, the exceptional paradigm of GPM-3, a protein and state-specific bicyclic peptide, is the first chemically identified GAP (GTPase-activating protein) modulator with a high binding affinity for Gαi protein. Computational analyses identified and assessed the structure of the bicyclic peptides, novel ligand-protein interaction sites, and their subsequent impact on the nucleotide binding site. This approach can therefore lead the way for the development of efficient chemical biological probes targeting Gαi protein modulation within a cellular context.

Low frequency of cytomegalovirus (CMV) disease despite high prevalence of CMV viraemia in patients with advanced HIV infection: a clinical and immunological 48-week follow-up study.

OBJECTIVES: The aim of the study was to investigate the dynamics of cytomegalovirus (CMV) replication and CMV-specific immune response recovery after antiretroviral treatment (ART) initiation in patients with advanced HIV infection. METHODS: A prospective observational study of patients with HIV infection and CD4 counts of < 100 cells/µL was carried out (September 2015 to July 2018). HIV viral load (VL), CD4 count and CMV VL were determined by quantitative polymerase chain reaction (PCR) at baseline and at 4, 12, 24 and 48 weeks, and CMV-specific immune response was determined by QuantiFERON-CMV assay at baseline and 48 weeks. All patients were started on ART but only those with CMV end-organ disease (EOD) received anti-CMV treatment. RESULTS: Fifty-three patients with a median age of 43.6 [interquartile range (IQR) 36.7-52.4] years were included in the study. At baseline, the median CD4 count was 30 cells/µL (IQR 20-60 cells/µL) and the median HIV VL was 462 000 HIV-1 RNA copies/mL (IQR 186 000-1 300 000 copies/mL). At baseline, 32% patients had detectable CMV viraemia but none had detectable CMV viraemia at 48 weeks. Only one of 53 (1.9%) patients developed EOD during follow-up. Seven (13.2%) patients were lost to follow-up and six (11.3%) died; none of the deaths was related to CMV. Similar percentages of patients had a CMV-specific immune response at baseline (71.7%) and at 48 weeks (70.0%). The magnitude of this response tended to increase over time [median 1.63 (IQR 0.15-5.77) IU/mL at baseline vs. median 2.5 (IQR 0.1-8.325) IU/mL at 48 weeks; P = 0.11]. We did not find any risk factors associated with 48-week mortality. CONCLUSIONS: Although the prevalence of CMV viraemia in patients with advanced HIV infection remains high, achieving a good immunological recovery through ART is enough to suppress CMV viraemia, without an increased risk of CMV EOD. The prevalence of a CMV-specific immune response was high and endured over time.

Las características epidemiológicas y clínicas de la epidemia de sífilis en Barcelona / The Epidemiological and Clinical Characteristics of the Epidemic of Syphilis in Barcelona

Introducción: Desde el año 2000 se ha descrito un aumento progresivo de los casos de sífilis en diferentes ciudades europeas, sobre todo en hombres que tienen sexo con hombres (HSH). Las manifestaciones clínicas de la sífilis pueden estar influidas por la coinfección del VIH o por el antecedente de sífilis. El objetivo del presente estudio es describir las características epidemiológicas y clínicas de los casos de sífilis precoz diagnosticados en Barcelona. Métodos: Estudio retrospectivo de casos de sífilis precoz diagnosticados en Barcelona (2003-2013). Se revisaron las historias clínicas y los datos epidemiológicos y clínicos fueron recogidos de forma estructurada. Las variables se compararon según el estatus serológico del VIH y el antecedente de sífilis. Resultados: Se diagnosticaron 1.702 casos de sífilis precoz (37% primaria, 48% secundaria y 14% latente precoz), 93% de ellos en HSH. Entre ellos, el 40% presentaba una coinfección por VIH. Los casos de sífilis en pacientes VIH positivos estaban asociados con un episodio previo de sífilis (aOR, 5,2 [IC del 95%, 3,32-8,24]) y con haber tenido sexo anal desprotegido (aOR, 1,75 [IC del 95%, 1,17-2,63]). Los casos con antecedentes de sífilis se presentaron con menor frecuencia como sífilis primaria (27,5% vs. 40%) (aOR, 0,58 [IC del 95%, 0,44-0,77]). Un año después del tratamiento, la evolución clínica y serológica fue similar en los pacientes VIH positivo y negativo. Conclusiones: La epidemia de sífilis en Barcelona afecta desproporcionalmente a HSH y está estrechamente relacionada con el VIH. La forma de presentación de la sífilis está influida por el antecedente de sífilis y por el VIH, sin diferencias significativas en cuanto a la evolución un año después del tratamiento

