Utility of a machine-guided tool for assessing risk behaviour associated with contracting HIV in three sites in South Africa.

Introduction: Digital data collection and the associated mobile health technologies have allowed for the recent exploration of artificial intelligence as a tool for combatting the HIV epidemic. Machine learning has been found to be useful both in HIV risk prediction and as a decision support tool for guiding pre-exposure prophylaxis (PrEP) treatment. This paper reports data from two sequential studies evaluating the viability of using machine learning to predict the susceptibility of adults to HIV infection using responses from a digital survey deployed in a high burden, low-resource setting. Methods: 1036 and 593 participants were recruited across two trials. The first trial was a cross-sectional study in one location and the second trial was a cohort study across three trial sites. The data from the studies were merged, partitioned using standard techniques, and then used to train and evaluate multiple different machine learning models and select and evaluate a final model. Variable importance estimates were calculated using the PIMP and SHAP methodologies. Results: Characteristics associated with HIV were consistent across both studies. Overall, HIV positive patients had a higher median age (34 [IQR: 29-39] vs 26 [IQR 22-33], p < 0.001), and were more likely to be female (155/703 [22%] vs 107/927 [12%], p < 0.001). HIV positive participants also had more commonly gone a year or more since their last HIV test (183/262 [70%] vs 540/1368 [39%], p < 0.001) and were less likely to report consistent condom usage (113/262 [43%] vs 758/1368 [55%], p < 0.001). Patients who reported TB symptoms were more likely to be HIV positive. The trained models had accuracy values (AUROCs) ranging from 78.5% to 82.8%. A boosted tree model performed best with a sensitivity of 84% (95% CI 72-92), specificity of 71% (95% CI 67-76), and a negative predictive value of 95% (95% CI 93-96) in a hold-out dataset. Age, duration since last HIV test, and number of male sexual partners were consistently three of the four most important variables across both variable importance estimates. Conclusions: This study has highlighted the synergies present between mobile health and machine learning in HIV. It has been demonstrated that a viable ML model can be built using digital survey data from an low-middle income setting with potential utility in directing health resources.

Scaffold Geometry-Imposed Anisotropic Mechanical Loading Guides the Evolution of the Mechanical State of Engineered Cardiovascular Tissues in vitro.

Cardiovascular tissue engineering is a promising approach to develop grafts that, in contrast to current replacement grafts, have the capacity to grow and remodel like native tissues. This approach largely depends on cell-driven tissue growth and remodeling, which are highly complex processes that are difficult to control inside the scaffolds used for tissue engineering. For several tissue engineering approaches, adverse tissue growth and remodeling outcomes were reported, such as aneurysm formation in vascular grafts, and leaflet retraction in heart valve grafts. It is increasingly recognized that the outcome of tissue growth and remodeling, either physiological or pathological, depends at least partly on the establishment of a homeostatic mechanical state, where one or more mechanical quantities in a tissue are maintained in equilibrium. To design long-term functioning tissue engineering strategies, understanding how scaffold parameters such as geometry affect the mechanical state of a construct, and how this state guides tissue growth and remodeling, is therefore crucial. Here, we studied how anisotropic versus isotropic mechanical loading-as imposed by initial scaffold geometry-influences tissue growth, remodeling, and the evolution of the mechanical state and geometry of tissue-engineered cardiovascular constructs in vitro. Using a custom-built bioreactor platform and nondestructive mechanical testing, we monitored the mechanical and geometric changes of elliptical and circular, vascular cell-seeded, polycaprolactone-bisurea scaffolds during 14 days of dynamic loading. The elliptical and circular scaffold geometries were designed using finite element analysis, to induce anisotropic and isotropic dynamic loading, respectively, with similar maximum stretch when cultured in the bioreactor platform. We found that the initial scaffold geometry-induced (an)isotropic loading of the engineered constructs differentially dictated the evolution of their mechanical state and geometry over time, as well as their final structural organization. These findings demonstrate that controlling the initial mechanical state of tissue-engineered constructs via scaffold geometry can be used to influence tissue growth and remodeling and determine tissue outcomes.

