PopART-IBM, a highly efficient stochastic individual-based simulation model of generalised HIV epidemics developed in the context of the HPTN 071 (PopART) trial.

Mathematical models are powerful tools in HIV epidemiology, producing quantitative projections of key indicators such as HIV incidence and prevalence. In order to improve the accuracy of predictions, such models need to incorporate a number of behavioural and biological heterogeneities, especially those related to the sexual network within which HIV transmission occurs. An individual-based model, which explicitly models sexual partnerships, is thus often the most natural type of model to choose. In this paper we present PopART-IBM, a computationally efficient individual-based model capable of simulating 50 years of an HIV epidemic in a large, high-prevalence community in under a minute. We show how the model calibrates within a Bayesian inference framework to detailed age- and sex-stratified data from multiple sources on HIV prevalence, awareness of HIV status, ART status, and viral suppression for an HPTN 071 (PopART) study community in Zambia, and present future projections of HIV prevalence and incidence for this community in the absence of trial intervention.

Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis.

OBJECTIVES: Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database. METHODS: Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression. RESULTS: Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model. CONCLUSIONS: The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.

Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2nd -line therapy for relapsed and refractory multiple myeloma - a phase II trial.

The combination of lenalidomide (Revlimid® , R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose-limiting haematotoxicity restricted its use in extensively pre-treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46-83]) and were treated with B 75 mg/m2  days 1, 2; R 25 mg days 1-21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28-day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol-defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients.

Adaptive prior weighting in generalized regression.

The prior distribution is a key ingredient in Bayesian inference. Prior information on regression coefficients may come from different sources and may or may not be in conflict with the observed data. Various methods have been proposed to quantify a potential prior-data conflict, such as Box's p-value. However, there are no clear recommendations how to react to possible prior-data conflict in generalized regression models. To address this deficiency, we propose to adaptively weight a prespecified multivariate normal prior distribution on the regression coefficients. To this end, we relate empirical Bayes estimates of prior weight to Box's p-value and propose alternative fully Bayesian approaches. Prior weighting can be done for the joint prior distribution of the regression coefficients or-under prior independence-separately for prespecified blocks of regression coefficients. We outline how the proposed methodology can be implemented using integrated nested Laplace approximations (INLA) and illustrate the applicability with a Bayesian logistic regression model for data from a cross-sectional study. We also provide a simulation study that shows excellent performance of our approach in the case of prior misspecification in terms of root mean squared error and coverage. Supplementary Materials give details on software implementation and code and another application to binary longitudinal data from a randomized clinical trial using a Bayesian generalized linear mixed model.

Economic Aspects of Morbidity Caused by Ureteral Stents.

OBJECTIVE: To assess the economic burden of temporary ureteral stenting. METHODS: The German version of the ureteral stent symptom questionnaire was completed by 74 patients with unilateral inserted indwelling stents. Cost accounting was performed considering the costs of ureteral stents, drugs, consultation of healthcare professionals, hospitalization, stent extraction and work incapacity due to stent-related problems. RESULTS: Total costs arising from stent-related problems amounted to US dollars (USD) 133,355, median USD 455 (113-11,948) for the entire stent indwelling time, and USD 15 (4-398) per patient per day. Costs (USD total/median (range)) arose mainly from work incapacity (104,154/0 (0-11, 498)), followed by healthcare professional consultation (9,177/0 (0-612)), drug costs (8,736/111 (0-427)), stent material (8,390/113), stent removal (2,235/0 (0-1,769)) and outpatient hospital care (663/0 (0-663)). Most patients also showed a reduced capacity for work due to symptoms associated with indwelling stents. CONCLUSION: The economic burden of morbidity associated with indwelling ureteral stents is considerably high and should be taken into account when performing ureteral stenting, especially in cases where it is not strictly indicated and when stent removal is scheduled.

Network meta-analysis with integrated nested Laplace approximations.

Analyzing the collected evidence of a systematic review in form of a network meta-analysis (NMA) enjoys increasing popularity and provides a valuable instrument for decision making. Bayesian inference of NMA models is often propagated, especially if correlated random effects for multiarm trials are included. The standard choice for Bayesian inference is Markov chain Monte Carlo (MCMC) sampling, which is computationally intensive. An alternative to MCMC sampling is the recently suggested approximate Bayesian method of integrated nested Laplace approximations (INLA) that dramatically saves computation time without any substantial loss in accuracy. We show how INLA apply to NMA models for summary level as well as trial-arm level data. Specifically, we outline the modeling of multiarm trials and inference for functional contrasts with INLA. We demonstrate how INLA facilitate the assessment of network inconsistency with node-splitting. Three applications illustrate the use of INLA for a NMA.