Background: Since 2000, substantial increases in syphilis have been reported in metropolitan areas of Western countries, with increases noted among men who have sex with men (MSM). Clinical manifestations of syphilis might be influenced by concomitant VIH infection and previous episodes of syphilis. The objectives of this study were to describe the epidemiological and clinical characteristics of the cases of syphilis diagnosed in Barcelona. Methods: Retrospective study of cases with early syphilis diagnosed in the referral STI Unit of Barcelona from January 2003 to December 2013. Revision of medical records with structured collection of epidemiological and clinical data. Univariate and multivariate statistical analyses comparing the characteristics of MSM cases with and without VIH infection and with and without previous syphilis. Results: A total of 1702 cases of syphilis (37% primary, 48% secondary and 14% early latent) were diagnosed, 93% of them in MSM. Among MSM 40% were coinfected with VIH, VIH-positive cases were associated with a previous syphilis (aOR, 5.2 [95% CI, 3.32-8.24]) and with unprotected anal intercourse (aOR, 1.75 [95%CI, 1.17-2.63]). Cases with a history of syphilis presented less often with primary syphilis compared to those without it (27.5% vs. 40%) (aOR, 0.58 [95% CI, 0.44-0.77]). One year after treatment, the clinical and serological evolution were similar between VIH-positive and VIH-negative cases. Conclusion: The epidemic of syphilis in Barcelona disproportionately affects MSM and is closelly linked to VIH infection. The presentation of syphilis is influenced by VIH infection and by previous history of syphilis, without significant differences in their evolution after one year of treatment

The Epidemiological and Clinical Characteristics of the Epidemic of Syphilis in Barcelona. / Las características epidemiológicas y clínicas de la epidemia de sífilis en Barcelona.

BACKGROUND: Since 2000, substantial increases in syphilis have been reported in metropolitan areas of Western countries, with increases noted among men who have sex with men (MSM). Clinical manifestations of syphilis might be influenced by concomitant VIH infection and previous episodes of syphilis. The objectives of this study were to describe the epidemiological and clinical characteristics of the cases of syphilis diagnosed in Barcelona. METHODS: Retrospective study of cases with early syphilis diagnosed in the referral STI Unit of Barcelona from January 2003 to December 2013. Revision of medical records with structured collection of epidemiological and clinical data. Univariate and multivariate statistical analyses comparing the characteristics of MSM cases with and without VIH infection and with and without previous syphilis. RESULTS: A total of 1702 cases of syphilis (37% primary, 48% secondary and 14% early latent) were diagnosed, 93% of them in MSM. Among MSM 40% were coinfected with VIH, VIH-positive cases were associated with a previous syphilis (aOR, 5.2 [95% CI, 3.32-8.24]) and with unprotected anal intercourse (aOR, 1.75 [95%CI, 1.17-2.63]). Cases with a history of syphilis presented less often with primary syphilis compared to those without it (27.5% vs. 40%) (aOR, 0.58 [95% CI, 0.44-0.77]). One year after treatment, the clinical and serological evolution were similar between VIH-positive and VIH-negative cases. CONCLUSION: The epidemic of syphilis in Barcelona disproportionately affects MSM and is closelly linked to VIH infection. The presentation of syphilis is influenced by VIH infection and by previous history of syphilis, without significant differences in their evolution after one year of treatment.

A national Health and Work Strategy: a search for evidence.

