Natural language processing analysis of the theories of people with multiple sclerosis about causes of their disease.

BACKGROUND: While potential risk factors for multiple sclerosis (MS) have been extensively researched, it remains unclear how persons with MS theorize about their MS. Such theories may affect mental health and treatment adherence. Using natural language processing techniques, we investigated large-scale text data about theories that persons with MS have about the causes of their disease. We examined the topics into which their theories could be grouped and the prevalence of each theory topic. METHODS: A total of 486 participants of the Swiss MS Registry longitudinal citizen science project provided text data on their theories about the etiology of MS. We used the transformer-based BERTopic Python library for topic modeling to identify underlying topics. We then conducted an in-depth characterization of the topics and assessed their prevalence. RESULTS: The topic modeling analysis identifies 19 distinct topics that participants theorize as causal for their MS. The topics most frequently cited are Mental Distress (31.5%), Stress (Exhaustion, Work) (29.8%), Heredity/Familial Aggregation (27.4%), and Diet, Obesity (16.0%). The 19 theory topics can be grouped into four high-level categories: physical health (mentioned by 56.2% of all participants), mental health (mentioned by 53.7%), risk factors established in the scientific literature (genetics, Epstein-Barr virus, smoking, vitamin D deficiency/low sunlight exposure; mentioned by 47.7%), and fate/coincidence (mentioned by 3.1%). Our study highlights the importance of mental health issues for theories participants have about the causes of their MS. CONCLUSIONS: Our findings emphasize the importance of communication between healthcare professionals and persons with MS about the pathogenesis of MS, the scientific evidence base and mental health.

Multiple sclerosis (MS) is a disease that affects the brain and spinal cord, causing a wide range of symptoms. Our study investigated what people living with the disease think causes MS. We analyzed the replies given by 486 people who were questioned about their MS to look for patterns in the responses. We identified 19 distinct themes, notably mental and work-related stress, genetics, and dietary factors, which we grouped into 4 categories: physical health, mental health, established scientific risk factors, and chance. We found that mental health problems were viewed as a key factor for MS. Our work highlights the need for healthcare professionals to have transparent conversations with people with MS about what is known about the disease course and potential causes. In addition, it highlights the importance of fully informing and supporting people with MS regarding their mental health.

Digital Transformation of Public Health for Noncommunicable Diseases: Narrative Viewpoint of Challenges and Opportunities.

The recent SARS-CoV-2 pandemic underscored the effectiveness and rapid deployment of digital public health interventions, notably the digital proximity tracing apps, leveraging Bluetooth capabilities to trace and notify users about potential infection exposures. Backed by renowned organizations such as the World Health Organization and the European Union, digital proximity tracings showcased the promise of digital public health. As the world pivots from pandemic responses, it becomes imperative to address noncommunicable diseases (NCDs) that account for a vast majority of health care expenses and premature disability-adjusted life years lost. The narrative of digital transformation in the realm of NCD public health is distinct from infectious diseases. Public health, with its multifaceted approach from disciplines such as medicine, epidemiology, and psychology, focuses on promoting healthy living and choices through functions categorized as "Assessment," "Policy Development," "Resource Allocation," "Assurance," and "Access." The power of artificial intelligence (AI) in this digital transformation is noteworthy. AI can automate repetitive tasks, facilitating health care providers to prioritize personal interactions, especially those that cannot be digitalized like emotional support. Moreover, AI presents tools for individuals to be proactive in their health management. However, the human touch remains irreplaceable; AI serves as a companion guiding through the health care landscape. Digital evolution, while revolutionary, poses its own set of challenges. Issues of equity and access are at the forefront. Vulnerable populations, whether due to economic constraints, geographical barriers, or digital illiteracy, face the threat of being marginalized further. This transformation mandates an inclusive strategy, focusing on not amplifying existing health disparities but eliminating them. Population-level digital interventions in NCD prevention demand societal agreement. Policies, like smoking bans or sugar taxes, though effective, might affect those not directly benefiting. Hence, all involved parties, from policy makers to the public, should have a balanced perspective on the advantages, risks, and expenses of these digital shifts. For a successful digital shift in public health, especially concerning NCDs, AI's potential to enhance efficiency, effectiveness, user experience, and equity-the "quadruple aim"-is undeniable. However, it is vital that AI-driven initiatives in public health domains remain purposeful, offering improvements without compromising other objectives. The broader success of digital public health hinges on transparent benchmarks and criteria, ensuring maximum benefits without sidelining minorities or vulnerable groups. Especially in population-centric decisions, like resource allocation, AI's ability to avoid bias is paramount. Therefore, the continuous involvement of stakeholders, including patients and minority groups, remains pivotal in the progression of AI-integrated digital public health.