Association of risk assessment at diagnosis with healthcare resource utilization and health-related quality of life outcomes in pulmonary arterial hypertension.

We aimed to describe the clinical characteristics, healthcare resource utilization (HCRU) and costs, health-related quality of life (HRQoL), and survival for patients with pulmonary arterial hypertension (PAH), stratified by 1-year mortality risk at diagnosis. Adults diagnosed with PAH at the Sheffield Pulmonary Vascular Disease Unit between 2012 and 2019 were included. Patients were categorized as low, intermediate, or high risk for 1-year mortality at diagnosis. Demographics, clinical characteristics, comorbidities, HCRU, costs, HRQoL, and survival were analyzed. Overall, 1717 patients were included: 72 (5%) at low risk, 941 (62%) at intermediate risk, and 496 (33%) at high risk. Low-risk patients had lower HCRU prediagnosis and 1-year postdiagnosis than intermediate- or high-risk patients. Postdiagnosis, there were significant changes in HCRU, particularly inpatient hospitalizations and accident and emergency (A&E) visits among high-risk patients. At 3 years postdiagnosis, HCRU for all measures was similar across risk groups. Low-risk patients had lower EmPHasis-10 scores (indicating better HRQoL) at diagnosis and at 1-year follow-up compared with intermediate- and high-risk patients; only the score in the high-risk group improved. Median overall survival decreased as risk category increased in analyzed subgroups. Low-risk status was associated with better 1-year survival and HRQoL compared with intermediate- and high-risk patients. HCRU decreased in high-risk patients postdiagnosis, with the most marked reduction in A&E admissions. The pattern of decreased per-patient inpatient hospitalizations and A&E visits at 3 years postdiagnosis suggests that a diagnosis of PAH helps to decrease HCRU in areas that are key drivers of costs.

Risk assessment and real-world outcomes in chronic thromboembolic pulmonary hypertension: insights from a UK pulmonary hypertension referral service.

OBJECTIVES: This study was conducted to evaluate the ability of risk assessment to predict healthcare resource utilisation (HCRU), costs, treatments, health-related quality of life (HRQoL) and survival in patients diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH). DESIGN: Retrospective observational study. SETTING: Pulmonary hypertension referral centre in the UK. PARTICIPANTS: Adults diagnosed with CTEPH between 1 January 2012 and 30 June 2019 were included. Cohorts were retrospectively defined for operated patients (received pulmonary endarterectomy (PEA)) and not operated; further subgroups were defined based on risk score (low, intermediate or high risk for 1-year mortality) at diagnosis. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographics, clinical characteristics, comorbidities, treatment patterns, HRQoL, HCRU, costs and survival outcomes were analysed. RESULTS: Overall, 683 patients were analysed (268 (39%) operated; 415 (61%) not operated). Most patients in the operated and not-operated cohorts were intermediate risk (63%; 53%) or high risk (23%; 31%) at diagnosis. Intermediate-risk and high-risk patients had higher HCRU and costs than low-risk patients. Outpatient and accident and emergency visits were lower postdiagnosis for both cohorts and all risk groups versus prediagnosis. HRQoL scores noticeably improved in the operated cohort post-PEA, and less so in the not-operated cohort at 6-18 months postdiagnosis. Survival at 5 years was 83% (operated) and 49% (not operated) and was lower for intermediate-risk and high-risk patients compared with low-risk patients. CONCLUSIONS: Findings from this study support that risk assessment at diagnosis is prognostic for mortality in patients with CTEPH. Low-risk patients have better survival and HRQoL and lower HCRU and costs compared with intermediate-risk and high-risk patients.

Healthcare resource utilization and quality of life in patients with sarcoidosis-associated pulmonary hypertension.

