Tracing HIV-1 strains that imprint broadly neutralizing antibody responses.

Understanding the determinants of broadly neutralizing antibody (bNAb) evolution is crucial for the development of bNAb-based HIV vaccines1. Despite emerging information on cofactors that promote bNAb evolution in natural HIV-1 infections, in which the induction of bNAbs is genuinely rare2, information on the impact of the infecting virus strain on determining the breadth and specificity of the antibody responses to HIV-1 is lacking. Here we analyse the influence of viral antigens in shaping antibody responses in humans. We call the ability of a virus strain to induce similar antibody responses across different hosts its antibody-imprinting capacity, which from an evolutionary biology perspective corresponds to the viral heritability of the antibody responses. Analysis of 53 measured parameters of HIV-1-binding and neutralizing antibody responses in a cohort of 303 HIV-1 transmission pairs (individuals who harboured highly related HIV-1 strains and were putative direct transmission partners or members of an HIV-1 transmission chain) revealed that the effect of the infecting virus on the outcome of the bNAb response is moderate in magnitude but highly significant. We introduce the concept of bNAb-imprinting viruses and provide evidence for the existence of such viruses in a systematic screening of our cohort. The bNAb-imprinting capacity can be substantial, as indicated by a transmission pair with highly similar HIV-1 antibody responses and strong bNAb activity. Identification of viruses that have bNAb-imprinting capacities and their characterization may thus provide the potential to develop lead immunogens.

Unsupervised machine learning predicts future sexual behaviour and sexually transmitted infections among HIV-positive men who have sex with men.

Machine learning is increasingly introduced into medical fields, yet there is limited evidence for its benefit over more commonly used statistical methods in epidemiological studies. We introduce an unsupervised machine learning framework for longitudinal features and evaluate it using sexual behaviour data from the last 20 years from over 3'700 participants in the Swiss HIV Cohort Study (SHCS). We use hierarchical clustering to find subgroups of men who have sex with men in the SHCS with similar sexual behaviour up to May 2017, and apply regression to test whether these clusters enhance predictions of sexual behaviour or sexually transmitted diseases (STIs) after May 2017 beyond what can be predicted with conventional parameters. We find that behavioural clusters enhance model performance according to likelihood ratio test, Akaike information criterion and area under the receiver operator characteristic curve for all outcomes studied, and according to Bayesian information criterion for five out of ten outcomes, with particularly good performance for predicting future sexual behaviour and recurrent STIs. We thus assess a methodology that can be used as an alternative means for creating exposure categories from longitudinal data in epidemiological models, and can contribute to the understanding of time-varying risk factors.

A Systematic Molecular Epidemiology Screen Reveals Numerous Human Immunodeficiency Virus (HIV) Type 1 Superinfections in the Swiss HIV Cohort Study.

BACKGROUND: Studying human immunodeficiency virus type 1 (HIV-1) superinfection is important to understand virus transmission, disease progression, and vaccine design. But detection remains challenging, with low sampling frequencies and insufficient longitudinal samples. METHODS: Using the Swiss HIV Cohort Study (SHCS), we developed a molecular epidemiology screening for superinfections. A phylogeny built from 22 243 HIV-1 partial polymerase sequences was used to identify potential superinfections among 4575 SHCS participants with longitudinal sequences. A subset of potential superinfections was tested by near-full-length viral genome sequencing (NFVGS) of biobanked plasma samples. RESULTS: Based on phylogenetic and distance criteria, 325 potential HIV-1 superinfections were identified and categorized by their likelihood of being detected as superinfections due to sample misidentification. NFVGS was performed for 128 potential superinfections; of these, 52 were confirmed by NFVGS, 15 were not confirmed, and for 61 sampling did not allow confirming or rejecting superinfection because the sequenced samples did not include the relevant time points causing the superinfection signal in the original screen. Thus, NFVGS could support 52 of 67 adequately sampled potential superinfections. CONCLUSIONS: This cohort-based molecular approach identified, to our knowledge, the largest population of confirmed superinfections, showing that, while rare with a prevalence of 1%-7%, superinfections are not negligible events.