The value of a QALY towards the end of life and its determinants: Experimental evidence.

OBJECTIVES: Individual and societal willingness to pay (WTP) for end-of-life medical interventions continue to be subject to considerable uncertainty. This study aims at deriving both types of WTP estimates for an extension of survival time and an improvement of quality of life amounting to a QALY. METHODS: A discrete choice experiment (DCE) involving a hypothetical novel drug for the treatment of terminal cancer involving 1529 Swiss residents was performed in 2014. In its individual setting, respondents choose between the status quo and a hypothetical drug with varying characteristics and out-of-pocket payments, adopting the perspective of a terminal cancer patient. In the societal setting, participants are asked to choose between the status quo and a social health insurance contract with and without coverage of the novel drug and a varying insurance contribution. RESULTS: In the individual setting, respondents put a higher value on their quality of life than on their survival time whereas in the societal setting, they put a higher value on extra survival time. The combination of the two extensions results in a mean individual WTP per QALY of CHF 96,150 (1 CHF = 1 USD as of 2014). Mean societal WTP for a QALY even amounts to CHF 213,500 in favor of an adult patient, CHF 255,600 for a child, and CHF 153,600 for a person aged over 70 years, respectively. While estimated societal values consistently exceed their individual counterparts, they vary considerably with respondents' socioeconomic characteristics in both settings. CONCLUSIONS: This research finds that individual WTP for an extension of survival time to one year is dominated by WTP for health-related quality of life whereas for societal WTP, it is the other way round. Both individual and societal WTP values exhibit a great deal of heterogeneity, with the latter depending on the type of beneficiary.

Association of age and disease duration with comorbidities and disability: A study of the Swiss Multiple Sclerosis Registry.

BACKGROUND: While comorbidities increase with age, duration of multiple sclerosis (MS) leads to disability accumulation in persons with MS. The influence of ageing vis-a-vis MS duration remains largely unexplored. We studied the independent associations of ageing and MS duration with disability and comorbidities in the Swiss MS Registry participants. METHODS: Self-reported data was cross-sectionally analyzed using confounder-adjusted logistic regression models for 6 outcomes: cancer, type 2 diabetes (T2D), hypertension, cardiac diseases, depression, and having at least moderate or severe gait disability. Using cubic splines, we explored non-linear changes in risk shapes. RESULTS: Among 1615 participants age was associated with cardiac diseases (OR 1.05, 95% CI [1.02, 2.08]), hypertension (OR 1.08, 95% CI [1.06, 2.10]), T2D (OR 1.10, 95%CI [1.05, 1.16]) and cancer (OR 1.04, 95% CI [1.01, 1.07]). MS duration was not associated with comorbidities, except for cardiac diseases (OR 1.03, 95% CI [1.00, 1.06]). MS duration and age were independently associated with having at least moderate gait disability (OR 1.06, 95% CI [1.04, 1.07]; OR 1.04, 95% CI [1.02, 1.05], respectively), and MS duration was associated with severe gait disability (OR 1.05, 95% CI [1.03, 1.08]). The spline analysis suggested a non-linear increase of having at least moderate gait disability with age. CONCLUSIONS: Presence of comorbidities was largely associated with age only. Having at least moderate gait disability was associated with both age and MS duration, while having severe gait disabity was associated with MS duration only.

Surgical procedures in inpatient versus outpatient settings and its potential impact on follow-up costs.