BACKGROUND: The Health and Safety Executive's new Health and Work Strategy is based on an up-to-date assessment of workplace health priorities. Rather than replicating traditional prioritization approaches, a broader assessment of health and work priorities was carried out using a range of stakeholders. AIMS: To develop a set of health priorities for further research and intervention activity. METHODS: Four exercises were carried out, including internal prioritization, two external web-hosted questionnaire studies of younger workers and occupational health professionals, focus groups and tele-depth interviews with workplace health and safety professionals. RESULTS: The highest rated internal priorities (weighted priority scores) were identified as mesothelioma (70), lung cancer (69.25), chronic obstructive pulmonary disease (COPD; 69), musculoskeletal disorders (MSDs; 66.25), hearing loss (65.75), stress (65.5), asthma (64.5) and hand-arm vibration syndrome (61.5). Using the three highest ranked criteria developed by occupational health professionals ((i) the preventability of the condition, (ii) the impact of the condition and (iii) the number of workers affected), mesothelioma, lung cancer, COPD, MSDs, hearing loss, stress and asthma were identified as the top seven priorities. Generic issues identified included ageing and work, obesity, newer technologies, and ethnicity and cultures of workforces. Apprentices identified stress, depression, anxiety, musculoskeletal and respiratory disorders, fatigue and workload as important workplace health considerations. CONCLUSIONS: This process identified a number of expected and new areas of health research interest. We believe the findings reflect the real world requirements of work as assessed by occupational health and safety practitioners and workers.

Discontinuation of dolutegravir, elvitegravir/cobicistat and raltegravir because of toxicity in a prospective cohort.

OBJECTIVES: The aim of the study was to assess the rates of discontinuation of integrase inhibitor regimens because of any neuropsychiatric adverse event (NPAE) and the factors associated with discontinuation. METHODS: A population-based, prospective, multicentre cohort study was carried out. Treatment-naïve subjects starting therapy with a regimen containing integrase inhibitors, or those switching to such a regimen, with plasma HIV-1 RNA < 50 HIV-1 RNA copies/mL in 14 hospitals in Catalonia or the Balearic Islands (Spain) were included in the study. Every discontinuation because of adverse events (AEs) was double-checked directly with treating physicians. Multivariable Cox models identified factors correlated with discontinuation. RESULTS: A total of 4165 subjects (37% treatment-naïve) started regimens containing dolutegravir (n = 1650; 91% with abacavir), raltegravir (n = 930) or elvitegravir/cobicistat (n = 1585). There were no significant differences among regimens in the rate of discontinuation because of any AE. Rates of discontinuation because of NPAEs were low but higher for dolutegravir/abacavir/lamivudine [2.1%; 2.9 (95% confidence interval (CI) 2.0, 4.2) discontinuations/100 patients/year] versus elvitegravir/cobicistat (0.5%; 0.8 (95% CI 0.3, 1.5) discontinuations/100 patients/year], with significant differences among centres for dolutegravir/abacavir/lamivudine and NPAEs (P = 0.003). We identified an association of female gender and lower CD4 count with increased risk of discontinuation because of any AE [Incidence ratio (IR) 2.3 (95% CI 1.4, 4.0) and 1.8 (95% CI 1.1, 2.8), respectively]. Female gender, age > 60 years and abacavir use were not associated with NPAE discontinuations. NPAEs were commonly grade 1-2, and had been present before and improved after drug withdrawal. CONCLUSIONS: In this large prospective cohort study, patients receiving dolutegravir, raltegravir or elvitegravir/cobicistat did not show significant differences in the rate of discontinuation because of any toxicity. The rate of discontinuations because of NPAEs was low, but was significantly higher for dolutegravir than for elvitegravir/cobicistat, with significant differences among centres, suggesting that greater predisposition to believe that a given adverse event is caused by a given drug of some treating physicians might play a role in the discordance seen between cohorts.

Cell-Permeable Bicyclic Peptidyl Inhibitors against NEMO-IκB Kinase Interaction Directly from a Combinatorial Library.