Lateralized vs. classic Grammont-style reverse shoulder arthroplasty for cuff deficiency Hamada stage 1-3: does the design make a difference?

BACKGROUND: Reverse shoulder arthroplasty (RSA) with a lateralized design is thought to improve outcomes. Our aim was to compare RSA with the classic Grammont prosthesis against a prosthesis with 135° inclination and a lateralized glenosphere for cuff-deficient shoulders. METHODS: Patients with irreparable massive posterosuperior rotator cuff tear Hamada grade 1-3 underwent RSA and were documented prospectively up to 24 months postsurgery. Comparative RSA groups were "lateralized" (L), with 135° humeral inclination and 36+4-mm lateralized glenosphere (n = 44), and "Grammont" (G), with 155° humeral inclination and 36+2-mm eccentric glenosphere (n = 23). Range of motion including the Apley scratch test, abduction strength, Constant-Murley score (CS), and Shoulder Pain and Disability Index (SPADI) were assessed. Anteroposterior and axial radiographs were evaluated at 24 months, and additional measurements of scapular neck and glenoid anatomy, baseplate and glenosphere position, center of rotation, humeral offset, and lateralization and distalization shoulder angles were made. Linear regression and mixed models adjusted for sex differences and preoperative values were applied. RESULTS: Overall CS and SPADI outcomes were not significantly different between groups (P ≥ .654). For group L, external rotation remained stable up to the 2-year follow-up and was higher than for group G (P = .012 ); a greater proportion of group L patients could reach the lumbar vertebra 3 (L3) (70% vs. 48% in group G) (P = .26). Group G had a higher inferior glenosphere overhang (P = .020) and center of rotation (COR) medialization (P < .001), whereas group L had higher humeral offset (P < .001) and lateralization shoulder angle (P < .001) with a trend toward higher baseplate positioning (P = .045). The rate of scapular notching was 2.9 times higher for group G than group L (P = .001). CONCLUSION: RSA with 135° humeral inclination and a lateralized glenosphere shows similar outcome scores as the classic Grammont design but enables better preservation of external rotation and reduces the rate of scapular notching compared with the classic Grammont design in Hamada 1-3 patients with irreparable posterosuperior tears.

Antiretroviral Drugs Associated With Subclinical Coronary Artery Disease in the Swiss Human Immunodeficiency Virus Cohort Study.

BACKGROUND: Coronary artery disease (CAD) events have been associated with certain antiretroviral therapy (ART) agents. In contrast, the influence of ART on subclinical atherosclerosis is not clear. The study objective was to assess the association between individual ART agents and the prevalence and extent of subclinical CAD. METHODS: Coronary artery calcium (CAC) scoring and coronary computed tomography angiography (CCTA) were performed in ≥45-year-old Swiss Human Immunodeficiency Virus Cohort Study participants. The following subclinical CAD endpoints were analyzed separately: CAC score >0, any plaque, calcified plaque, noncalcified/mixed plaque, segment involvement score (SIS), and segment severity score (SSS). Logistic regression models calculated by inverse probability of treatment weights (IPTW) were used to explore associations between subclinical CAD and cumulative exposure to the 10 most frequently used drugs. RESULTS: There were 403 patients who underwent CCTA. A CAC score >0 was recorded in 188 (47%), any plaque in 214 (53%), calcified plaque in 151 (38%), and noncalcified/mixed plaque in 150 (37%) participants. A CAC score >0 was negatively associated with efavirenz (IPTW adjusted odds ratio per 5 years 0.73, 95% confidence interval [CI] 0.56-0.96), tenofovir disoproxil fumarate (0.68, 95% CI 0.49-0.95), and lopinavir (0.64, 95% CI 0.43-0.96). Any plaque was negatively associated with tenofovir disoproxil fumarate (0.71, 95% CI 0.51-0.99). Calcified plaque was negatively associated with efavirenz (0.7, 95% CI 0.57-0.97). Noncalcified/mixed plaque was positively associated with abacavir (1.46, 95% CI 1.08-1.98) and negatively associated with emtricitabine (0.67, 95% CI 0.46-0.99). For SSS and SIS, we found no association with any drug. CONCLUSIONS: An increased risk of noncalcified/mixed plaque was only found in patients exposed to abacavir. Emtricitabine was negatively associated with noncalcified/mixed plaque, while tenofovir disoproxil fumarate and efavirenz were negatively associated with any plaque and calcified plaque, respectively.