OBJECTIVE: We examined real-world effects of cantonal legislations to direct surgery patients from the inpatient to the outpatient setting in Switzerland. METHODS: Analyses were based on claims data of the Helsana Group, a leading Swiss health insurance. The study population consisted of 13'145 (in 2014), 12'455 (in 2016), and 12'875 (in 2018) insured persons aged >18 years who had haemorrhoidectomy, inguinal hernia repair, varicose vein surgery, knee arthroscopy/meniscectomy or surgery of the cervix/uterus. We assessed the proportion of inpatient procedures, index costs, length of hospital stays, outpatient costs and hospitalizations during follow-up, stratified by procedure, in-/outpatient setting, and the presence (enacted/effective in 2018) of a cantonal legislation. We used difference-in-differences methods to study the impact of cantonal legislations. RESULTS: Overall, the proportion of procedures performed in the inpatient setting decreased between 2014 and 2018 (p < 0.001). The decrease between 2016 and 2018 was significantly steeper in cantons with a legislation (p < 0.001; effect size: 0.57; 95% CI: 0.51, 0.64), leading to steeper decreases in healthcare costs of index procedures in cantons with a legislation, with no impact on length of hospital stays. The legislation also had no impact on outpatient costs or hospitalizations during follow-up. CONCLUSIONS: The cantonal legislations achieved the intended effects of inpatient surgery substitution by outpatient surgery, with no evidence suggesting negative effects on costs or hospitalizations during follow-up.

Onset Symptom Clusters in Multiple Sclerosis: Characteristics, Comorbidities, and Risk Factors.

Background: Multiple sclerosis (MS) symptoms are expected to aggregate in specific patterns across different stages of the disease. Here, we studied the clustering of onset symptoms and examined their characteristics, comorbidity patterns and associations with potential risk factors. Methods: Data stem from the Swiss Multiple Sclerosis Registry, a prospective study including 2,063 participants by November 2019. MS onset symptoms were clustered using latent class analysis (LCA). The latent classes were further examined using information on socio-demographic characteristics, MS-related features, potential risk factors, and comorbid diseases. Results: The LCA model with six classes (frequencies ranging from 12 to 24%) was selected for further analyses. The latent classes comprised a multiple symptoms class with high probabilities across several symptoms, contrasting with two classes with solitary onset symptoms: vision problems and paresthesia. Two gait classes emerged between these extremes: the gait-balance class and the gait-paralysis class. The last class was the fatigue-weakness-class, also accompanied by depression symptoms, memory, and gastro-intestinal problems. There was a moderate variation by sex and by MS types. The multiple symptoms class yielded increased comorbidity with other autoimmune disorders. Similar to the fatigue-weakness class, the multiple symptoms class showed associations with angina, skin diseases, migraine, and lifetime prevalence of smoking. Mononucleosis was more frequently reported in the fatigue-weakness and the paresthesia class. Familial aggregation did not differ among the classes. Conclusions: Clustering of MS onset symptoms provides new perspectives on the heterogeneity of MS. The clusters comprise different potential risk factors and comorbidities. They point toward different risk mechanisms.

Impact of Adrenal Function on Hemostasis/Endothelial Function in Patients Undergoing Surgery.

CONTEXT: Glucocorticoids regulate hemostatic and endothelial function, and they are critical for adaptive functions during surgery. No data regarding the impact of adrenal function on hemostasis and endothelial function in the perioperative setting are available. OBJECTIVE: We assessed the association of adrenal response to adrenocorticotropic hormone (ACTH) and markers of endothelial/hemostatic function in surgical patients. METHODS: This prospective observational study, conducted at a tertiary care hospital, included 60 patients (35 male/25 female) undergoing abdominal surgery. Adrenal function was evaluated by low-dose ACTH stimulation test on the day before, during, and the day after surgery. According to their stimulated cortisol level (cutoff ≥ 500 nmol/L), patients were classified as having normal hypothalamic-pituitary-adrenal (HPA)-axis function (nHPA) or deficient HPA-axis function (dHPA). Parameters of endothelial function (soluble vascular cell adhesion molecule-1, thrombomodulin) and hemostasis (fibrinogen, von Willebrand factor antigen, factor VIII [FVIII]) were measured during surgery. RESULTS: Twenty-one patients had dHPA and 39 had nHPA. Compared with nHPA, patients with dHPA had significantly lower peak cortisol before (median 568 vs 425 nmol/L, P < 0.001) and during (693 vs 544 nmol/L, P < 0.001) surgery and lower postoperative hemoglobin levels (116 g/L vs 105 g/L, P = 0.049). FVIII was significantly reduced in patients with dHPA in uni- and multivariable analyses; other factors displayed no significant differences. Coagulation factors/endothelial markers changed progressively in relation to stimulated cortisol levels and showed a turning point at cortisol levels between 500 and 600 nmol/L. CONCLUSIONS: Patients with dHPA undergoing abdominal surgery demonstrate impaired hemostasis which can translate into excessive blood loss.