Macrocyclic peptides are capable of binding to flat protein surfaces such as the interfaces of protein-protein interactions with antibody-like affinity and specificity, but generally lack cell permeability in order to access intracellular targets. In this work, we designed and synthesized a large combinatorial library of cell-permeable bicyclic peptides, in which the first ring consisted of randomized peptide sequences for potential binding to a target of interest, while the second ring featured a family of different cell-penetrating motifs, for both cell penetration and target binding. The library was screened against the IκB kinase α/ß (IKKα/ß)-binding domain of NF-κB essential modulator (NEMO), resulting in the discovery of several cell-permeable bicyclic peptides, which inhibited the NEMO-IKKß interaction with low µM IC50 values. Further optimization of one of the hits led to a relatively potent and cell-permeable NEMO inhibitor (IC50 = 1.0 µM), which selectively inhibited canonical NF-κB signaling in mammalian cells and the proliferation of cisplatin-resistant ovarian cancer cells. The inhibitor provides a useful tool for investigating the biological functions of NEMO/NF-κB and a potential lead for further development of a novel class of anti-inflammatory and anticancer drugs.

Saudi dental hygienists' opinions regarding establishing a professional association.

AIM: To assess the opinions of dental hygienists in Saudi Arabia regarding the establishment of a professional association including the role it should have to meet their professional needs. METHODS: A cross-sectional electronic survey using Qualtrics was utilized. IRB exemption was obtained prior to distribution. Although there are 298 licensed Saudi dental hygienists in Saudi Arabia, email addresses were only available for 101 respondents: those obtained previously by direct contact for the purpose of initiation of a professional association and those referred by the direct contacts. Subjects were emailed a link to the survey. RESULTS: Seventy-seven subjects responded fully to the survey yielding a response rate of 70.3%. Most 91.5% (n = 65) of the respondents favoured the establishment of a Saudi dental hygiene professional association. Eighty-eight per cent (n = 59) responded that such an association would promote development of the profession in the country at least somewhat and 86.6% (n = 58) agreed that their professional needs could be met by its establishment. Interestingly, half of those who did not support the creation of the professional association believed it would promote development of the profession and meet professional needs. CONCLUSIONS: A representative sample of dental hygienists in Saudi Arabia support the establishment of a professional association and feel that it would advocate and promote the dental hygiene profession in the country and meet their professional needs.

Bicyclic Peptides as Next-Generation Therapeutics.

Bicyclic peptides have greater conformational rigidity and metabolic stability than linear and monocyclic peptides and are capable of binding to challenging drug targets with antibody-like affinity and specificity. Powerful combinatorial library technologies have recently been developed to rapidly synthesize and screen large bicyclic peptide libraries for ligands against enzymes, receptors, and protein-protein interaction targets. Bicyclic peptides have been developed as potential therapeutics against a wide range of diseases, drug targeting agents, imaging/diagnostic probes, and research tools. In this Minireview, we provide a summary of the recent progresses on the synthesis and applications of bicyclic peptides.

Enhancing the Cell Permeability and Metabolic Stability of Peptidyl Drugs by Reversible Bicyclization.

Therapeutic applications of peptides are currently limited by their proteolytic instability and impermeability to the cell membrane. A general, reversible bicyclization strategy is now reported to increase both the proteolytic stability and cell permeability of peptidyl drugs. A peptide drug is fused with a short cell-penetrating motif and converted into a conformationally constrained bicyclic structure through the formation of a pair of disulfide bonds. The resulting bicyclic peptide has greatly enhanced proteolytic stability as well as cell-permeability. Once inside the cell, the disulfide bonds are reduced to produce a linear, biologically active peptide. This strategy was applied to generate a cell-permeable bicyclic peptidyl inhibitor against the NEMO-IKK interaction.

Safe Reduction in CD4 Cell Count Monitoring in Stable, Virally Suppressed Patients With HIV Infection or HIV/Hepatitis C Virus Coinfection.