Playing a musical instrument is associated with slower cognitive decline in community-dwelling older adults.

BACKGROUND: Elucidating behavioral protective factors for cognitive decline and dementia can have a far-reaching impact. AIMS: To describe the association of present and past musical instrument playing with cognitive function in cognitively intact older adults. METHOD: A post hoc observational analysis of the Zurich Disability Prevention Trial. Past and present musical instrument playing was correlated with Mini-Mental State Examination (MMSE) and EuroQol-Visual Analogue Scale (EQ-VAS) using linear regression at baseline and mixed-model linear regression over 1 year. RESULTS: Two hundred community dwelling adults age 70 and older (mean age 77.7) were included. There were 48.5% (97/200) participants, who ever played a musical instrument; 35% (70/200) played in the past and 13.5% (27/200) played at present. At baseline, present players had a suggestively higher adjusted-MMSE than never players (28.9 vs. 28.5, p value 0.059). Over 12 months, compared to never players, ever players showed a significantly better improvement from baseline in adjusted-MMSE (0.29 vs. - 0.12, p value 0.007). The association remained significant even after restricting to participants without higher education (p value 0.03). Over time, no differences were observed for EQ-VAS (p value 0.45). However, past players had the largest decline in health-related quality of life at 12 months. DISCUSSION: The support for a protective association in our observational study suggests the need for clinical trials to examine the effect of playing a musical instrument on cognitive function and decline. Both returning to play after an interruption and learning to play from the beginning should be examined. CONCLUSIONS: Present and past musical instrument playing may assist in preserving cognitive function in community-dwelling older adults.

Short-term safety, function, and quality of life in patients treated with Univers Revers prosthesis: a multicenter 2-year follow-up case series.

BACKGROUND: The use of reverse total shoulder arthroplasty (RTSA) has dramatically increased in recent years with the advent of new prosthesis designs regularly entering the market. We define the rate of local complications during the first 2 years after RTSA with the Univers Revers prosthesis and describe the changes in radiologic outcomes, as well as function, pain, satisfaction, and quality of life. METHODS: This multicenter, prospective case series included rotator cuff tear arthropathy patients who underwent RTSA with the Univers Revers. Incidence percentages of complications and pathologic radiographic changes were documented. Mixed-model linear regression was used to examine changes in range of motion, shoulder function (Constant score, Shoulder Pain and Disability Index, Subjective Shoulder Value), and quality of life (EQ-5D-5L [European Quality of Life 5 Dimensions 5 Level] and EQ-VAS [EuroQol Visual Analog Scale]). RESULTS: Of 187 patients, 59.4% were women, and the mean age was 75.3 years (range, 56-91 years). Twenty-five percent of patients had a postoperative complication; 5 complications were severe (2.7%, 5 of 187), whereby 2 were implant related (1.1%; 95% confidence interval [CI], 0.1%-3.8%). The incidence of scapular notching was 10.6% (95% CI, 6.5%-16%). After 2 years, abduction, flexion, and abduction strength improved by 54° (95% CI, 50°-58°), 57° (95% CI, 53°-60°), and 5 kg (95% CI, 4-5 kg), respectively (P < .001), whereas external rotation at 0° (1°; 95% CI, -1° to 3°) did not improve (P = .4). The Constant score improved by 39 (95% CI, 38-41); Shoulder Pain and Disability Index, by 50 (95% CI, 47-52); and Subjective Shoulder Value, by 43 (95% CI, 41-45) (P < .001). Furthermore, the EQ-5D-5L index value improved by 0.31 (95% CI, 0.30-0.33), and the EQ-VAS score improved by 16 (95% CI, 14-18) (P < .001). CONCLUSION: Our case series showed a low complication rate with a consistent clinically relevant and statistically significant improvement across most clinical and patient-reported outcomes for the Univers Revers. Long-term safety requires further investigation.