Temporal trends and regional disparities in cancer screening utilization: an observational Swiss claims-based study.

BACKGROUND: We examined colorectal, breast, and prostate cancer screening utilization in eligible populations within three data cross-sections, and identified factors potentially modifying cancer screening utilization in Swiss adults. METHODS: The study is based on health insurance claims data of the Helsana Group. The Helsana Group is one of the largest health insurers in Switzerland, insuring approximately 15% of the entire Swiss population across all regions and age groups. We assessed proportions of the eligible populations receiving colonoscopy/fecal occult blood testing (FOBT), mammography, or prostate-specific antigen (PSA) testing in the years 2014, 2016, and 2018, and calculated average marginal effects of individual, temporal, regional, insurance-, supply-, and system-related variables on testing utilization using logistic regression. RESULTS: Overall, 8.3% of the eligible population received colonoscopy/FOBT in 2014, 8.9% in 2016, and 9.2% in 2018. In these years, 20.9, 21.2, and 20.4% of the eligible female population received mammography, and 30.5, 31.1, and 31.8% of the eligible male population had PSA testing. Adjusted testing utilization varied little between 2014 and 2018; there was an increasing trend of 0.8% (0.6-1.0%) for colonoscopy/FOBT and of 0.5% (0.2-0.8%) for PSA testing, while mammography use decreased by 1.5% (1.2-1.7%). Generally, testing utilization was higher in French-speaking and Italian-speaking compared to German-speaking region for all screening types. Cantonal programs for breast cancer screening were associated with an increase of 7.1% in mammography utilization. In contrast, a high density of relevant specialist physicians showed null or even negative associations with screening utilization. CONCLUSIONS: Variation in cancer screening utilization was modest over time, but considerable between regions. Regional variation was highest for mammography use where recommendations are debated most controversially, and the implementation of programs differed the most.

Variation of colorectal, breast and prostate cancer screening activity in Switzerland: Influence of insurance, policy and guidelines.

Variation in utilization of healthcare services is influenced by patient, provider and healthcare system characteristics. It could also be related to the evidence supporting their use, as reflected in the availability and strength of recommendations in clinical guidelines. In this study, we analyzed the geographic variation of colorectal, breast and prostate cancer screening utilization in Switzerland and the influence of available guidelines and different modifiers of access. Colonoscopy, mammography and prostate specific antigen (PSA) testing use in eligible population in 2014 was assessed with administrative claims data. We ran a multilevel multivariable logistic regression model and calculated Moran's I and regional level median odds ratio (MOR) statistics to explore residual geographic variation. In total, an estimated 8.1% of eligible persons received colonoscopy, 22.3% mammography and 31.3% PSA testing. Low deductibles, supplementary health insurance and enrollment in a managed care plan were associated with higher screening utilization. Cantonal breast cancer screening programs were also associated with higher utilization. Spatial clustering was observed in the raw regional utilization of all services, but only for prostate cancer screening in regional residuals of the multilevel model. MOR was highest for prostate cancer screening (1.24) and lowest for colorectal cancer screening (1.16). The reasons for the variation of the prostate cancer screening utilization, not recommended routinely without explicit shared decision-making, could be further investigated by adding provider characteristics and patient preference information. This first cross-comparison of different cancer screening patterns indicates that the strength of recommendations, mediated by specific health policies facilitating screening, may indeed contribute to variation.

Variation of preoperative chest radiography utilization in Switzerland and its influencing factors: a multilevel study with claims data.