BACKGROUND: It has been suggested that routine CD4 cell count monitoring in human immunodeficiency virus (HIV)-monoinfected patients with suppressed viral loads and CD4 cell counts >300 cell/µL could be reduced to annual. HIV/hepatitis C virus (HCV) coinfection is frequent, but evidence supporting similar reductions in CD4 cell count monitoring is lacking for this population. We determined whether CD4 cell count monitoring could be reduced in monoinfected and coinfected patients by estimating the probability of maintaining CD4 cell counts ≥200 cells/µL during continuous HIV suppression. METHODS: The PISCIS Cohort study included data from 14 539 patients aged ≥16 years from 10 hospitals in Catalonia and 2 in the Balearic Islands (Spain) since January 1998. All patients who had at least one period of 6 months of continuous HIV suppression were included in this analysis. Cumulative probabilities with 95% confidence intervals were calculated using the Kaplan-Meier estimator stratified by the initial CD4 cell count at the period of continuous suppression initiation. RESULTS: A total of 8695 patients were included. CD4 cell counts fell to <200 cells/µL in 7.4% patients, and the proportion was lower in patients with an initial count >350 cells/µL (1.8%) and higher in those with an initial count of 200-249 cells/µL (23.1%). CD4 cell counts fell to <200 cells/µL in 5.7% of monoinfected and 11.1% of coinfected patients. Of monoinfected patients with an initial CD4 cell count of 300-349 cells/µL, 95.6% maintained counts ≥200 cells/µL. In the coinfected group with the same initial count, this rate was lower, but 97.6% of coinfected patients with initial counts >350 cells/µL maintained counts ≥200 cells/µL. CONCLUSIONS: From our data, it can be inferred that CD4 cell count monitoring can be safely performed annually in HIV-monoinfected patients with CD4 cell counts >300 cells/µL and HIV/HCV-coinfected patients with counts >350 cells/µL.

Improvement of BMD after Switching from Lopinavir/R Plus Two Nucleos(T)ide Reverse Transcriptase Inhibitors to Lopinavir/R Plus Lamivudine: OLE-LIP Substudy.

OBJECTIVE: To compare 48-week changes in bone mineral density (BMD) and body fat distribution between patients continuing lopinavir/ritonavir and two NRTIs and those switching to lopinavir/ritonavir and lamivudine. METHODS: Substudy of a randomized, open-label, multicenter OLE study was carried out. Adult HIV-infected patients with <50 copies/mL for ≥6 months were randomized (1:1) to continue lopinavir/ritonavir and two NRTIs or switching to lopinavir/ritonavir and lamivudine. Dual-energy X-ray absorptiometry (DXA) was performed at baseline and after 48 weeks to measure bone composition and body fat distribution in both the groups. RESULTS: Forty-one patients (dual-therapy, n = 23; triple-therapy, n = 18) of 239, who received at least one dose of study medication, completed the study: median age, 42 years, 71% male, 73% Caucasian. At week 48, total BMD increased by 1.04% (95% CI, 0.06 to 2.01%) among patients switching to dual-therapy, whereas no significant changes occurred in patients maintaining triple-therapy. Dual-therapy and older age were independently associated with total BMD increase. Among patients discontinuing tenofovir-DF, a significant increase was seen in total BMD (1.43; 95% CI, -0.04 to 2.91) and total hip (1.33%; 95% CI, 0.44 to 2.22%). A non-statistically significant decrease in femoral and spinal BMD was observed in patients who discontinued abacavir and in those continuing triple-therapy. Regarding fat distribution, no significant changes were seen in both the treatment groups. DISCUSSION: BMD increased following switching to lopinavir/ritonavir plus lamivudine in HIV-infected patients on suppressive triple-therapy with lopinavir/ritonavir and two NRTIs including tenofovir-DF.

The effectiveness of electrocautery ablation for the treatment of high-grade anal intraepithelial neoplasia in HIV-infected men who have sex with men.