Dissecting HIV Virulence: Heritability of Setpoint Viral Load, CD4+ T-Cell Decline, and Per-Parasite Pathogenicity.

Pathogen strains may differ in virulence because they attain different loads in their hosts, or because they induce different disease-causing mechanisms independent of their load. In evolutionary ecology, the latter is referred to as "per-parasite pathogenicity". Using viral load and CD4+ T-cell measures from 2014 HIV-1 subtype B-infected individuals enrolled in the Swiss HIV Cohort Study, we investigated if virulence-measured as the rate of decline of CD4+ T cells-and per-parasite pathogenicity are heritable from donor to recipient. We estimated heritability by donor-recipient regressions applied to 196 previously identified transmission pairs, and by phylogenetic mixed models applied to a phylogenetic tree inferred from HIV pol sequences. Regressing the CD4+ T-cell declines and per-parasite pathogenicities of the transmission pairs did not yield heritability estimates significantly different from zero. With the phylogenetic mixed model, however, our best estimate for the heritability of the CD4+ T-cell decline is 17% (5-30%), and that of the per-parasite pathogenicity is 17% (4-29%). Further, we confirm that the set-point viral load is heritable, and estimate a heritability of 29% (12-46%). Interestingly, the pattern of evolution of all these traits differs significantly from neutrality, and is most consistent with stabilizing selection for the set-point viral load, and with directional selection for the CD4+ T-cell decline and the per-parasite pathogenicity. Our analysis shows that the viral genotype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor.

Subclinical coronary artery disease in Swiss HIV-positive and HIV-negative persons.

Aims: HIV-positive persons have increased cardiovascular event rates but data on the prevalence of subclinical atherosclerosis compared with HIV-negative persons are not uniform. We assessed subclinical atherosclerosis utilizing coronary artery calcium (CAC) scoring and coronary computed tomography angiography (CCTA) in 428 HIV-positive participants of the Swiss HIV Cohort Study and 276 HIV-negative controls concurrently referred for clinically indicated CCTA. Methods and results: We assessed the association of HIV infection, cardiovascular risk profile, and HIV-related factors with subclinical atherosclerosis in univariable and multivariable analyses. HIV-positive participants (median duration of HIV infection, 15 years) were younger than HIV-negative participants (median age 52 vs. 56 years; P < 0.01) but had similar median 10-year Framingham risk scores (9.0% vs. 9.7%; P = 0.40). The prevalence of CAC score >0 (53% vs. 56.2%; P = 0.42) and median CAC scores (47 vs. 47; P = 0.80) were similar, as was the prevalence of any, non-calcified/mixed, and high-risk plaque. In multivariable adjusted analysis, HIV-positive participants had a lower prevalence of calcified plaque than HIV-negative participants [36.9% vs. 48.6%, P < 0.01; adjusted odds ratio (aOR) 0.57; 95% confidence interval (CI) 0.40-0.82; P < 0.01], lower coronary segment severity score (aOR 0.72; 95% CI 0.53-0.99; P = 0.04), and lower segment involvement score (aOR 0.71, 95% CI 0.52-0.97; P = 0.03). Advanced immunosuppression was associated with non-calcified/mixed plaque (aOR 1.97; 95% CI 1.09-3.56; P = 0.02). Conclusion: HIV-positive persons in Switzerland had a similar degree of non-calcified/mixed plaque and high-risk plaque, and may have less calcified coronary plaque, and lower coronary atherosclerosis involvement and severity scores than HIV-negative persons with similar Framingham risk scores.

High Rates of Subsequent Asymptomatic Sexually Transmitted Infections and Risky Sexual Behavior in Patients Initially Presenting With Primary Human Immunodeficiency Virus-1 Infection.