Clinical recommendations discourage routine use of preoperative chest radiography (POCR). However, there remains much uncertainty about its utilization, especially variation across small areas. We aimed to assess the variation of POCR use across small regions, and to explore its influencing factors. Patients undergoing inpatient surgery during 2013 to 2015 were identified from insurance claims data. Possible influencing factors of POCR included socio-demographics, health insurance choices, and clinical characteristics. We performed multilevel modelling with region and hospital as random effects. We calculated 80% interval odds ratios (IOR-80) to describe the effect of hospital type, and median odds ratios (MOR) to assess the degree of higher level variation. Utilization rates of POCR varied from 2.5% to 44.4% across regions. Higher age, intrathoracic pathology, and multi-morbidity were positively associated with the use of POCR. Female gender, choice of high franchise and supplementary hospital insurance showed a negative association. MOR was 1.25 and 1.69 for region and hospital levels, respectively. IOR-80s for hospital type were wide and covered the value of one. We observed substantial variation of POCR utilization across small regions in Switzerland. Even after controlling for multiple factors, variation across small regions and hospitals remained. Underlying mechanisms need to be studied further.

Death at no cost? Persons with no health insurance claims in the last year of life in Switzerland.

BACKGROUND: Lack of health insurance claims (HIC) in the last year of life might indicate suboptimal end-of-life care, but reasons for no HIC are not fully understood because information on causes of death is often missing. We investigated association of no HIC with characteristics of individuals and their place of residence. METHODS: We analysed HIC of persons who died between 2008 and 2010, which were obtained from six providers of mandatory Swiss health insurance. We probabilistically linked these persons to death certificates to get cause of death information and analysed data using sex-stratified, multivariable logistic regression. Supplementary analyses looked at selected subgroups of persons according to the primary cause of death. RESULTS: The study population included 113,277 persons (46% males). Among these persons, 1199 (proportion 0.022, 95% CI: 0.021-0.024) males and 803 (0.013, 95% CI: 0.012-0.014) females had no HIC during the last year of life. We found sociodemographic and health differentials in the lack of HIC at the last year of life among these 2002 persons. The likelihood of having no HIC decreased steeply with older age. Those who died of cancer were more likely to have HIC (adjusted odds ratio for males 0.17, 95% CI: 0.13-0.22; females 0.19, 95% CI: 0.12-0.28) whereas those dying of mental and behavioural disorders (AOR males 1.83, 95% CI:1.42-2.37; females 1.65, 95% CI: 1.27-2.14), and males dying of suicide (AOR 2.15, 95% CI: 1.72-2.69) and accidents (AOR 2.41, 95% CI: 1.96-2.97) were more likely to have none. Single, widowed, and divorced persons also were more likely to have no HIC (AORs in range of 1.29-1.80). There was little or no association between the lack of HIC and characteristics of region of residence. Patterns of no HIC differed across main causes of death. Associations with age and civil status differed in particular for persons who died of cancer, suicide, accidents and assaults, and mental and behavioural disorders. CONCLUSIONS: Particular groups might be more likely to not seek care or not report health insurance costs to insurers. Researchers should be aware of this aspect of health insurance data and account for persons who lack HIC.

Cost trajectories from the final life year reveal intensity of end-of-life care and can help to guide palliative care interventions.

OBJECTIVE: Exploration of healthcare utilisation patterns in the final life year to assess palliative care potential. METHODS: Retrospective cluster analyses (k-means) of anonymised healthcare expenditure (HCE) trajectories, derived from health insurance claims of a representative sample of Swiss decedents who died between 2008 and 2010 (2 age classes: 4818 <66 years, 22 691 elderly). RESULTS: 3 (<66 years) and 5 (elderly) trajectory groups were identified, whose shapes were dominated by HCE from inpatient care in hospitals and at nursing homes. In each age class, the most expensive group (average cumulative HCE for <66 years: SFr 84 295; elderly: SFr 84 941) also had the largest abundance of cancers (<66 years: 55%; elderly: 32%) and showed signs of continued treatment intensification until shortly before death. Although sizes of these high-cost groups were comparatively small (26% in younger; 6% in elderly), they contributed substantially to the end-of-life HCE in each age class (62% and 18%, respectively).As age increased, these potential target groups for palliative care gained in share among <66-year olds (from 9% in children to 28% in 60-65-year olds), but decreased from 17% (66-70-year olds) to 1% (>90-year olds) among elderly. CONCLUSIONS: Cost trajectory clustering is well suited for first-pass population screenings of groups that warrant closer inspection to improve end-of-life healthcare allocation. The Swiss data suggest that many decedents undergo intensive medical treatment until shortly before death. Investigations into the clinical circumstances and motives of patients and physicians may help to guide palliative care.