Task-related measures of short-interval intracortical inhibition and GABA levels in healthy young and older adults: A multimodal TMS-MRS study.

Establishing the associations between magnetic resonance spectroscopy (MRS)-assessed gamma-aminobutyric acid (GABA) levels and transcranial magnetic stimulation (TMS)-derived 'task-related' modulations in GABAA receptor-mediated inhibition and how these associations change with advancing age is a topic of interest in the field of human neuroscience. In this study, we identified the relationship between GABA levels and task-related modulations in GABAA receptor-mediated inhibition in the dominant (left) and non-dominant (right) sensorimotor (SM) cortices. GABA levels were measured using edited MRS and task-related GABAA receptor-mediated inhibition was measured using a short-interval intracortical inhibition (SICI) TMS protocol during the preparation and premotor period of a choice reaction time (CRT) task in 25 young (aged 18-33 years) and 25 older (aged 60-74 years) adults. Our results demonstrated that GABA levels in both SM voxels were lower in older adults as compared to younger adults; and higher SM GABA levels in the dominant as compared to the non-dominant SM voxel pointed to a lateralization effect, irrespective of age group. Furthermore, older adults showed decreased GABAA receptor-mediated inhibition in the preparation phase of the CRT task within the dominant primary motor cortex (M1), as compared to young adults. Finally, results from an exploratory correlation analysis pointed towards positive relationships between MRS-assessed GABA levels and TMS-derived task-related SICI measures. However, after correction for multiple comparisons none of the correlations remained significant.

Age-Related Declines in Motor Performance are Associated With Decreased Segregation of Large-Scale Resting State Brain Networks.

Aging is typically associated with substantial declines in motor functioning as well as robust changes in the functional organization of brain networks. Previous research has investigated the link between these 2 age-varying factors but examinations were predominantly limited to the functional organization within motor-related brain networks. Little is known about the relationship between age-related behavioral impairments and changes in functional organization at the whole brain (i.e., multiple network) level. This knowledge gap is surprising given that the decreased segregation of brain networks (i.e., increased internetwork connectivity) can be considered a hallmark of the aging process. Accordingly, we investigated the association between declines in motor performance across the adult lifespan (20-75 years) and age-related modulations of functional connectivity within and between resting state networks. Results indicated that stronger internetwork resting state connectivity observed as a function of age was significantly related to worse motor performance. Moreover, performance had a significantly stronger association with the strength of internetwork as compared with intranetwork connectivity, including connectivity within motor networks. These findings suggest that age-related declines in motor performance may be attributed to a breakdown in the functional organization of large-scale brain networks rather than simply age-related connectivity changes within motor-related networks.

Molecular and Serological Intraocular Fluid Analysis of Coxiella burnetii-seropositive Patients with Concurrent Idiopathic Uveitis.

PURPOSE: Previous studies have suggested a link between Q fever and uveitis. We determined whether Coxiella burnetii causes intraocular infection in C. burnetii-seropositive patients with idiopathic uveitis. METHODS: From a retrospective observational case series, paired aqueous humor and serum samples from 10 C. burnetii-seropositive patients with idiopathic uveitis were examined for intraocular antibody production by using the Goldmann-Witmer coefficient and by polymerase chain reaction (PCR). RESULTS: Although intraocular IgG against C. burnetii was detected, no intraocular antibody production was observed (low Goldmann Wittmer coefficients). All PCR results were negative. CONCLUSIONS: Uveitis due to an intraocular infection with C. burnetii is unlikely.

Delayed HIV testing in internal medicine clinics - a missed opportunity.

As HIV infection may be non-symptomatic for many years, many HIV-infected individuals are not aware of their infection. At a certain point in time non-specific symptoms may occur for which patients are likely be referred to internal medicine outpatient clinics. In the absence of systematic screening for HIV and in particular in patients who do not have classical risk factors for HIV, the diagnosis of HIV infection may easily be overlooked. In this manuscript it is illustrated that this diagnostic and therapeutic delay can lead to increased morbidity and mortality. Moreover, undiagnosed individuals are on average more likely to transmit HIV than diagnosed individuals. It is important for public health to identify people harbouring HIV infection, as this is expected to reduce the number of new infections. HIV infection should be considered a possible cause of unexplained symptoms in an early stage of the diagnostic process, in particular in patients with symptoms such as unexplained fever, lymphadenopathy or weight loss or in the presence of conditions suggestive of possible immune deficiency, regardless of the absence of risk factors.