Background: Knowledge of the risk factors of individuals with an asymptomatic sexually transmitted infection (STI) is essential for implementation of targeted STI screening strategies. Methods: Between June 2015 and January 2017, an STI screening was offered to all participants in the Zurich Primary human immunodeficiency virus (HIV)-1 Infection study. Patients were tested for gonorrhea, chlamydia, syphilis, and hepatitis C virus (HCV). Results: Of 214 participants, 174 (81%) were screened at least once. Most patients were men who have sex with men (MSM) (87.4%). Presenting with a primary HIV infection was associated with higher odds for later risky sexual behavior, as compared with presenting in the chronic phase (odds ratio [OR], 5.58; 95% confidence interval [CI], 3.68-8.8). In total, 79 STIs were detected, reflecting a high period prevalence of 33.3% (58 of 174 patients). Sixty-six percent of patients (52 of 79) were asymptomatic. Most common STIs were chlamydia (50.6%; 40 of 79 patients), gonorrhea (25.3%; 20 of 79), and syphilis (19%; 15 of 79). In a multivariable model, engaging in insertive (OR, 6.48; 95% CI, 1.14-36.76) or both insertive and receptive (4.61; 1.01-20.96) anal intercourse, STI symptoms (3.4; 1.68-6.89), and condomless sex (2.06; 1.14-3.74) were positively correlated with a positive screening result. The hazard of an incident STI increased with the presence of STI symptoms (hazard ratio, 3.03; 95% CI, 1.17-7.84) and any recent drug use (2.63; 1-6.9). Conclusions: A trimonthly STI screening including asymptomatic individuals should be considered in this population, particularly in MSM who report sexual risk behavior. Clinical Trial Registration: NCT 00537966.

Low prevalence of transmitted HIV-1 drug resistance detected by a dried blood spot (DBS)-based next-generation sequencing (NGS) method in newly diagnosed individuals in Cameroon in the years 2015-16.

Objectives: To determine the most recent prevalence, transmission patterns and risk factors of transmitted drug-resistance mutations (TDRMs) in Cameroon, we initiated a multicentre study monitoring HIV-1 drug resistance in newly HIV-1-diagnosed individuals using a novel next-generation sequencing (NGS) assay applicable to fingerprick dried blood spot (DBS) samples. Methods: Fingerprick DBS samples and questionnaires were collected from 360 newly HIV-1-diagnosed individuals in four hospitals in urban areas in Cameroon in the years 2015-16. We developed an HIV-1 protease and reverse transcriptase drug resistance genotyping assay applicable to DBS samples and HIV-1 genomes of groups M, N and O. The WHO 2009 list of mutations for surveillance of transmitted drug-resistant HIV strains was used to analyse TDRMs. Results: Applying our 'DBS-NGS-genotypic resistance test', baseline HIV-1 drug resistance data were successfully obtained from 82.8% (298/360) of newly diagnosed individuals. At nucleotide frequencies >15%, TDRMs to NRTIs were observed in 3.0% (9/298), to NNRTIs in 4.0% (12/298) and to PIs in 1.3% (3/240). The NNRTI mutation K103N was most commonly detected (2.7%). Expanding the analysis to low-abundance TDRMs, i.e. 3%-15%, 12 additional individuals (4.0%) harbouring TDRMs were identified. Having unprotected sex with a known HIV-1-positive person was significantly associated with the transmission of DRMs (adjusted OR 9.6; 95% CI 1.79-51.3). Conclusions: The prevalence of transmitted HIV-1 drug resistance is currently low in the study sites in Cameroon. Evidence of some risky sexual behaviours depicts a public health problem with possible implications for the prevention of new HIV-1 infections.

Parent-offspring regression to estimate the heritability of an HIV-1 trait in a realistic setup.

BACKGROUND: Parent-offspring (PO) regression is a central tool to determine the heritability of phenotypic traits; i.e., the relative extent to which those traits are controlled by genetic factors. The applicability of PO regression to viral traits is unclear because the direction of viral transmission-who is the donor (parent) and who is the recipient (offspring)-is typically unknown and viral phylogenies are sparsely sampled. METHODS: We assessed the applicability of PO regression in a realistic setting using Ornstein-Uhlenbeck simulated data on phylogenies built from 11,442 Swiss HIV Cohort Study (SHCS) partial pol sequences and set-point viral load (SPVL) data from 3293 patients. RESULTS: We found that the misidentification of donor and recipient plays a minor role in estimating heritability and showed that sparse sampling does not influence the mean heritability estimated by PO regression. A mixed-effect model approach yielded the same heritability as PO regression but could be extended to clusters of size greater than 2 and allowed for the correction of confounding effects. Finally, we used both methods to estimate SPVL heritability in the SHCS. We employed a wide range of transmission pair criteria to measure heritability and found a strong dependence of the heritability estimates to these criteria. For the most conservative genetic distance criteria, for which heritability estimates are conceptually expected to be closest to true heritability, we found estimates ranging from 32 to 46% across different bootstrap criteria. For less conservative distance criteria, we found estimates ranging down to 8%. All estimates did not change substantially after adjusting for host-demographic factors in the mixed-effect model (±2%). CONCLUSIONS: For conservative transmission pair criteria, both PO regression and mixed-effect models are flexible and robust tools to estimate the contribution of viral genetic effects to viral traits under real-world settings. Overall, we find a strong effect of viral genetics on SPVL that is not confounded by host demographics.