Iron metabolism in patients with Graves' hyperthyroidism.

OBJECTIVES: Graves' hyperthyroidism (GH) interferes with iron metabolism and elevates ferritin. The precise mechanisms remain unclear. The influence of thyroid hormones on the synthesis/regulation of hepcidin, an important regulator of iron metabolism, remains uncharacterized. DESIGN: Prospective observational study. PATIENTS: We included patients (n = 31) with new-onset and untreated GH. MEASUREMENTS: Laboratory parameters indicative of iron metabolism (ferritin, transferrin, hepcidin), inflammatory markers/cytokines and smoking status were assessed at the diagnosis of GH (T0) and at euthyroidism (T1) in the same patients using multivariable analyses. Hepcidin was measured by mass spectrometry (hepcidinMS ) and ELISA (hepcidinEL ). The impact of T3 on hepatic hepcidin expression was studied in a cell culture model using HepG2 cells. RESULTS: Median ferritin levels were significantly lower and transferrin significantly higher at T1 than at T0. HepcidinMS levels were lower in males and females at T1 (statistically significant in males only). No statistically significant difference in hepcidinEL was detected between T0 and T1. Plasma levels of inflammatory markers (high-sensitive CRP, procalcitonin) and cytokines (interleukin 6, interleukin 1ß, tumour necrosis factor α) were not different between T0 and T1. Smokers tended to have lower fT3 and fT4 at T0 than nonsmoking GH patients. T3 significantly induced hepcidin mRNA expression in HepG2 cells. CONCLUSIONS: Iron metabolism in patients with GH undergoes dynamic changes in patients with GH that resemble an acute-phase reaction. Inflammatory parameters and cytokines were unaffected by thyroid status. Gender and smoking status had an impact on ferritin, hepcidin and thyroid hormones.

Cancer co-occurrence patterns in Parkinson's disease and multiple sclerosis-Do they mirror immune system imbalances?

BACKGROUND: To examine the site-specific cancer mortality among deaths registered with Parkinson's disease (PD) and multiple sclerosis (MS). We focused on the patterns related to the most frequent cancers. METHODS: We analyzed Swiss mortality data over a 39-year period (1969-2007), using a statistical approach applicable to unique daabases, i.e. when no linkage with morbidity databases or disease registries is possible. It was based on a case-control design with bootstrapping to derive standardized mortality ratios (SMR). The cases were defined by the cancer-PD or cancer-MS co-registrations, whereas the controls were drawn from the remaining records with cancer deaths (matching criteria: sex, age, language region of Switzerland, subperiods 1969-1981, 1982-1994, 1995-2007). RESULTS: For PD we found lower SMRs in lung and liver cancer and higher SMRs in melanoma/skin cancer, and in cancers of breast and prostate. As for MS, the SMR in lung cancer was lower than expected, whereas SMRs in colorectal, breast and bladder cancer were higher. CONCLUSIONS: A common pattern of associations can be observed in PD and MS, with a lower risk of lung cancer and higher risk of breast cancer than expected. Thus, PD and MS resemble other conditions with similar (schizophrenia) or reversed patterns (rheumatoid arthritis, immunosuppression after organ transplantation).

The role of migration and domestic transmission in the spread of HIV-1 non-B subtypes in Switzerland.