A retrospective, observational cohort study was conducted to generate real-world evidence in adult patients diagnosed with sarcoidosis-associated pulmonary hypertension (SAPH) at a referral center in England between 2012 and 2019. Data from the referral center electronic medical record database were linked to the National Health Service Hospital Episode Statistics database to collect and analyze patient demographics, clinical characteristics, comorbidities, treatment patterns, health-related quality of life (HRQoL; assessed using the EmPHasis-10 questionnaire), healthcare resource utilization (HCRU), costs, and survival. Sixty-two patients with SAPH were identified. At diagnosis, 84% were in WHO functional class III and presented with significant pulmonary hemodynamic impairment. Cardiovascular and respiratory comorbidities were commonly reported prediagnosis. Median EmPHasis-10 score at diagnosis was 34, indicative of poor HRQoL. In the 1st year after diagnosis, median (Q1, Q3) per-patient HCRU was 1 (0, 2) all-cause inpatient hospitalizations; 3 (2, 4) same-day hospitalizations; and 9 (6, 11) outpatient consultations. In 24 patients who were hospitalized longer than 1 day in the 1st year after diagnosis, the median duration of hospitalization was 4 days. With a median follow-up of 1.8 years, the median overall survival was 2.9 years. In this cohort of patients with SAPH, poor HRQoL and high HCRU were observed following diagnosis. To our knowledge, this is the first study to report on HRQoL and HCRU in patients with SAPH. More research is needed on treatment options for this population with high unmet needs.

Projected outcomes of universal testing and treatment in a generalised HIV epidemic in Zambia and South Africa (the HPTN 071 [PopART] trial): a modelling study.

BACKGROUND: The long-term impact of universal home-based testing and treatment as part of universal testing and treatment (UTT) on HIV incidence is unknown. We made projections using a detailed individual-based model of the effect of the intervention delivered in the HPTN 071 (PopART) cluster-randomised trial. METHODS: In this modelling study, we fitted an individual-based model to the HIV epidemic and HIV care cascade in 21 high prevalence communities in Zambia and South Africa that were part of the PopART cluster-randomised trial (intervention period Nov 1, 2013, to Dec 31, 2017). The model represents coverage of home-based testing and counselling by age and sex, delivered as part of the trial, antiretroviral therapy (ART) uptake, and any changes in national guidelines on ART eligibility. In PopART, communities were randomly assigned to one of three arms: arm A received the full PopART intervention for all individuals who tested positive for HIV, arm B received the intervention with ART provided in accordance with national guidelines, and arm C received standard of care. We fitted the model to trial data twice using Approximate Bayesian Computation, once before data unblinding and then again after data unblinding. We compared projections of intervention impact with observed effects, and for four different scenarios of UTT up to Jan 1, 2030 in the study communities. FINDINGS: Compared with standard of care, a 51% (95% credible interval 40-60) reduction in HIV incidence is projected if the trial intervention (arms A and B combined) is continued from 2020 to 2030, over and above a declining trend in HIV incidence under standard of care. INTERPRETATION: A widespread and continued commitment to UTT via home-based testing and counselling can have a substantial effect on HIV incidence in high prevalence communities. FUNDING: National Institute of Allergy and Infectious Diseases, US President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health.

Relationship Between Time From Diagnosis and Morbidity/Mortality in Pulmonary Arterial Hypertension: Results From the Phase III GRIPHON Study.

BACKGROUND: Early initiation of pulmonary arterial hypertension (PAH) therapies is associated with improved long-term outcomes, yet data on the early use of prostacyclin pathway agents are limited. In these post hoc analyses of the Prostacyclin (PGI2) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON) study, the largest randomized controlled trial for PAH to date, the prognostic value of time from diagnosis and its impact on treatment response were examined. RESEARCH QUESTION: How does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH? STUDY DESIGN AND METHODS: The GRIPHON study randomly assigned 1,156 patients with PAH to selexipag or placebo treatment. Patients were categorized post hoc into a time from diagnosis of ≤ 6 months and > 6 months at randomization. Hazard ratios (selexipag vs placebo) were calculated for the primary end point of morbidity/mortality by time from diagnosis using Cox proportional hazard models. RESULTS: Time from diagnosis was ≤ 6 months in 34.9% and > 6 months in 65.1% of patients. Time from diagnosis was prognostic of morbidity/mortality, with newly diagnosed patients having a poorer long-term outcome than patients diagnosed for longer. Compared with placebo, selexipag reduced the risk of morbidity/mortality in patients with a time from diagnosis of ≤ 6 months and > 6 months, with a more pronounced effect in newly diagnosed patients (hazard ratio, 0.45 [95% CI, 0.33-0.63] and 0.74 [95% CI, 0.57-0.96], respectively; P = .0219 for interaction). INTERPRETATION: In the GRIPHON study, newly diagnosed PAH patients had a worse prognosis than patients with a longer time from diagnosis. The benefit of selexipag treatment on disease progression was more pronounced in patients treated earlier than in patients treated later. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov.

Cost and cost-effectiveness of a universal HIV testing and treatment intervention in Zambia and South Africa: evidence and projections from the HPTN 071 (PopART) trial.