Dually Active HIV/HBV Antiretrovirals as Protection Against Incident Hepatitis B Infections: Potential for Prophylaxis.

BACKGROUND: Hepatitis B virus (HBV) has a detrimental effect on human immunodeficiency virus (HIV) natural course, and HBV vaccination is less effective in the HIV infected. We examine the protective effect of dually active antiretroviral therapy (DAART) for HIV/HBV (tenofovir, lamivudine, and emtricitabine) in a large cohort encompassing heterosexuals, men who have sex with men, and intravenous drug users who are HIV infected yet susceptible to HBV, with comprehensive follow-up data about risky behavior and immunological profiles. METHODS: We defined an incident HBV infection as the presence of any of HBV serological markers (hepatitis B surface antigen, anti-hepatitis B core antibodies, or HBV DNA) after a negative baseline test result for anti-hepatitis B core antibodies. Patients with positive anti-hepatitis B surface antigen serology were excluded. Cox proportional hazards models were used, with an incident case of HBV infection as the outcome variable. RESULTS: We analyzed 1716 eligible patients from the Swiss HIV Cohort Study with 177 incident HBV cases. DAART was negatively associated with incident HBV infection (hazard ratio [HR], 0.4; 95% confidence interval [CI], .2-.6). This protective association was robust to adjustment (HR, 0.3; 95% CI, .2-.5) for condomless sex, square-root-transformed CD4 cell count, drug use, and patient demographics. Condomless sex (HR, 1.9; 95% CI, 1.4-2.6), being a man who has sex with men (2.7; 1.7-4.2), and being an intravenous drug user (3.8; 2.4-6.1) were all associated with a higher hazard of contracting HBV. CONCLUSIONS: Our study suggests that DAART, independently of CD4 cell count and risky behavior, has a potentially strong public health impact, including pre-exposure prophylaxis of HBV coinfection in the HIV infected.

Persistent Infections by Nontyphoidal Salmonella in Humans: Epidemiology and Genetics.

BACKGROUND: Although chronic infections by typhoidal Salmonella are well-known, prolonged human infections by nontyphoidal Salmonella (NTS) are poorly characterized. METHODS: We retrospectively analyzed 48 345 culture-confirmed NTS infections that occurred in Israel 1995-2012. A case-control study was performed to identify risk factors associated with persistent infections. Whole-genome-sequencing, pulsed-field gel electrophoresis (PFGE), and a mouse infection model were used to study genetic and phenotypic differences between same-patient persistent, recurring isolates. RESULTS: In total, 1047 cases of persistent NTS infections, comprising 2.2% of all reported cases of salmonellosis, were identified. The persistence periods ranged between 30 days to 8.3 years. The majority (93%) of the persistently infected patients were immunocompetent, and 65% were symptomatic with relapsing diarrhea, indicating a distinct clinical manifestation from the asymptomatic carriage of typhoidal Salmonella. Four NTS serovars (Mbandaka, Bredeney, Infantis and Virchow) were found to be significantly more frequently associated with persistence than others. Comparative genomics between early and later isolates obtained from the same patients confirmed clonal infection and showed 0 to 10 SNPs between persistent isolates. A different composition of mobile genetic elements (plasmids and phages) or amino acid substitutions in global regulators was identified in multiple cases. These changes resulted in differences in phenotype and virulence between early and later same-patient isolates. CONCLUSIONS: These results illuminate the overlooked clinical manifestation of persistent salmonellosis that can serve as a human reservoir for NTS infections. Additionally, we demonstrate mechanisms of in-host microevolution and exhibit their potential to shape Salmonella pathogenicity, antimicrobial resistance and host-pathogen interactions.

