Successful Human Infection with P. falciparum Using Three Aseptic Anopheles stephensi Mosquitoes: A New Model for Controlled Human Malaria Infection

Controlled human malaria infection (CHMI) is a powerful method for assessing the efficacy of anti-malaria vaccines and drugs targeting pre-erythrocytic and erythrocytic stages of the parasite. CHMI has heretofore required the bites of 5 Plasmodium falciparum (Pf) sporozoite (SPZ)-infected mosquitoes to reliably induce Pf malaria. We reported that CHMI using the bites of 3 PfSPZ-infected mosquitoes reared aseptically in compliance with current good manufacturing practices (cGMP) was successful in 6 participants. Here, we report results from a subsequent CHMI study using 3 PfSPZ-infected mosquitoes reared aseptically to validate the initial clinical trial. We also compare results of safety, tolerability, and transmission dynamics in participants undergoing CHMI using 3 PfSPZ-infected mosquitoes reared aseptically to published studies of CHMI using 5 mosquitoes. Nineteen adults aged 18–40 years were bitten by 3 Anopheles stephensi mosquitoes infected with the chloroquine-sensitive NF54 strain of Pf. All 19 participants developed malaria (100%); 12 of 19 (63%) on Day 11. The mean pre-patent period was 258.3 hours (range 210.5–333.8). The geometric mean parasitemia at first diagnosis by microscopy was 9.5 parasites/µL (range 2–44). Quantitative polymerase chain reaction (qPCR) detected parasites an average of 79.8 hours (range 43.8–116.7) before microscopy. The mosquitoes had a geometric mean of 37,894 PfSPZ/mosquito (range 3,500–152,200). Exposure to the bites of 3 aseptically-raised, PfSPZ-infected mosquitoes is a safe, effective procedure for CHMI in malaria-naïve adults. The aseptic model should be considered as a new standard for CHMI trials in non-endemic areas. Microscopy is the gold standard used for the diagnosis of Pf malaria after CHMI, but qPCR identifies parasites earlier. If qPCR continues to be shown to be highly specific, and can be made to be practical, rapid, and standardized, it should be considered as an alternative for diagnosis.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00744133","term_id":"NCT00744133"}}NCT00744133 {"type":"clinical-trial","attrs":{"text":"NCT00744133","term_id":"NCT00744133"}}NCT00744133     

Into the Square and out of the Box: The effects of Quadrato Motor Training on Creativity and Alpha Coherence

The objective of the present study was to investigate the body-cognitive relationship through behavioral and electrophysiological measures in an attempt to uncover the underlying mediating neuronal mechanism for movement-induced cognitive change. To this end we examined the effects of Quadrato Motor Training (QMT), a new whole-body training paradigm on cognitive performance, including creativity and reaction time tasks, and electrophysiological change, using a within-subject pre-post design. Creativity was studied by means of the Alternate Uses Task, measuring ideational fluency and ideational flexibility. Electrophysiological effects were measured in terms of alpha power and coherence. In order to determine whether training-induced changes were driven by the cognitive or the motor aspects of the training, we used two control groups: Verbal Training (VT, identical cognitive training with verbal response) and Simple Motor Training (SMT, similar motor training with reduced choice requirements). Twenty-seven participants were randomly assigned to one of the groups. Following QMT, we found enhanced inter-hemispheric and intra-hemispheric alpha coherence, and increased ideational flexibility, which was not the case for either the SMT or VT groups. These findings indicate that it is the combination of the motor and cognitive aspects embedded in the QMT which is important for increasing ideational flexibility and alpha coherence.     