BACKGROUND: By analyzing human immunodeficiency virus type 1 (HIV-1) pol sequences from the Swiss HIV Cohort Study (SHCS), we explored whether the prevalence of non-B subtypes reflects domestic transmission or migration patterns. METHODS: Swiss non-B sequences and sequences collected abroad were pooled to construct maximum likelihood trees, which were analyzed for Swiss-specific subepidemics, (subtrees including ≥80% Swiss sequences, bootstrap >70%; macroscale analysis) or evidence for domestic transmission (sequence pairs with genetic distance <1.5%, bootstrap ≥98%; microscale analysis). RESULTS: Of 8287 SHCS participants, 1732 (21%) were infected with non-B subtypes, of which A (n = 328), C (n = 272), CRF01_AE (n = 258), and CRF02_AG (n = 285) were studied further. The macroscale analysis revealed that 21% (A), 16% (C), 24% (CRF01_AE), and 28% (CRF02_AG) belonged to Swiss-specific subepidemics. The microscale analysis identified 26 possible transmission pairs: 3 (12%) including only homosexual Swiss men of white ethnicity; 3 (12%) including homosexual white men from Switzerland and partners from foreign countries; and 10 (38%) involving heterosexual white Swiss men and females of different nationality and predominantly nonwhite ethnicity. CONCLUSIONS: Of all non-B infections diagnosed in Switzerland, <25% could be prevented by domestic interventions. Awareness should be raised among immigrants and Swiss individuals with partners from high prevalence countries to contain the spread of non-B subtypes.

Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study.

BACKGROUND: The effect of transmitted drug resistance (TDR) on first-line combination antiretroviral therapy (cART) for HIV-1 needs further study to inform choice of optimum drug regimens. We investigated the effect of TDR on outcome in the first year of cART within a large European collaboration. METHODS: HIV-infected patients of any age were included if they started cART (at least three antiretroviral drugs) for the first time after Jan 1, 1998, and were antiretroviral naive and had at least one sample for a genotypic test taken before the start of cART. We used the WHO drug resistance list and the Stanford algorithm to classify patients into three resistance categories: no TDR, at least one mutation and fully-active cART, or at least one mutation and resistant to at least one prescribed drug. Virological failure was defined as time to the first of two consecutive viral load measurements over 500 copies per mL after 6 months of therapy. FINDINGS: Of 10,056 patients from 25 cohorts, 9102 (90·5%) had HIV without TDR, 475 (4·7%) had at least one mutation but received fully-active cART, and 479 (4·8%) had at least one mutation and resistance to at least one drug. Cumulative Kaplan-Meier estimates for virological failure at 12 months were 4·2% (95% CI 3·8-4·7) for patients in the no TDR group, 4·7% (2·9-7·5) for those in the TDR and fully-active cART group, and 15·1% (11·9-19·0) for those in the TDR and resistant group (log-rank p<0·0001). The hazard ratio for the difference in virological failure between patients with TDR and resistance to at least one drug and those without TDR was 3·13 (95% CI 2·33-4·20, p<0·0001). The hazard ratio for the difference between patients with TDR receiving fully-active cART and patients without TDR was 1·47 (95% CI 0·19-2·38, p=0·12). In stratified analysis, the hazard ratio for the risk of virological failure in patients with TDR who received fully-active cART that included a non-nucleoside reverse transcriptase inhibitor (NNRTI) compared with those without TDR was 2·0 (95% CI 0·9-4·7, p=0·093). INTERPRETATION: These findings confirm present treatment guidelines for HIV, which state that the initial treatment choice should be based on resistance testing in treatment-naive patients. FUNDING: European Community's Seventh Framework Programme FP7/2007-2013 and Gilead.

B cells from HIV-infected patients with primary central nervous system lymphoma display an activated phenotype and have a blunted TNF-α response to TLR9 triggering.

Each cell in HIV-associated primary central nervous system lymphoma (PCNSL) harbors latent EBV. Notably, the triggering of TLR9, a key event in HIV pathogenesis, also promotes EBV latency and transformation. We hypothesized that because only a minority of HIV-infected patients develops PCNSL, their B cells exhibit aberrant signaling responses to TLR9 triggering. We found higher levels of IL-6, CD80, and CD86 expression at baseline in B cells of those patients than in B cells of matched controls, whereas TNF-a expression was lower. Notably, on TLR9 triggering with CpG 2006, CD80 and TNF-α were up-regulated to a lesser extent in B cells of the former than in those of matched controls. The reduced up-regulation of CD80 might be explained by its higher baseline expression resulting in a more blunted response rather than a specific deficit of the signaling response to TLR9 triggering. However, this cannot explain the blunted TNF-α response, which warrants further investigation. Finally, since increased IL-6 expression is linked to EBV-associated Hodgkin's lymphoma, the enhanced baseline expression of IL-6 might be important in the pathogenesis of PCNSL in HIV-infected patients.