OBJECTIVES: Electrocautery is one of the main treatment options for high-grade anal intraepithelial neoplasia (HGAIN). However, data regarding its efficacy are scarce. The aim of the study was to evaluate the effectiveness of electrocautery for the treatment of HGAIN. METHODS: An observational study of HIV-infected men who have sex with men (MSM) who underwent screening for anal dysplasia was carried out. The on-treatment effectiveness of electrocautery was evaluated (according to biopsy findings measured 6-8 weeks after treatment) in patients with HGAIN. A complete response was defined as resolution of anal intraepithelial neoplasia (AIN), a partial response as regression to low-grade AIN and recurrence as biopsy-proven HGAIN during follow-up. RESULTS: From May 2009 to November 2014, 21.9% (126 of 576) of patients screened were found to have HGAIN. Electrocautery effectiveness was evaluated in 83 patients. A complete response was observed in 27 patients [32.5%; 95% confidence interval (CI) 23.4-53.2%], a partial response in 28 patients (33.7%; 95% CI 24.5-44.4%) and persistence in 28 patients (33.7%; 95% CI 24.5-44.4%). The patients with the most successful results (81.8%) required two to four sessions of electrocautery. After a mean follow-up of 12.1 months, 14 of 55 patients with a response (25.4%; 95% CI 15.8-38.3%) developed recurrent HGAIN within a mean time of 29.9 months (95% CI 22-37.7 months). No patient progressed to invasive cancer during the study or developed serious adverse events after treatment. No factors associated with poor response or recurrences were observed. CONCLUSIONS: Although electrocautery is the standard treatment for anal dysplasia, almost 50% of patients with HGAIN in our study did not respond or relapsed. New treatment strategies are necessary to optimize the management of anal dysplasia.

Outcome of neuropsychiatric symptoms related to an antiretroviral drug following its substitution by nevirapine: the RELAX study.

OBJECTIVES: The primary objective was to evaluate the improvement in neuropsychiatric symptoms attributed to an antiretroviral drug after that drug was substituted with nevirapine. The secondary objective was to evaluate the impact on patient adherence and quality of life. METHODS: A prospective, observational study was carried out that included patients with HIV-1 plasma suppression for whom an antiretroviral drug was substituted with nevirapine because of central nervous system (CNS) side effects, a Pittsburgh Sleep Quality Index (PSQI) score > 5 or a Hospital Anxiety and Depression Scale (HADS) score ≥ 10, and who had not initiated psychoactive drug treatment during the prior 6 weeks. Evaluations were carried out at baseline and 1 and 3 months after the switch using the PSQI, HADS, Epworth Sleepiness Scale, Medical Outcomes Study-Short Form 30 items (MOS-SF-30) and Simplified Medication Adherence Questionnaire (SMAQ). RESULTS: A total of 129 patients were included in the study. The drug substituted was mainly efavirenz (89.9%), and reasons for the switch included sleep disturbances (75.2%), anxiety (65.1%), depression (38.7%), attention disturbances (31%), and other reasons (31%), with a mean of 2.4 neuropsychiatric disturbances per patient. A statistically significant improvement was observed in all the tests evaluating neuropsychiatric symptoms and adherence at 1 and 3 months. The CD4 lymphocyte count remained stable (P = 0.096). Three (2.3%) patients had a detectable plasma HIV-1 RNA at the end of the study. Nine patients (6.9%) withdrew because of nevirapine-related toxicity (rash in seven patients and hypertransaminasaemia in two patients, none of which were > grade 2). CONCLUSIONS: The switch to nevirapine from a drug causing neuropsychiatric disturbances (primarily efavirenz) in subjects with virological suppression was effective in resolving those disturbances, with an improvement in all the parameters studied. This led to better adherence to treatment and quality of life, with no detrimental effect on their immunological and virological control.

Switching from zidovudine/lamivudine to tenofovir/emtricitabine improves fat distribution as measured by fat mass ratio.

OBJECTIVES: Fat mass ratio (FMR) has been suggested as an objective indicator of abnormal body fat distribution in HIV infection. Although it could provide more comprehensive information on body fat changes than limb fat mass, FMR has scarcely been used in clinical trials examining body fat distribution in HIV-infected patients. METHODS: A subanalysis of a controlled, randomized clinical trial in virologically suppressed HIV-1-infected men switching from zidovudine (ZDV)/lamivudine (3TC) to emtricitabine (FTC)/tenofovir (TDF) versus continuing on ZDV/3TC was carried out. FMR was assessed by dual X-ray absorptiometry (DEXA) for a period of 72 weeks. Lipoatrophy was defined as FMR ≥ 1.5. Multivariate linear regression models for the change in FMR from baseline were fitted. RESULTS: Sixty-five men were randomized and treated (28 in the FTC/TDF arm and 37 in the ZDV/3TC arm), and 57 completed the study (25 and 32 in each arm, respectively). In the FTC/TDF arm, adjusted mean FMR decreased by 0.52 at week 72 (P = 0.014), and in the ZDV/3TC arm it increased by 0.13 (P = 0.491; P between arms = 0.023). Among subjects with lipoatrophy (baseline FMR ≥ 1.5), adjusted FMR decreased by 0.76 (P = 0.003) in the FTC/TDF arm and increased by 0.21 (P = 0.411; P between arms = 0.009) in the ZDV/3TC arm. Baseline FMR and treatment group were significant predictors (P < 0.05) of post-baseline changes in FMR. CONCLUSIONS: Switching from ZDV/3TC to FTC/TDF led to an improvement in FMR, compared with progressive worsening of FMR in subjects receiving ZDV/3TC, showing that fat mass not only increased but was also distributed in a healthier way after the switch.