HIV-1 Transmission During Recent Infection and During Treatment Interruptions as Major Drivers of New Infections in the Swiss HIV Cohort Study.

BACKGROUND: Reducing the fraction of transmissions during recent human immunodeficiency virus (HIV) infection is essential for the population-level success of "treatment as prevention". METHODS: A phylogenetic tree was constructed with 19 604 Swiss sequences and 90 994 non-Swiss background sequences. Swiss transmission pairs were identified using 104 combinations of genetic distance (1%-2.5%) and bootstrap (50%-100%) thresholds, to examine the effect of those criteria. Monophyletic pairs were classified as recent or chronic transmission based on the time interval between estimated seroconversion dates. Logistic regression with adjustment for clinical and demographic characteristics was used to identify risk factors associated with transmission during recent or chronic infection. FINDINGS: Seroconversion dates were estimated for 4079 patients on the phylogeny, and comprised between 71 (distance, 1%; bootstrap, 100%) to 378 transmission pairs (distance, 2.5%; bootstrap, 50%). We found that 43.7% (range, 41%-56%) of the transmissions occurred during the first year of infection. Stricter phylogenetic definition of transmission pairs was associated with higher recent-phase transmission fraction. Chronic-phase viral load area under the curve (adjusted odds ratio, 3; 95% confidence interval, 1.64-5.48) and time to antiretroviral therapy (ART) start (adjusted odds ratio 1.4/y; 1.11-1.77) were associated with chronic-phase transmission as opposed to recent transmission. Importantly, at least 14% of the chronic-phase transmission events occurred after the transmitter had interrupted ART. CONCLUSIONS: We demonstrate a high fraction of transmission during recent HIV infection but also chronic transmissions after interruption of ART in Switzerland. Both represent key issues for treatment as prevention and underline the importance of early diagnosis and of early and continuous treatment.

Integrative analysis of Salmonellosis in Israel reveals association of Salmonella enterica Serovar 9,12:l,v:- with extraintestinal infections, dissemination of endemic S. enterica Serovar Typhimurium DT104 biotypes, and severe underreporting of outbreaks.

Salmonella enterica is the leading etiologic agent of bacterial food-borne outbreaks worldwide. This ubiquitous species contains more than 2,600 serovars that may differ in their host specificity, clinical manifestations, and epidemiology. To characterize salmonellosis epidemiology in Israel and to study the association of nontyphoidal Salmonella (NTS) serovars with invasive infections, 48,345 Salmonella cases reported and serotyped at the National Salmonella Reference Center between 1995 and 2012 were analyzed. A quasi-Poisson regression was used to identify irregular clusters of illness, and pulsed-field gel electrophoresis in conjunction with whole-genome sequencing was applied to molecularly characterize strains of interest. Three hundred twenty-nine human salmonellosis clusters were identified, representing an annual average of 23 (95% confidence interval [CI], 20 to 26) potential outbreaks. We show that the previously unsequenced S. enterica serovar 9,12:l,v:- belongs to the B clade of Salmonella enterica subspecies enterica, and we show its frequent association with extraintestinal infections, compared to other NTS serovars. Furthermore, we identified the dissemination of two prevalent Salmonella enterica serovar Typhimurium DT104 clones in Israel, which are genetically distinct from other global DT104 isolates. Accumulatively, these findings indicate a severe underreporting of Salmonella outbreaks in Israel and provide insights into the epidemiology and genomics of prevalent serovars, responsible for recurring illness.

Glenoid Component Loosening in Anatomic Total Shoulder Arthroplasty: Association between Radiological Predictors and Clinical Parameters-An Observational Study.