Dynamic actor network analysis for diffuse pollution in the province of North-Holland.

Diffuse pollution problems involve numerous different organizations and this requires decision makers to involve different actors if they want to develop policies that have a chance of being implemented effectively. A first step in such interactive policy development would be to gain an overview of the different actors involved in diffuse pollution problems, as well as their views on the problem, their interests and their means to influence policy development and implementation. Dynamic Actor Network Analysis (DANA) offers a method that helps analysts in providing such an overview, and the use of this method is explored through its application to a case in the Dutch province of North Holland. The described case specifically focuses on the use of herbicides in public space and involves actors from regional water management authorities, municipalities and private sector users. An important finding is that there is an imbalance in the perceptions of actors that needs to be addressed by water management authorities. The paper concludes that DANA is a promising tool for offering new and useful insights to decision makers, although more practical experience is needed to better assess the utility of this analysis tool.

Adhesion molecule expression in local-macrophage-depleted rats bearing orthotopic corneal allografts.

BACKGROUND: Rejection of corneal grafts is dependent on influx of T lymphocytes and macrophages. This process is partly regulated by adhesion molecules. Earlier investigations showed that corneal graft rejection in rats could be prevented by clodronate liposomes that selectively eliminate macrophages. In the present study the effect of macrophage depletion on adhesion molecule expression after corneal allotransplantation was investigated. METHODS: Orthotopic corneal allografts were performed, after which rats received subconjunctival injections with clodronate liposomes or remained untreated. On various postoperative days, grafted rats were killed and mid-eye sections were stained for expression of ICAM-1 (CD54) and beta(2)-integrins (CD18 and CD11b/c). RESULTS: In the clodronate liposome-treated group grafts were not rejected, while in untreated rats grafts had a mean survival time of 12 days. During the first postoperative days a slightly enhanced expression of ICAM-1 in the conjunctiva and allografted cornea of clodronate liposome-treated recipients was seen. On day 12, however, ICAM-1 expression was markedly downregulated in the allografts of this treated group. The expression of beta(2)-integrins was also significantly decreased in the allografts and recipient corneas of treated rats at this time point. CONCLUSION: Prolonged corneal graft survival in rats, obtained via local depletion of macrophages, correlates with diminished expression of adhesion molecules.

Nuclear spin conversion in polyatomic molecules.

Except for ortho- and para-H2, little is known about nuclear spin isomers (or spin modifications) of molecules. The main reason is the lack of practical enrichment techniques. Recently, a few enrichment methods were developed, which opened up new possibilities in the field. These methods are briefly reviewed. Substantial progress in the field has been made by the introduction of light-induced drift as a gas-phase separation tool. This is illustrated by extensive data on CH3F, which reveal that the gas-phase ortho-para conversion is governed by intramolecular mixing of the nuclear spin states. The role of direct ortho-para transitions is small. Various aspects of the conversion were investigated in detail: pressure and collision partner dependence, isotope effect, and temperature dependence. The most decisive information on the spin conversion mechanism is derived from the observation of level-crossing resonances in an electric field and the quantum Zeno effect induced by collisions.

Thrombotic thrombocytopenic purpura: a rare but potential life-threatening complication following ticlopidine administration.

Thrombotic thrombocytopenic purpura (TTP) is a known, although rare, complication of ticlopidine treatment. It typically appears within the first days or weeks after initiation of therapy. We describe a case of TTP in a 75-year-old patient, due to ticlopidine, occurring three weeks after coronary stent implantation. The patient responded favourably to fresh frozen plasma exchanges. We are reporting this case to emphasize that prognosis depends on prompt diagnosis and early treatment, implying careful biochemical monitoring.

