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.

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.

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.

Longitudinal Progression of Subclinical Coronary Atherosclerosis in Swiss HIV-Positive Compared With HIV-Negative Persons Undergoing Coronary Calcium Score Scan and CT Angiography.

BACKGROUND: People with HIV (HIV+) may have increased cardiovascular event rates compared with HIV-negative (HIV-) persons. Cross-sectional data from the United States and Switzerland, based on coronary artery calcium scan (CAC) and coronary computed tomography angiography (CCTA), suggest, respectively, increased and similar prevalence of subclinical atherosclerosis in HIV+ vs HIV- persons. METHODS: We repeated CAC/CCTA in 340 HIV+ and 90 HIV- study participants >2 years after baseline CAC/CCTA. We assessed the association of HIV infection, Framingham risk score (FRS), and HIV-related factors with the progression of subclinical atherosclerosis. RESULTS: HIV+ were younger than HIV- participants (median age, 52 vs 56 years; P < .01) but had similar median 10-year FRS (8.9% vs 9.0%; P = .82); 94% had suppressed HIV viral load. In univariable and multivariable analyses, FRS was associated with the incidence rate ratio (IRR) of new subclinical atherosclerosis at the follow-up CAC/CCTA, but HIV infection was not: any plaque (adjusted IRR for HIV+ vs HIV- participants, 1.21; 95% CI, 0.62-2.35), calcified plaque (adjusted IRR for HIV+ vs HIV- participants, 1.06; 95% CI, 0.56-2), noncalcified/mixed plaque (adjusted IRR for HIV+ vs HIV- participants, 1.24; 95% CI, 0.69-2.21), and high-risk plaque (adjusted IRR for HIV+ vs HIV- participants, 1.46; 95% CI, 0.66-3.20). Progression of CAC score between baseline and follow-up CAC/CCTA was similar in HIV+ (median annualized change [interquartile range {IQR}], 0.41 [0-10.19]) and HIV- participants (median annualized change [IQR], 2.38 [0-16.29]; P = .11), as was progression of coronary segment severity score (HIV+: median annualized change [IQR], 0 [0-0.47]; HIV-: median annualized change [IQR], 0 [0-0.52]; P = .10) and coronary segment involvement score (HIV+: median annualized change [IQR], 0 [0-0.45]; HIV-: median annualized change [IQR], 0 [0-0.41]; P = .25). CONCLUSIONS: In this longitudinal CAC/CCTA study from Switzerland, Framingham risk score was associated with progression of subclinical atherosclerosis, but HIV infection was not.

The Schulthess local Shoulder Arthroplasty Registry (SAR): cohort profile.

PURPOSE: Clinical registries are essential for evaluation of surgical outcomes. The Schulthess Shoulder Arthroplasty Registry (SAR) was established in 2006 to evaluate safety, function, quality-of-life and patient satisfaction in patients undergoing shoulder arthroplasty. PARTICIPANTS: Adult patients undergoing anatomic or reverse shoulder joint replacement at the Schulthess Klinik, a high-volume, leading orthopaedic surgery centre in Zürich, Switzerland. FINDINGS TO DATE: Between March 2006 and December 2019, the registry covered 98% of eligible operations. Overall, 2332 patients were enrolled with a total of 2796 operations and 11 147 person-years of follow-up. Mean age at baseline was 71 (range: 20-95), 65% were women. Most common indication was rotator cuff tears with osteoarthritis (42%) and the mean preoperative Constant Score was 31 (±15). The most frequent arthroplasty type was reverse, increasing from 61% in 2006-2010 to 86% in 2015-2019. Functional recovery peaked at 12-month postoperatively and did not show a clinically relevant deterioration during the first ten follow-up years. Since its establishment, the registry was used to address multiple pertinent clinical and methodological questions. Primary focus was on comparing different implant configurations (eg, glenosphere diameter) and surgical techniques (eg, latissimus dorsi transfer) to maximise functional recovery. Additionally, the cohort contributed to the determination of the clinical relevance and validity of radiological monitoring of cortical bone resorption and scapular notching. Finally, SAR data helped to demonstrate that returning to sports was among key patient expectations after reverse shoulder arthroplasty. FUTURE PLANS: As first patients are approaching the 15 years follow-up landmark, the registry will continue providing essential data on long-term functional outcomes, implant stability, revision rates and aetiologies as well as patient satisfaction and quality-of-life. In addition to research and quality-control, the cohort data will be brought back to the patients by bolstering real-time clinical decision support.