Liver stiffness and aspartate aminotransferase levels predict the risk for liver fibrosis progression in hepatitis C virus/HIV-coinfected patients.

OBJECTIVES: The aim of the study was to investigate liver fibrosis outcome and the risk factors associated with liver fibrosis progression in hepatitis C virus (HCV)/HIV-coinfected patients. METHODS: We prospectively obtained liver stiffness measurements by transient elastography in a cohort of 154 HCV/HIV-coinfected patients, mostly Caucasian men on suppressive antiretroviral treatment, with the aim of determining the risk for liver stiffness measurement (LSM) increase and to identify the predictive factors for liver fibrosis progression. To evaluate LSM trends over time, a linear mixed regression model with LSM level as the outcome and duration of follow-up in years as the main covariate was fitted. RESULTS: After a median follow-up time of 40 months, the median increase in LSM was 1.05 kPa/year [95% confidence interval (CI) 0.72-1.38 kPa/year]. Fibrosis stage progression was seen in 47% of patients, and 17% progressed to cirrhosis. Aspartate aminotransferase (AST) levels and liver fibrosis stage at baseline were identified as independent predictors of LSM change. Patients with F3 (LSM 9.6-14.5 kPa) or AST levels ≥ 64 IU/L at baseline were at higher risk for accelerated LSM increase (ranging from 1.45 to 2.61 kPa/year), whereas LSM change was very slow among patients with both F0-F1 (LSM ≤ 7.5 kPa) and AST levels ≤ 64 IU/L at baseline (0.34 to 0.58 kPa/year). An intermediate risk for LSM increase (from 0.78 to 1.03 kPa/year) was seen in patients with F2 (LSM 7.6-9.5 kPa) and AST baseline levels ≤ 64 IU/L. CONCLUSIONS: AST levels and liver stiffness at baseline allow stratification of the risk for fibrosis progression and might be clinically useful to guide HCV treatment decisions in HIV-infected patients.

Association of pre-pregnancy BMI and postpartum weight retention with postpartum HbA1c among women with Type 1 diabetes.

AIM: To examine the association of pre-pregnancy BMI and postpartum weight retention with postpartum HbA(1c) levels in women with Type 1 diabetes. METHODS: We longitudinally evaluated 136 women with Type 1 diabetes who received prenatal, pregnancy, and postpartum care through Joslin Diabetes Center's Diabetes and Pregnancy Program between 2004 and 2009. Weight, BMI and HbA(1c) concentrations were assessed before the index pregnancy and repeatedly monitored after delivery until 12 months postpartum. We used linear mixed models to assess the association of postpartum HbA(1c) with pre-pregnancy BMI and postpartum weight retention. RESULTS: The mean HbA(1c) concentration increased from 49 mmol/mol (6.6%) at 6 weeks postpartum to 58 mmol/mol (7.5%) by 10 months postpartum, a level similar to the mean pre-pregnancy HbA(1c) concentration. Postpartum weight retention showed a linearly decreasing trend of 0.06 kg/week (P < 0.0001), with -0.1 kg average postpartum weight retention by 1 year postpartum. Compared with women with a pre-pregnancy BMI ≥ 25 kg/m², women with a lower pre-pregnancy BMI maintained a 3.4 mmol/mol (0.31%) lower HbA(1c) concentration, after adjusting for several sociodemographic, reproductive and diabetes-related factors (P = 0.03). There was a suggestion of a time-varying positive association between HbA1c and postpartum weight retention, with the most significant difference of 3.7 mmol/mol (0.34%; P = 0.05) at 30 weeks postpartum among women with postpartum weight retention ≥ 5 kg vs those with postpartum weight retention < 5 kg. CONCLUSIONS: Pre-pregnancy BMI and postpartum weight retention were positively associated with HbA(1c) during the first postpartum year in women with Type 1 diabetes. Interventions to modify the behaviours associated with these body weight factors before pregnancy and after delivery may help women with Type 1 diabetes maintain good glycaemic control after pregnancy.