BACKGROUND: The HPTN 071 (PopART) trial showed that a combination HIV prevention package including universal HIV testing and treatment (UTT) reduced population-level incidence of HIV compared with standard care. However, evidence is scarce on the costs and cost-effectiveness of such an intervention. METHODS: Using an individual-based model, we simulated the PopART intervention and standard care with antiretroviral therapy (ART) provided according to national guidelines for the 21 trial communities in Zambia and South Africa (for all individuals aged >14 years), with model parameters and primary cost data collected during the PopART trial and from published sources. Two intervention scenarios were modelled: annual rounds of PopART from 2014 to 2030 (PopART 2014-30; as the UNAIDS Fast-Track target year) and three rounds of PopART throughout the trial intervention period (PopART 2014-17). For each country, we calculated incremental cost-effectiveness ratios (ICERs) as the cost per disability-adjusted life-year (DALY) and cost per HIV infection averted. Cost-effectiveness acceptability curves were used to indicate the probability of PopART being cost-effective compared with standard care at different thresholds of cost per DALY averted. We also assessed budget impact by projecting undiscounted costs of the intervention compared with standard care up to 2030. FINDINGS: During 2014-17, the mean cost per person per year of delivering home-based HIV counselling and testing, linkage to care, promotion of ART adherence, and voluntary medical male circumcision via community HIV care providers for the simulated population was US$6·53 (SD 0·29) in Zambia and US$7·93 (0·16) in South Africa. In the PopART 2014-30 scenario, median ICERs for PopART delivered annually until 2030 were $2111 (95% credible interval [CrI] 1827-2462) per HIV infection averted in Zambia and $3248 (2472-3963) per HIV infection averted in South Africa; and $593 (95% CrI 526-674) per DALY averted in Zambia and $645 (538-757) per DALY averted in South Africa. In the PopART 2014-17 scenario, PopART averted one infection at a cost of $1318 (1098-1591) in Zambia and $2236 (1601-2916) in South Africa, and averted one DALY at $258 (225-298) in Zambia and $326 (266-391) in South Africa, when outcomes were projected until 2030. The intervention had almost 100% probability of being cost-effective at thresholds greater than $700 per DALY averted in Zambia, and greater than $800 per DALY averted in South Africa, in the PopART 2014-30 scenario. Incremental programme costs for annual rounds until 2030 were $46·12 million (for a mean of 341 323 people) in Zambia and $30·24 million (for a mean of 165 852 people) in South Africa. INTERPRETATION: Combination prevention with universal home-based testing can be delivered at low annual cost per person but accumulates to a considerable amount when scaled for a growing population. Combination prevention including UTT is cost-effective at thresholds greater than $800 per DALY averted and can be an efficient strategy to reduce HIV incidence in high-prevalence settings. FUNDING: US National Institutes of Health, President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation.

Improving Patient Education Materials: A Practical Algorithm from Development to Validation.

OBJECTIVES: To generate an algorithm for systematic development and validation of written patient information in accordance with well-established and validated psychometric and statistical methods that can be applied to different fields of medicine. METHODS: A literature search was carried out in PubMed and Google Scholar. Methods were selected and combined to an algorithm. Feasibility and practicability is tested by the development of patient education materials on "ureteral stenting". RESULTS: The algorithm includes 4 study phases. After internal audit expert, readability of the first version is objectified using the Flesch Reading Ease formula. This draft is tested by a few patients performing semi-structured interviews using "The think aloud method" by Someren et al. Content validity is evaluated by a written survey by external consultants in accordance with Lawshe's "Quantitative approach to content validity". The final leaflet is developed at a consensus meeting and validated by patients based on the Consumer Information Rating Form. The new algorithm could be tested by the development of patient education materials on "ureteral stenting" as a test run. CONCLUSION: We developed an algorithm for systematic development and validation of written patient information in accordance with well-established, validated psychometric and statistical methods. This algorithm can be applied to arbitrary fields of medicine.

36-Months follow-up assessment after cessation and resuming of enzyme replacement therapy in late onset Pompe disease: data from the Swiss Pompe Registry.