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.

Differences in social and mental well-being of long-term survivors among people who inject drugs and other participants in the Swiss HIV Cohort Study: 1980-2018.

BACKGROUND: People living with HIV who were diagnosed before highly active antiretroviral therapy became available in 1996 and who survived at least 15 years after HIV diagnosis, termed long-term survivors (LTS), form a particularly vulnerable population. We study social, clinical and mental factors of LTS in the Swiss HIV Cohort Study, with a particular focus on people who inject drugs (PWID). METHODS: We quantified differences between PWID LTS, and men who have sex with men (MSM) and heterosexual (HET) LTS. Using phylogenetic methods, we distinguished between heterosexual LTS who most likely shared a social network with PWID at the time of infection, termed clusteredHET, and those who did not, termed HET not clustered (HETnc). The analysis was performed using data collected at least 15 years post diagnosis. RESULTS: Overall, 1,663 of 5,686 (29.2%) PWID were LTS. We found significant differences between PWID LTS and MSM/HETnc LTS regarding self-reported depression (59.4% versus 43.3%; odds ratio [OR]=1.8; P<0.001), incarceration (30.6% versus 7.0%; OR=6.9; P<0.001) and full work ability (25.4% versus 59.0%; OR=0.27; P<0.001). ClusteredHET were less vulnerable with respect to these variables than PWID LTS but more at risk compared with MSM/HETnc LTS, indicating that clusteredHET are closer to PWID with regard to social and mental aspects compared with all MSM/HETnc. CONCLUSIONS: Even more than 15 years post HIV diagnosis, special care for HIV-positive PWID is needed, with emphasis on mental health and social integration of PWID LTS.

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.

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.

Effect of Monthly High-Dose Vitamin D on Mental Health in Older Adults: Secondary Analysis of a RCT.

OBJECTIVES: To test the effect of monthly high-dose vitamin D supplementation on mental health in pre-frail older adults. DESIGN: Ancillary study of a 1-year double-blind randomized clinical trial conducted in Zurich, Switzerland. SETTING AND PARTICIPANTS: A total of 200 community-dwelling adults 70 years and older with a prior fall event in the last year. Participants were randomized to receive 24 000 IU vitamin D3 (considered standard of care), 60 000 IU vitamin D3 , or 24 000 IU vitamin D3 plus 300 µg calcifediol per month. MEASURES: The primary end point was the Mental Component Summary (MCS) of the SF-36. Secondary end points were the SF-36 Mental Health (MH) subscale and the Geriatric Depression Scale (GDS-15). RESULTS: Participants' mean age was 78 years (67% women), and 58% were vitamin D deficient (<20 ng/mL). Over time, primary and secondary end points did not differ significantly among the three treatment groups or in subgroups by vitamin D status at baseline. Given the lack of a true placebo group, we explored in a predefined observational analysis the change in mental health scales by achieved 25(OH)D levels at 12 months. After adjusting for confounders, participants achieving the highest 25(OH)D quartile (Q) at 12 months (44.7-98.9 ng/mL) had the greatest improvements in MCS (Q4 = 0.79 vs Q1 = -2.9; p = .03) and MH scales (Q4 = 2.54 vs Q1 = -3.07; p = .03); these associations were strongest among participants who were vitamin D deficient at baseline. No association was found for GDS (p = .89). CONCLUSIONS: For mental health, our study suggests no benefit of higher monthly doses of vitamin D3 compared with the standard monthly dose of 24 000 IU. However, irrespective of vitamin D treatment dose, achieving higher 25(OH)D levels at 12-month follow-up was associated with a small, clinically uncertain but statistically significant improvement in mental health scores.

Effect of 800 IU Versus 2000 IU Vitamin D3 With or Without a Simple Home Exercise Program on Functional Recovery After Hip Fracture: A Randomized Controlled Trial.