Lemierre's syndrome, the forgotten disease.

Lemierre's syndrome is a rare and potentially fatal entity affecting otherwise healthy and young adults. The infection originates in the throat and spreads via a septic trombophlebitis of the internal jugular vein, with development of distant septic emboli. This clinical picture is characteristic but many clinicians are unaware of the condition and diagnosis is often delayed with potentially fatal consequences.

Sialoendoscopy in the management of salivary gland disorders--4 years experience.

Sialoendoscopy is a minimally invasive technique used in the diagnosis and management of salivary gland disorders with promising success rates. Our objective is to describe our experience in sialoendoscopy, outlining our technique, success rates and complications, and to compare our data to those reported in the literature. A retrospective review and data analysis of all sialoendoscopic procedures performed by our service between 2006 and 2010 was performed. 41 patients were identified. 4 (9.7%) patients had normal findings, 2 (4.8%) had anatomical variants, 4 (9.7%) had benign strictures, 11 (26.8%) had mucinous debris and 20 (48%) had obstructing stones. Stone removal was successful in 19 (95%) of the 20 cases and symptomatic relief was achieved in 34 (83%) cases. In our experience a single interventional modality was used, despite that our success rates are similar to those reported in the literature where multiple therapeutic modalities were used.

Early lipid changes with atazanavir/ritonavir or darunavir/ritonavir.

OBJECTIVES: Ritonavir-boosted atazanavir and darunavir are protease inhibitors that are recommended for initial treatment of HIV infection because each has shown better lipid effects and overall tolerability than ritonavir-boosted lopinavir. The extent to which lipid effects and overall tolerability differ between treatments with atazanavir and darunavir and whether atazanavir-induced hyperbilirubinaemia may result in more favourable metabolic effects are issues that remain to be resolved. METHODS: A 96-week randomized clinical trial was carried out. The primary endpoint was change in total cholesterol at 24 weeks. Secondary endpoints were changes in lipids other than total cholesterol, insulin sensitivity, total bilirubin, estimated glomerular filtration rate, and CD4 and CD8 cell counts, and the proportion of patients with plasma HIV RNA < 50 HIV-1 RNA copies/mL and study drug discontinuation because of adverse effects at 24 weeks. Analyses were intent-to-treat. RESULTS: One hundred and seventy-eight patients received once-daily treatment with either atazanavir/ritonavir (n = 90) or darunavir/ritonavir (n = 88) plus tenofovir/emtricitabine. At 24 weeks, mean total cholesterol had increased by 7.26 and 11.47 mg/dL in the atazanavir/ritonavir and darunavir/ritonavir arms, respectively [estimated difference -4.21 mg/dL; 95% confidence interval (CI) -12.11 to +3.69 mg/dL; P = 0.75]. However, the ratio of total to high-density lipoprotein (HDL) cholesterol tended to show a greater decrease with atazanavir/ritonavir compared with darunavir/ritonavir (estimated difference -1.02; 95% CI -2.35 to +0.13; P = 0.07). Total bilirubin significantly increased with atazanavir/ritonavir (estimated difference +1.87 mg/dL; 95% CI +1.58 to +2.16 mg/dL; P < 0.01), but bilirubin changes were not associated with lipid changes. Secondary endpoints other than total bilirubin were not significantly different between arms. CONCLUSIONS: Atazanavir/ritonavir and darunavir/ritonavir plus tenofovir/emtricitabine did not show significant differences in total cholesterol change or overall tolerability at 24 weeks. However, there was a trend towards a lower total to HDL cholesterol ratio with atazanavir/ritonavir and this effect was unrelated to bilirubin.