Mortality of HIV-infected patients starting potent antiretroviral therapy: comparison with the general population in nine industrialized countries.

BACKGROUND: Mortality in HIV-infected patients has declined substantially with combination antiretroviral therapy (ART), but it is unclear whether it has reached that of the general population. We compared mortality in patients starting ART in nine countries of Europe and North America with the corresponding general population, taking into account their response to ART. METHODS: Eligible patients were enrolled in prospective cohort studies participating in the ART Cohort Collaboration. We calculated the ratio of observed to expected deaths from all causes [standardized mortality ratio (SMR)], measuring time from 6 months after starting ART, according to risk group, clinical stage at the start of ART and CD4 cell count and viral load at 6 months. Expected numbers of deaths were obtained from age-, sex- and country-specific mortality rates. RESULTS: Among 29 935 eligible patients, 1134 deaths were recorded in 131 510 person-years of follow-up. The median age was 37 years, 8162 (27%) patients were females, 4400 (15%) were injecting drug users (IDUs) and 6738 (23%) had AIDS when starting ART. At 6 months, 23 539 patients (79%) had viral load measurements or=350 cells/microL and suppressed viral replication to 10 were 4, 14 and 47%. CONCLUSIONS: In industrialized countries, the mortality experience of HIV-infected patients who start ART and survive the first 6 months continues to be higher than in the general population, but for many patients excess mortality is moderate and comparable with patients having other chronic conditions. Much of the excess mortality might be prevented by earlier diagnosis of HIV followed by timely initiation of ART.

Potent human immunodeficiency virus-neutralizing and complement lysis activities of antibodies are not obligatorily linked.

To evaluate the contribution of complement-mediated lysis to the in vivo activities of neutralizing antibodies, we analyzed the influence of complement activation on treatment success in a recent passive immunization trial with the neutralizing monoclonal antibodies 2G12, 2F5, and 4E10. Administration of monoclonal antibodies led to an immediate, high activation of the complement system even in the absence of viremia in the 14 participating human immunodeficiency virus-infected individuals. Lysis activity measured in patient plasma increased during passive immunization; however, the increases were modest and only partially attributable to the administration of antibodies. We found that unlike neutralization activity, lysis activity was not associated with treatment success in this trial. Compared to complement lysis mounted by the polyclonal antibody response in vivo, monoclonal antibodies were weak inducers of this activity, suggesting that polyclonal responses are more effective in reaching the required threshold of complement activation. Importantly, strong neutralization activity of the monoclonal antibodies did not predict complement lysis activity against patient and reference viruses, suggesting that these activities are not linked. In summary, our data support the notion that the in vivo activities of 2G12, 2F5, and 4E10 are likely due to direct neutralization or Fc receptor-mediated mechanisms such as phagocytosis and antibody-dependent cellular cytotoxicity.

Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 infection.

BACKGROUND: To explore the possibility that antibody-mediated complement lysis contributes to viremia control in HIV-1 infection, we measured the activity of patient plasma in mediating complement lysis of autologous primary virus. METHODS AND FINDINGS: Sera from two groups of patients-25 with acute HIV-1 infection and 31 with chronic infection-were used in this study. We developed a novel real-time PCR-based assay strategy that allows reliable and sensitive quantification of virus lysis by complement. Plasma derived at the time of virus isolation induced complement lysis of the autologous virus isolate in the majority of patients. Overall lysis activity against the autologous virus and the heterologous primary virus strain JR-FL was higher at chronic disease stages than during the acute phase. Most strikingly, we found that plasma virus load levels during the acute but not the chronic infection phase correlated inversely with the autologous complement lysis activity. Antibody reactivity to the envelope (Env) proteins gp120 and gp41 were positively correlated with the lysis activity against JR-FL, indicating that anti-Env responses mediated complement lysis. Neutralization and complement lysis activity against autologous viruses were not associated, suggesting that complement lysis is predominantly caused by non-neutralizing antibodies. CONCLUSIONS: Collectively our data provide evidence that antibody-mediated complement virion lysis develops rapidly and is effective early in the course of infection; thus it should be considered a parameter that, in concert with other immune functions, steers viremia control in vivo.