Feasibility of Tomotherapy-Based Image-Guided Radiotherapy to Reduce Aspiration Risk in Patients with Non-Laryngeal and Non-Pharyngeal Head and Neck Cancer

Purpose

The study aims to assess the feasibility of Tomotherapy-based image-guided radiotherapy (IGRT) to reduce the aspiration risk in patients with non-laryngeal and non-hypopharyngeal cancer. A retrospective review of 48 patients undergoing radiation for non-laryngeal and non-hypopharyngeal head and neck cancers was conducted. All patients had a modified barium swallow (MBS) prior to treatment, which was repeated one month following radiotherapy. Mean middle and inferior pharyngeal dose was recorded and correlated with the MBS results to determine aspiration risk.

Results

Mean pharyngeal dose was 23.2 Gy for the whole group. Two patients (4.2%) developed trace aspiration following radiotherapy which resolved with swallowing therapy. At a median follow-up of 19 months (1–48 months), all patients were able to resume normal oral feeding without aspiration.

Conclusion and Clinical Relevance

IGRT may reduce the aspiration risk by decreasing the mean pharyngeal dose in the presence of large cervical lymph nodes. Further prospective studies with IGRT should be performed in patients with non-laryngeal and non-hypopharyngeal head and neck cancers to verify this hypothesis.     

High Prevalence of Cryptococcal Antigenemia among HIV-infected Patients Receiving Antiretroviral Therapy in Ethiopia

Background

Cryptococcal disease is estimated to be responsible for significant mortality in Sub-Saharan Africa; however, only scarce epidemiology data exists. We sought to evaluate the prevalence of and risk factors for cryptococcal antigenemia in Ethiopia.

Methods

Consecutive adult HIV-infected patients from two public HIV clinics in Addis Ababa, Ethiopia were enrolled into the study. A CD4 count ≤200 cells/μl was required for study participation. Patients receiving anti-retroviral therapy (ART) were not excluded. A cryptococcal antigen test was performed for all patients along with an interview, physical exam, and medical chart abstraction. Logistic regression analysis was used to assess risk factors for cryptococcal antigenemia.

Results

369 HIV-infected patients were enrolled; mean CD4 123 cells/μl and 74% receiving ART. The overall prevalence of cryptococcal antigenemia was 8.4%; 11% in patients with a CD4 count <100 cells/μl, 8.9% with CD4 100 to 150 cells/μl and 5.7% with CD4150-200 cell/μl. 84% of patients with cryptococcal antigenemia were receiving ART. In multivariable analysis, increasing age, self reported fever, CD4 count <100 cells/μl, and site of screening were associated with an increased risk of cryptococcal antigenemia. No individual or combination of clinical symptoms had optimal sensitivity or specificity for cryptococcal antigenemia.

Conclusion

Cryptococcal antigenemia is high in Ethiopia and rapid scale up of screening programs is needed. Screening should be implemented for HIV-infected patients with low CD4 counts regardless of symptoms or receipt of ART. Further study into the effect of location and environment on cryptococcal disease is warranted.     

Handling Ibuprofen Increases Pain Tolerance and Decreases Perceived Pain Intensity in a Cold Pressor Test

Pain contributes to health care costs, missed work and school, and lower quality of life. Extant research on psychological interventions for pain has focused primarily on developing skills that individuals can apply to manage their pain. Rather than examining internal factors that influence pain tolerance (e.g., pain management skills), the current work examines factors external to an individual that can increase pain tolerance. Specifically, the current study examined the nonconscious influence of exposure to meaningful objects on the perception of pain. Participants (N = 54) completed a cold pressor test, examined either ibuprofen or a control object, then completed another cold pressor test. In the second test, participants who previously examined ibuprofen reported experiencing less intense pain and tolerated immersion longer (relative to baseline) than those who examined the control object. Theoretical and applied implications of these findings are discussed.     