OBJECTIVES: To evaluate 2 simple strategies, vitamin D3 and a home exercise program, in functional recovery during the first year after hip fracture. DESIGN: Secondary analysis of a factorial clinical trial. Patients were randomly allocated to 800 IU (standard of care) or 2000 IU vitamin D3 and a daily instruction of a simple home exercise program (SHEP) or standard physiotherapy alone during acute care. SETTING AND PARTICIPANTS: Acute hip fracture patients aged ≥65 years, after hip fracture surgery, admitted to a large hospital in Zurich, Switzerland. MEASURES: Three objective measures of lower extremity function were assessed at baseline and 6 and 12 months, with the Timed Up and Go test (TUG) as the primary endpoint, and knee flexor and extensor strength, and a self-reported physical function score (PF-10) as secondary endpoints. Linear mixed model regression analyses were based on intention to treat, adjusting for baseline function, time, age, sex, and baseline 25-hydroxyvitamin D level. RESULTS: We enrolled 173 patients (79.2% women; mean age 84 years; 77.5% living at home). A significant interaction was found between vitamin D3 dose and SHEP for TUG (P = .045). Thus, findings compared the standard of care reference arm with 800 IU vitamin D3 without SHEP to 3 interventions arms (800 IU vitamin D3+SHEP; 2000 IU vitamin D3 without SHEP; 2000 IU vitamin D3+SHEP). For TUG, over 12 months the 800 IU vitamin D3+SHEP group performed significantly better than the standard-of-care group (13.8 vs 19.5 seconds; P = .01). Findings for knee flexor strength were in line with TUG results and approached significance (P = .07), whereas knee extensor strength and PF-10 did not differ by treatments. CONCLUSIONS/IMPLICATIONS: For functional recovery after hip fracture, combining home exercise with 800 IU vitamin D3 is superior to no home exercise or 2000 IU vitamin D3. None of the interventions improved subjective physical functioning.

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.

Inferring the age difference in HIV transmission pairs by applying phylogenetic methods on the HIV transmission network of the Swiss HIV Cohort Study.

Age-mixing patterns are of key importance for understanding the dynamics of human immunodeficiency virus (HIV)-epidemics and target public health interventions. We use the densely sampled Swiss HIV Cohort Study (SHCS) resistance database to study the age difference at infection in HIV transmission pairs using phylogenetic methods. In addition, we investigate whether the mean age difference of pairs in the phylogenetic tree is influenced by sampling as well as by additional distance thresholds for including pairs. HIV-1 pol-sequences of 11,922 SHCS patients and approximately 240,000 Los Alamos background sequences were used to build a phylogenetic tree. Using this tree, 100 per cent down to 1 per cent of the tips were sampled repeatedly to generate pruned trees (N = 500 for each sample proportion), of which pairs of SHCS patients were extracted. The mean of the absolute age differences of the pairs, measured as the absolute difference of the birth years, was analyzed with respect to this sample proportion and a distance criterion for inclusion of the pairs. In addition, the transmission groups men having sex with men (MSM), intravenous drug users (IDU), and heterosexuals (HET) were analyzed separately. Considering the tree with all 11,922 SHCS patients, 2,991 pairs could be extracted, with 954 (31.9 per cent) MSM-pairs, 635 (21.2 per cent) HET-pairs, 414 (13.8 per cent) IDU-pairs, and 352 (11.8 per cent) HET/IDU-pairs. For all transmission groups, the age difference at infection was significantly (P < 0.001) smaller for pairs in the tree compared with randomly assigned pairs, meaning that patients of similar age are more likely to be pairs. The mean age difference in the phylogenetic analysis, using a fixed distance of 0.05, was 9.2, 9.0, 7.3 and 5.6 years for MSM-, HET-, HET/IDU-, and IDU-pairs, respectively. Decreasing the cophenetic distance threshold from 0.05 to 0.01 significantly decreased the mean age difference. Similarly, repeated sampling of 100 per cent down to 1 per cent of the tips revealed an increased age difference at lower sample proportions. HIV-transmission is age-assortative, but the age difference of transmission pairs detected by phylogenetic analyses depends on both sampling proportion and distance criterion. The mean age difference decreases when using more conservative distance thresholds, implying an underestimation of age-assortativity when using liberal distance criteria. Similarly, overestimation of the mean age difference occurs for pairs from sparsely sampled trees, as it is often the case in sub-Saharan Africa.