Randomized coronary patency trial of double-bolus recombinant staphylokinase versus front-loaded alteplase in acute myocardial infarction.

One hundred two patients with evolving myocardial infarction of 6 hours' duration were given aspirin and intravenous heparin and randomly allocated to intravenous front-loaded, weight-adjusted rTPA administration over a 90-minute period (52 patients) or to two 15 mg doses of recombinant staphylokinase, 30 minutes apart (50 patients). Thrombolysis in Myocardial infarction (TIMI) perfusion grade 3 at 90 minutes was achieved in 68% (95% confidence interval, 55% to 81%) of patients treated with staphylokinase versus 57% (95% confidence interval, 43% to 72%) of patients treated with rTPA (p = not significant). Double-bolus staphylokinase was significantly more fibrin-specific than accelerated rTPA with residual fibrinogen at 90 minutes of 105% +/- 4.1% and 68% +/- 7.5%, respectively (p < 0.0001). Thirteen patients in each study group underwent angioplasty of the culprit coronary artery within the first 24 hours because of suboptimal recanalization (TIMI < 3). In the patients without prior coronary intervention, TIMI 3 at 24 hours was 100% after staphylokinase administration (n = 35) versus 79% after rTPA (n = 34) (p = 0.005). The distribution of inhospital events did not significantly differ between both groups. One patient receiving rTPA died in the hospital from ischemic stroke. Staphylokinase administration did not induce allergic reactions, but significant staphylokinase-neutralizing activity (> 5 micrograms/ml) and specific anti-staphylokinase IgG developed in 73% of patients after 2 weeks. Thus two 15 mg doses of staphylokinase induce early, complete, and sustained coronary artery patency at least as frequently as accelerated rTPA without associated fibrinogen degradation but with subsequent induction of circulating neutralizing antibodies.

Classification of normal and abnormal electrogastrograms using multilayer feedforward neural networks.

A neural network approach is proposed for the automated classification of the normal and abnormal EGG. Two learning algorithms, the quasi-Newton and the scaled conjugate gradient method for the multilayer feedforward neural networks (MFNN), are introduced and compared with the error backpropagation algorithm. The configurations of the MFNN are determined by experiment. The raw EGG data, its power spectral data, and its autoregressive moving average (ARMA) modelling parameters are used as the input to the MFNN and compared with each other. Three indexes (the percent correct, sum-squared error and complexity per iteration) are used to evaluate the performance of each learning algorithm. The results show that the scaled conjugate gradient algorithm performs best, in that it is robust and provides a super-linear convergence rate. The power spectral representation and the ARMA modelling parameters of the EGG are found to be better types of the input to the network for this specific application, both yielding a percent correctness of 95% on the test set. Although the results are focused on the classification of the EGG, this paper should provide useful information for the classification of other biomedical signals.

Renal responses to exercise in heart and kidney transplant patients.

There is a lack of information about renal responses in heart and kidney transplant patients after intense physical exercise. Eleven heart and ten kidney transplant recipients, as well as two control groups of healthy subjects, were given a maximum exercise test on a bicycle ergometer. One control group was also given a moderate load corresponding to the peak load of the kidney transplant group. Blood and urine samples were collected before and after exercise and assayed for lactate, creatinine, total protein, and albumin. The glomerular filtration rate remained stable at the end of exercise in the transplant patients, while there was a slight (17%) decrease in the control group. Albumin excretion rates after maximum exercise attained a mean of 237 micrograms.min-1 in the control group and a mean of 45 and 16 micrograms.min-1, respectively, in the heart and kidney groups. Postexercise proteinuria seemed to be related to the absolute intensity of the event, but kidney transplant patients showed a reduced effect as compared to heart transplant patients. We conclude that short-term, maximum exercise in heart and kidney transplant recipients is not detrimental to kidney function.

A randomized trial of recombinant staphylokinase versus alteplase for coronary artery patency in acute myocardial infarction. The STAR Trial Group.