In Situ Measurement of Solid Electrolyte Interphase Evolution on Silicon Anodes Using Atomic Force Microscopy

In situ measurements of the growth of solid electrolyte interphase (SEI) layer on silicon and the lithiation‐induced volume changes in silicon in lithium ion half‐cells are reported. Thin film amorphous silicon electrodes are fabricated in a configuration that allows unambiguous separation of the total thickness change into contribution from SEI thickness and silicon volume change. Electrodes are assembled into a custom‐designed electrochemical cell, which is integrated with an atomic force microscope. The electrodes are subjected to constant potential lithiation/delithiation at a sequence of potential values and the thickness measurements are made at each potential after equilibrium is reached. Experiments are carried out with two electrolytes—1.2 m lithium hexafluoro‐phosphate (LiPF₆) in ethylene carbonate (EC) and 1.2 m LiPF₆ in propylene carbonate (PC)—to investigate the influence of electrolyte composition on SEI evolution. It is observed that SEI formation occurs predominantly during the first lithiation and the maximum SEI thickness is ≈17 and 10 nm respectively for EC and PC electrolytes. This study also presents the measured Si expansion ratio versus equilibrium potential and charge capacity versus equilibrium potential; both relationships display hysteresis, which is explained in terms of the stress–potential coupling in silicon.     

Knowledge and Perceptions about Clinical Trials and the Use of Biomedical Samples: Findings from a Qualitative Study in Rural Northern Ghana

IntroductionClinical trials conducted in sub-Saharan Africa have helped to address the prevalent health challenges. The knowledge about how communities perceive clinical trials is however only now evolving. This study was conducted among parents whose children participated in past clinical trials in northern Ghana to assess their knowledge and perceptions of clinical trials and the use of biomedical samples.MethodThis was a qualitative study based on eighty in-depth interviews with parents. The participants were randomly selected from among parents whose children were enrolled in a clinical trial conducted in the Kassena-Nankana districts between 2000 and 2003. The interviews were transcribed and coded into emergent themes using Nvivo 9 software. The thematic analysis framework was used to analyze the data.ResultsStudy participants reported that clinical trials were carried out to determine the efficacy of drugs and to make sure that these drugs were suitable for human beings to use. The conduct of clinical trials was perceived to have helped to reduce the occurrence of diseases such as malaria, cerebrospinal meningitis and diarrhea. Quality of care was reported to be better in clinical trials than in the routine care. Parents indicated that participation in clinical trials positively influenced their health-seeking behavior. Apprehensions about blood draw and the use to which samples were put were expressed, with suspicion by a few participants that researchers sold blood samples. The issue of blood draw was most contentious.ConclusionParents perception about the conduct of clinical trials in the study districts is generally positive. However, misconceptions made about the use of blood samples in this study must be taken seriously and strategies found to improve transparency and greater community acceptability.     

Laser Doppler Flare Imaging and Quantitative Thermal Thresholds Testing Performance in Small and Mixed Fiber Neuropathies

IntroductionSmall fiber neuropathy might be a part of typical mixed small and large fiber neuropathy, or a distinct entity, affecting exclusively small nerve fibers.ObjectivesExplore the utility of small nerve fiber testing in patients with clinical presentation suggesting small fiber neuropathy, with and without evidence for concomitant large fiber neuropathy.MethodsPatients attending the neuromuscular clinic from 2012 to 2015 with a clinical presentation suggesting small nerve fiber impairment, who had Laser Doppler flare imaging (LDI_Flare) and quantitative thermal testing (QTT) were evaluated for this study. Patients with clinical or electrophysiological evidence for concomitant large fiber neuropathy were not excluded.ResultsThe sensitivities of LDI_Flare, cooling and heat threshold testing were 64%, 36%, and 0% respectively for clinically highly suggestive small fiber neuropathy, 64%, 56%, and 19% respectively for mixed fiber neuropathy, and 86%, 79%, and 29% respectively for diabetic mixed fiber neuropathy.DiscussionLDI_Flare and cooling thresholds testing are non-invasive small nerve fiber testing modalities, with moderate performance in patients with small and mixed fiber neuropathy, and excellent performance in diabetic mixed fiber neuropathy.     