INTRODUCTION: Although not curative, enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase enzyme has shown to be effective in the treatment of late-onset Pompe disease (LOPD). For this potentially life-long treatment, little is known on the clinical effect of cessation and resuming ERT. Due to a Swiss supreme court decision on ERT reimbursement, a temporary stop of ERT occurred in our study population. The aim of this study was to report the 36-months follow-up assessments after resuming ERT. METHODS: After resuming ERT, seven patients suffering from genetically and enzymatically confirmed LOPD had periodic, mandatory, prospective assessments of pulmonary function tests, muscle strength summary scores, distances walked in timed walking tests, and patient-reported questionnaires. Data were statistically analyzed for significant differences between time points at ERT cessation, at ERT resuming, and 36 months thereafter. RESULTS: After resuming ERT forced vital capacity (p = 0.007) and distance walked in the 6 min walk test (6-MWT, p = 0.011) significantly increased at 36 months. Compared to before ERT cessation, distance walked in 6-MWT at 36 months still remained significantly lower (p = 0.005). Self-reported scores in the fatigue severity scale significantly declined at 36 months after resuming ERT (p = 0.019). No other functional or reported parameter significantly changed at 36 months after resuming ERT. CONCLUSIONS: Our data suggests that long-term interruption of ERT in LOPD may lead to deterioration of clinical meaningful parameters and quality of life. In addition, a clinical restoration after ERT cessation is possible for most of the LOPD patients within a 36 months follow-up.

Long-Term Increase of Radiographic Damage and Disability in Patients with RA in Relation to Disease Duration in the Era of Biologics. Results from the SCQM Cohort.

OBJECTIVES: There is little information on the relation between disease duration, disability and radiographic outcome since the introduction of biologics into the therapy of rheumatoid arthritis (RA). No long -term cohort studies have been conducted on this subject so far. To analyse radiographic damage, disability, and disease activity in RA-patients dependent on disease duration in the Swiss national RA cohort (SCQM). METHODS: The primary outcome was the association between the radiographic destruction, assessed by Ratingen scores, and disease duration. All patients with at least one clinical visit were analysed with polynomial and multiple negative binomial models. RESULTS: The disease duration in the 8678 patients with available radiographs analysed ranged between less than 1 and more than 65 years (median 8.3). Disease duration and radiographic destruction were significantly associated with an average increase of Ratingen scores by 8.3% per year. Apart from disease duration, positive rheumatoid factor was the strongest predictor for radiographic destruction. While DAS28-scores remained stable in patients with a disease duration of more than 5 years (median DAS28 2.8), HAQ-DI scores increased continuously by 0.018 for each additional year. CONCLUSION: In this RA cohort, patients show a continuous increase of articular destruction and physical disability in parallel with disease duration. Even when nowadays a satisfactory control of disease activity can be achieved in most patients, RA remains a destructive disease leading to joint destruction and physical disability in many patients.

Endophenotyping in idiopathic adult onset cervical dystonia.

OBJECTIVE: Idiopathic adult onset cervical dystonia (IAOCD) is considered to be a partially penetrant autosomal dominant genetic condition. Dystonia may result from genetic and environmental factors. In this view, part of the physiology should be an endophenotype stemming from the genetic background. We assessed the most discriminative test to separate patients with IAOCD and healthy controls for further endophenotyping in non-affected 1st degree relatives. METHODS: We included patients with IAOCD, their 1st degree relatives and healthy controls. Tests performed: (1) Sensory temporal discrimination (visual, tactile, visuo-tactile), (2) Paired pulse paradigms using transcranial magnetic stimulation (TMS), (3) Mental rotation paradigms. RESULTS: 45 patients with IAOCD, 23 healthy controls and 14 non-affected 1st degree relatives were recruited. Visuo-tactile temporal discrimination separated best between controls and patients as well as between controls and 1st degree relatives. 36% of the latter had an abnormal visuo-tactile temporal discrimination. No difference between patients and healthy controls was found for the other paradigms. CONCLUSIONS: Visuo-tactile temporal discrimination separates controls from patients with IAOCD and its 1st degree relatives. 36% of the latter had abnormal visuo-tactile thresholds supporting the role of visuo-tactile temporal discrimination as an endophenotype for IAOCD. SIGNIFICANCE: Even though the study was of exploratory design, our findings expand the understanding of endophenotypes in IAOCD.

Heart rate variability decreases after 3 months of sustained treatment with fingolimod.