BACKGROUND: Recombinant staphylokinase (STAR) was shown recently to offer promise for coronary arterial thrombolysis in patients with evolving myocardial infarction. The present multicenter randomized open trial was designed to assess the thrombolytic efficacy, safety, and fibrin specificity of STAR relative to accelerated alteplase (recombinant tissue-type plasminogen activator [RTPA]). METHODS AND RESULTS: One hundred patients with evolving myocardial infarction of < 6 hours' duration and with ST-segment elevation were allocated to accelerated and weight-adjusted RTPA over 90 minutes (52 patients) or to STAR (the first 25 patients to 10 mg and the next 23 patients to 20 mg given intravenously over 30 minutes). All patients received aspirin and intravenous heparin. The main end points were coronary artery patency and plasma fibrinogen levels at 90 minutes. Thrombolysis in Myocardial Infarction (TIMI) perfusion grade 3 at 90 minutes was achieved in 62% of STAR patients versus 58% of RTPA patients (risk ratio, 1.1; 95% CI, 0.76 to 1.5). With 10 mg STAR, TIMI grade 3 patency was 50% (risk ratio, 0.86; 95% CI, 0.54 to 1.4 versus RTPA); with 20 mg STAR, it was 74% (risk ratio, 1.3; 95% CI, 0.90 to 1.8 versus RTPA). Residual fibrinogen levels at 90 minutes were 118 +/- 47% (mean +/- SD) of baseline with STAR and 68 +/- 42% with RTPA (P < .0005). STAR therapy was not associated with an excess mortality or electric, hemorrhagic, mechanical, or allergic complications. However, patients developed antibody-mediated STAR-neutralizing activity from the second week after STAR treatment. As an addendum to the randomized study, 5 patients were given 40 mg STAR over 30 minutes, resulting in TIMI perfusion grade 3 at 90 minutes in 4 patients without fibrinogen breakdown (residual levels at 90 minutes of 105 +/- 8% of baseline). CONCLUSIONS: STAR appears to be at least as effective for early coronary recanalization as and significantly more fibrin-specific than accelerated RTPA in patients with evolving myocardial infarction.

At equipotent doses, isradipine is better tolerated than amlodipine in patients with mild-to-moderate hypertension: a double-blind, randomized, parallel-group study.

1. The objective of this double-blind parallel-group study was to compare the tolerability of isradipine and amlodipine, specifically, the side-effects known to be related to the use of dihydropyridine calcium antagonists. 2. A total of 205 patients with mild-to-moderate essential hypertension were randomized to receive either the sustained-release (SRO) formulation of isradipine (n = 103) or amlodipine (n = 102), both at dosages of 5 mg once daily. Blood pressure measurements were taken at the end of the dosing interval to assess the antihypertensive efficacy of the two drugs. 3. Adverse reactions were assessed in two ways: a) spontaneously reported adverse events were recorded and investigated in depth for severity, duration, relation to the study drug, and outcome; b) a questionnaire was used to elicit specific adverse reactions known to be related to the use of dihydropyridine calcium antagonists which were evaluated for severity, duration, relation to the study drug, and outcome. 4. After 6 weeks of active treatment, both isradipine and amlodipine reduced mean sitting systolic/diastolic blood pressure: from 165.1/100.1 to 145.2/89.7 mm Hg with isradipine; and from 164.1/100.6 to 145.7/90.5 mm Hg with amlodipine. There was no difference in antihypertensive effect between isradipine and amlodipine (95% CI: -3.73 to 4.73 and -1.89 to 3.49 for differences in systolic and diastolic blood pressure, respectively). 5. The number of patients spontaneously reporting adverse events was significantly higher (P = 0.02; 95% CI: 3.1 to 26.7%) with amlodipine (33.3%) than with isradipine (18.4%).(ABSTRACT TRUNCATED AT 250 WORDS)

Tolerability of isradipine in the treatment of mild-to-moderate hypertension in general practice: a large-scale surveillance study.