The mechanisms of glenoid component loosening in anatomic total shoulder arthroplasty (aTSA) are still unclear, and it remains undetermined which specific radiographic features are associated with clinical outcomes. Patients with primary osteoarthritis who underwent aTSA with a stemless implant and a pegged glenoid between January 2011 and December 2016 were extracted from a local registry. Anteroposterior radiographs were evaluated at six, 12, 24 months, and five years post-TSA for lateral humeral offset (LHO), joint gap (JG), acromiohumeral distance (AHD), and radiolucency (modified Franklin score); 147 patients were included. Mixed-model linear regression was used. Both constant score (CS) and subjective shoulder value (SSV) markedly decreased at five years follow-up compared to one year (p < 0.001 for both). AHD, LHO, and JG all showed a consistent and statistically significant decline over time, with the joint gap decreasing by half. Consistently, smaller JG and AHD were correlated with lower SSV (p = 0.03 and p = 0.07, respectively). Massive loosening was associated with a 14.5 points lower SSV (p < 0.01). Finally, narrowing of the JG was significantly correlated with increased radiolucency (p < 0.001) and tended toward worse SSV (p = 0.06). In summary, radiographic parameters displaying medialization and cranialization after aTSA with a cemented pegged glenoid are useful predictors of impaired shoulder function.

Impact of Sports Activity on Medium-Term Clinical and Radiological Outcome after Reverse Shoulder Arthroplasty in Cuff Deficient Arthropathy; An Institutional Register-Based Analysis.

There is a lack of consensus on what physicians can recommend and what patients can expect concerning sports activity after reverse shoulder arthroplasty (RSA). The purpose of this retrospective register-based observational study was to investigate the association between participation in sports or physical activity involving the upper extremity and 5-year clinical and radiological outcomes for primary RSA patients. We screened the institutional arthroplasty registry for patients reporting the type and level of sports postoperatively after primary, unilateral RSA due to rotator cuff deficiency. One hundred thirty-eight patients with clinical and radiological outcomes documented at a minimum 5-year follow-up were divided into three groups comprising those who participated regularly in: sports mainly involving the upper extremity (sports upper extremities, SUE, n = 49), sports mainly involving the lower extremities (sports lower extremities, SLE, n = 21), and those who did not participate in sports at all (no sports, NS, n = 68). The participants had a mean age of 72 years (standard deviation (SD) 8) and were overall predominantly female patients (62%). Primary clinical outcomes included the Constant Score (CS) and Shoulder Pain and Disability Index (SPADI). Secondary radiographs were analyzed for radiolucent lines (RLL), signs of glenoid or humeral prosthesis loosening, bone resorption, bone formation, and scapular notching. A total number of 8 senior surgeons were involved in treatment of patients, and two types of prosthesis were used. The SUE group had non-significantly higher mean scores for CS (75 points) and SPADI (88 points) compared to SLE (71 and 78 points, respectively) and NS patients (66 and 78 points, respectively) (p ≥ 0.286). The incidence of RLL around the humeral diaphysis was higher in NS compared to SUE patients (32% versus 12%, respectively) (p = 0.025); all other radiological parameters were similar between the groups. There were no cases of loosening in the SUE group that led to revision surgery. Patients engaging in sports activities involving the upper extremity show similarly good functional scores 5 years post-RSA as the other groups, without additional signs of implant loosening as a result of increased shoulder use.

Data linkage to evaluate the long-term risk of HIV infection in individuals seeking post-exposure prophylaxis.

Evidence on the long-term risk of HIV infection in individuals taking HIV post-exposure prophylaxis remains limited. In this retrospective data linkage study, we evaluate the occurrence of HIV infection in 975 individuals who sought post-exposure prophylaxis in a tertiary hospital between 2007 and 2013. Using privacy preserving probabilistic linkage, we link these 975 records with two observational databases providing data on HIV events (Zurich Primary HIV Infection study and the Swiss HIV Cohort Study). This enables us to identify 22 HIV infections and to obtain long-term follow-up data, which reveal a median of 4.1 years between consultation for post-exposure prophylaxis and HIV diagnosis. Even though men who have sex with men constitute only 35.8% of those seeking post-exposure prophylaxis, all 22 events occur in this subgroup. These findings should strongly encourage early consideration of pre-exposure prophylaxis in men who have sex with men after a first episode of post-exposure prophylaxis.