The objective is to prospectively investigate short- and mid-term changes of heart rate variability (HRV) in patients with relapsing-remitting multiple sclerosis (RRMS), being started on fingolimod. In this prospective clinical trial, patient (n = 33) with RRMS starting treatment with fingolimod underwent a time-domain-based analysis of HRV (breathing at rest, deep breath, and in response to the Valsalva maneuver) shortly before, 4.5 h and 3 months after first intake. Blood pressure changes after the Valsalva maneuver were used as a marker of the sympathetic noradrenergic system. We used a non-invasive continuous beat-to-beat heart rate and blood pressure monitoring. In addition, the Fatigue Severity Scale and the refined and abbreviated Composite Autonomic Symptom Score were applied. Significant changes in HRV in RRMS patients, following treatment with fingolimod, were detected. After an initial increase in HRV, measured 4.5 h after the first intake of fingolimod, a substantial decrease in HRV occurred within 3 months on continuous treatment. There is a growing body of evidence for short-term cardiovascular side effects in continuous treatment with fingolimod, driven by the ANS. The mechanisms and the clinical relevance of the observed changes in HRV need further evaluation, especially in longer and larger prospective studies.

Absorption of Irrigation Fluid During Thulium Laser Vaporization of the Prostate.

PURPOSE: To assess the prevalence and extent of irrigation fluid absorption during thulium laser vaporization of the prostate. MATERIAL AND METHODS: Fifty-four patients undergoing thulium laser vaporization of the prostate were prospectively included into the trial at a tertiary referral center. Isotonic saline containing 1% ethanol was used for intraoperative irrigation. Absorption of irrigation fluid was measured periodically during the operation using the expired breath ethanol technique. Among others, intra- and postoperative changes in biochemical and hematological laboratory findings were assessed. RESULTS: Absorption of irrigation fluid was detected in 7 out of 54 (13%) patients with a median absorption volume of 265 mL (227-615). No significant differences of intra- and postoperative blood parameters were observed between absorbers and nonabsorbers. No risk factor (i.e., age, prostate size, surgery duration, applied energy, and amount of irrigation fluid) for the occurrence of fluid absorption could be identified. CONCLUSION: Absorption of irrigation fluid also occurs during thulium laser vaporization of the prostate and should be kept in mind, especially in patients at a high cardiovascular risk. However, compared with previously assessed resection and vaporization techniques, thulium vaporization might have a favorable safety profile regarding fluid absorption.

Impact of human papillomavirus on outcome in patients with oropharyngeal cancer treated with primary surgery.

BACKGROUND: Knowledge about prognostic factors in surgically treated patients with oropharyngeal squamous cell carcinoma (SCC) is limited. The purpose of this study was to identify influential factors on survival in a large cohort of patients with surgically treated oropharyngeal SCC. METHODS: Retrospective analysis of survival estimates in patients with surgically treated oropharyngeal SCC using tumoral positivity for human papillomavirus (HPV) and risk-of-death categories according to a study from 2010 as stratification factors. RESULTS: The 5-year overall survival (OS) and disease-specific survival (DSS) rates after surgery alone were higher in HPV-associated oropharyngeal SCC (OS 80% vs 62%; P = .01; DSS 92% vs 76%; P = .03). Patients in the low-risk category had higher survival rates (OS 91%; DSS 99%) than patients in the intermediate-risk group (OS 63%; DSS 83%), and high-risk group (OS 61%; DSS 75%). CONCLUSION: Nonsmokers with HPV-positive oropharyngeal SCC have a better prognosis than smokers with HPV-positive oropharyngeal SCC and also than patients with HPV-negative tumors when treated by surgery alone.

CD4/CD8 ratio and CD8 counts predict CD4 response in HIV-1-infected drug naive and in patients on cART.

Plasma HIV viral load is related to declining CD4 lymphocytes. The extent to which CD8 cells, in addition to RNA viral load, predict the depletion of CD4 cells is not well characterized so far. We examine if CD8 cell count is a prognostic factor for CD4 cell counts during an HIV infection.A longitudinal analysis is conducted using data from the Swiss HIV cohort study collected between January 2000 and October 2014. Linear mixed regression models were applied to observations from HIV-1-infected treatment naive patients (NAIVE) and cART-treated patients to predict the short-term evolution of CD4 cell counts. For each subgroup, it was quantified to which extent CD8 cell counts or CD4/CD8 ratios are prognostic factors for disease progression.In both subgroups, 2500 NAIVE and 8902 cART patients, past CD4 cells are positively (P < 0.0001) and past viral load is negatively (P < 0.0001) associated with the outcome. Including additionally past CD8 cell counts improves the fit significantly (P < 0.0001) and increases the marginal explained variation 31.7% to 40.7% for the NAIVE and from 44.1% to 50.7% for the cART group. The past CD4/CD8 ratio (instead of the past CD8 level) is positively associated with the outcome, increasing the explained variation further to 41.8% for NAIVE and 51.9% for cART.