The tolerability of isradipine was evaluated in an open trial of patients with mild-to-moderate essential hypertension as treated in general practice. The primary objective was to identify all adverse reactions, especially those that were newly occurring (greater than or equal to 6 reports), with a frequency greater than 1/1,000. Over 1,100 general practitioners and 5,526 patients participated in this trial. After a 2-week washout period, and a 3-week placebo run-in, patients with diastolic blood pressure (DBP) greater than or equal to 95 mm Hg were initially given isradipine at 1.25 mg twice daily. After 4 weeks, doses were doubled if DBP was greater than 90 mm Hg. If, after a further 4 weeks with doubled dosages, the DBP was still greater than 90 mm Hg, a second (nonspecified free-choice) antihypertensive agent was added to the treatment. Adverse events were recorded by open questioning. The incidence of adverse events was found to be similar to that with placebo; adverse events were generally mild or moderate in intensity and disappeared over time. No newly occurring adverse events were found. In conclusion, isradipine is safe and well tolerated at effective antihypertensive doses in patients with mild-to-moderate hypertension as treated in general practice.

Long-term (2-year) isradipine data in the treatment of mild-to-moderate hypertension.

At the end of a short-term (3-month) study of antihypertensive treatment of mild-to-moderate hypertension, 141 of the 200 study patients continued into a 2-year follow-up of isradipine as monotherapy or in combination with other antihypertensive agents. Although all 141 patients completed the first year, only 102 completed the study. Twenty-four patients dropped out: 2 with flushing; 1 each with arrhythmia, edema, angina, and headache; 12 who were noncompliant; 2 with disease unrelated to the study drug; and 4 for reasons unknown. Before the follow-up, 70% of the 141 patients were taking isradipine; after 2 years, 63% were still taking isradipine as monotherapy. During the follow-up study, the blood pressure remained stable (142.9/86.8 mm Hg after 3 months, and 142.9/86.2 mm Hg after 2 years), whereas the normalization rate was only slightly changed (73 vs. 75.2%). The incidence of reported adverse events decreased with time. At the end of the short-term study, 44.7% of patients had reported one or more adverse events; after 2 years of treatment, only 14.4% reported adverse events. Two patients had ECG signs of left ventricular hypertrophy: one showed no relevant changes while the other presented clear signs of regression. No clinically relevant laboratory abnormalities were noted during the study. In conclusion, isradipine is effective, well tolerated and safe in the long-term treatment of mild-to-moderate hypertension.

Exercise and heart transplantation. A review.

Results of heart transplantation as therapy for end-stage cardiac diseases are encouraging not only because of actuarial survival curves but also because of the recovered quality of life for the heart transplant recipient. Although heart transplantation drastically improves the physical capacity of the patients, heart recipients still have a reduced maximal aerobic capacity compared to healthy people. Altered resting and exercise haemodynamics, due to cardiac denervation, are a common finding after orthotopic heart transplantation: increases in heart rate and stroke volume at exercise are first linked with the augmented venous return and later with the increased plasmatic nor-adrenaline level. Maximal heart rate and stroke volume are both reduced when compared to innervated heart. Reduced cardiac output response to exercise therefore results in early anaerobic metabolism, acidosis, hyperventilation and diminished physical capacity. In spite of an altered ventilatory adaptation to exercise, characterised by hyperpnoea in most transplant patients, ventilation is not the limiting factor for exercise in heart recipients without associated obstructive pulmonary disease. Endurance training restores lean tissue, decreases submaximal minute ventilation, increases peak work output, maximal ventilation and peak heart rate. Guidelines for prescribing exercise are not yet standardised due to the limited number of studies on a sufficient cohort of heart recipients. Nevertheless, recommendations similar to those used for persons with coronary heart disease, with modifications due to the denervated heart, seem to be used. The cardiocirculatory and pulmonary capacity of heart transplant recipients allow them to undertake endurance sports activities such as walking, jogging, cycling and swimming, and these should be encouraged.

Efficacy of diclazuril against Eimeria dispersa in turkeys.

Diclazuril, a new anticoccidial drug, was tested for its efficacy against Eimeria dispersa in turkeys. A dose-titration study indicated that diclazuril at dosages of 0.5, 1, and 2 ppm in the feed was highly effective in terms of weight gain and suppression of lesions, abnormal droppings, and oocyst shedding.