The Cumulative Impact of Harm Reduction on the Swiss HIV Epidemic: Cohort Study, Mathematical Model, and Phylogenetic Analysis.

BACKGROUND: Human immunodeficiency virus (HIV) transmission among injecting drug users (IDUs) is increasing in the United States due to the recent opioid epidemic and is the leading mode of transmission in Eastern Europe. METHODS: To evaluate the overall impact of HIV harm reduction, we combined (1) data from the Swiss HIV Cohort Study and public sources with (2) a mathematical model expressed as a system of ordinary differential equations. The model reconstructs the national epidemic from the first case in 1980 until 2015. Phylogenetic cluster analysis of HIV-1 pol sequences was used to quantify the epidemic spillover from IDUs to the general population. RESULTS: Overall, harm reduction prevented 15903 (range, 15359-16448) HIV infections among IDUs until the end of 2015, 5446 acquired immune deficiency syndrome (AIDS) deaths (range, 5142-5752), and a peak HIV prevalence of 50.7%. Introduction of harm reduction 2 years earlier could have halved the epidemic, preventing 3161 (range, 822-5499) HIV infections and 1468 (range, 609-2326) AIDS deaths. Suddenly discontinuing all harm reduction in 2005 would have resulted in outbreak re-emergence with 1351 (range, 779-1925) additional HIV cases. Without harm reduction, the estimated additional number of heterosexuals infected by HIV-positive IDUs is estimated to have been 2540 (range, 2453-2627), which is equivalent to the total national reported incidence among heterosexuals in the period of 2007 to 2015. CONCLUSIONS: Our results suggest that a paramount, population-level impact occurred because of the harm reduction package, beyond factors that can be explained by a reduction in risk behavior and a decrease in the number of drug users over time.

Dietary Patterns and Physical Activity Correlate With Total Cholesterol Independently of Lipid-Lowering Drugs and Antiretroviral Therapy in Aging People Living With Human Immunodeficiency Virus.

BACKGROUND: Hypercholesterolemia is a well established risk factor for coronary heart disease and is highly prevalent among human immunodeficiency virus (HIV)-positive persons. Antiretroviral therapy (ART) can both directly modify total cholesterol and have drug-drug interactions with statins. This makes investigating modifiable behavioral predictors of total cholesterol a pertinent task. METHODS: To explore the association between diet and physical activity with cross-sectionally measured total cholesterol, we administered a validated Food-Frequency-Questionnaire to participants of the Swiss HIV Cohort Study ≥45 years old. Linear mixed-effects models were applied to explore the associations between dietary patterns and physical activity with total cholesterol, after adjustment for clinical and demographic covariates. RESULTS: In total, 395 patients were included. Forty percent (158 of 395) had elevated total cholesterol (>5.2 mmol/L), and 41% (164 of 395) were not regularly physically active. In multivariable analysis, 2 factors were positively associated with total cholesterol; female sex (ß = 0.562; 95% confidence interval [CI], 0.229-0.896) and the combined consumption of meat, refined/milled grains, carbonated beverages, and coffee (ß = 0.243; 95% CI, 0.047-0.439). On the other hand, regular physical activity (ß = -0.381; 95% CI, -0.626 to -0.136), lipid-lowering drugs (ß = -0.443; 95% CI -0.691 to -0.196), ART containing tenofovir (ß = -0.336; 95% CI -0.554 to -0.118), and black ethnicity (ß = -0.967; 95% CI -1.524 to -0.410) exhibited a negative association. CONCLUSIONS: We found independent associations between certain dietary patterns and physical activity with total cholesterol. Increasing physical activity might achieve cardiovascular and other health benefits in HIV-positive individuals. The clinical relevance of the identified dietary patterns requires further investigation in prospective cohort studies and randomized controlled trials.

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.

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.