The Therapeutic Potential of AN-7, a Novel Histone Deacetylase Inhibitor,for Treatment of Mycosis Fungoides/Sezary Syndrome Alone or with Doxorubicin

The 2 histone deacetylase inhibitors (HDACIs) approved for the treatment of cutaneous T-cell lymphoma (CTCL) including mycosis fungoides/sezary syndrome (MF/SS), suberoylanilide hydroxamic acid (SAHA) and romidepsin, are associated with low rates of overall response and high rates of adverse effects. Data regarding combination treatments with HDACIs is sparse. Butyroyloxymethyl diethylphosphate (AN-7) is a novel HDACI, which was found to have selective anticancer activity in several cell lines and animal models. The aim of this study was to compare the anticancer effects of AN-7 and SAHA, either alone or combined with doxorubicin, on MF/SS cell lines and peripheral blood lymphocytes (PBL) from patients with Sezary syndrome (SPBL). MyLa cells, Hut78 cells, SPBL, and PBL from healthy normal individuals (NPBL) were exposed to the test drugs, and the findings were analyzed by a viability assay, an apoptosis assay, and Western blot. AN-7 was more selectively toxic to MyLa cells, Hut78 cells, and SPBL (relative to NPBL) than SAHA and also acted more rapidly. Both drugs induced apoptosis in MF/SS cell lines, SAHA had a greater effect on MyLa cell line, while AN-7 induced greater apoptosis in SPBL; both caused an accumulation of acetylated histone H₃, but AN-7 was associated with earlier kinetics; and both caused a downregulation of the HDAC1 protein in MF/SS cell lines. AN-7 acted synergistically with doxorubicin in both MF/SS cell lines and SPBL, and antagonistically with doxorubicin in NPBL. By contrast, SAHA acted antagonistically with doxorubicin on MF/SS cell lines, SPBL, and NPBL, leaving <50% viable cells. In conclusion, AN-7 holds promise as a therapeutic agent in MF/SS and has several advantages over SAHA. Our data provide a rationale for combining AN-7, but not SAHA, with doxorubicin to induce the cell death in MF/SS.     

Dog Demography,Animal Bite Management and Rabies Knowledge-Attitude and Practices in the Awash Basin,Eastern Ethiopia

Background

Rabies is a viral zoonosis that has been described in limited numbers of studies in Ethiopia at large and among pastoralists in particular. This study assessed dog demography, bite wound prevalence and management, potential risk factors of disease transmission and knowledge attitude practice towards rabies among urban dwellers, pastoralists and health workers in Awash, Eastern Ethiopia.

Methodology

Information was collected by means of structured questionnaires and interviews and through medical and official records from the Agricultural and Health bureaus.

Principal Findings

Respondents totaled 539 (471 urban, 49 pastoralists, 19 medical). Dog(s) were owned in 33% urban and 75.5% pastoralist households respectively. Mean dog number per dog owning household was 1.50 (95%CI: 1.40–1.60) in urban and 2.05 (95%CI: 1.51–2.60) in pastoralists sites. Human Dog Ratio in Metahara was 4.7:1. No bite wounds records were kept in medical facilities, where staff recalled around 100 bites per year, 2/3 being in adults. Over 90% of the respondents claimed knowing rabies but up to 79.2% pastoralist did not know how dogs acquire the disease; 37.3% urban and 23% pastoralist did not know the symptoms of rabies in dogs; 36% urban and 44% pastoralists did not know rabies symptoms in people. Eighty percent of pastoralists did not know that the disease was fatal in people if untreated. Over half (58.7%) of pastoralist respondents go to traditional healers if bitten, despite a health extension worker program in place in the study area. Knowledge gaps were also shown amidst medical staff.

Conclusions

The study highlighted overall poor disease knowledge, severe under-reporting of human rabies cases, lack of record keeping and poor collaboration between the public and animal health sectors and communities in rabies control.