Adverse events and blinding in two randomized trials of hyperbaric oxygen for persistent post-concussive symptoms.

Safety monitoring and successful blinding are important features of randomized, blinded clinical trials. We report chamber- and protocol-related adverse events (AEs) for participants enrolled in two randomized, double-blind clinical trials of hyperbaric oxygen (HBO2) for persistent post-concussive symptoms clinicaltrials.gov identifiers NCT01306968, HOPPS, and NCT01611194, BIMA), as well as the success of maintaining the blind with a low-pressure sham control arm. In both studies, participants were randomized to receive HBO2 (1.5 atmospheres absolute, >99% oxygen) or sham chamber sessions (1.2 atmospheres absolute, room air). In 143 participants undergoing 4,245 chamber sessions, chamber-related adverse events were rare (1.1% in the HOPPS study, 2.2% in the BIMA study). Minor, non-limiting barotrauma was the most frequently reported. Rarely, some participants experienced headache with chamber sessions. No serious adverse events were associated with chamber sessions. An allocation questionnaire completed after intervention revealed that the sham control arm adequately protected the blind in both trials. Participants based allocation assumptions on symptom improvement or lack of symptom improvement and could not discern intervention arm by pressure, smell, taste, or gas flow.

Comparative ophthalmic assessment of patients receiving tafenoquine or chloroquine/primaquine in a randomized clinical trial for Plasmodium vivax malaria radical cure.

PURPOSE: Ophthalmic safety observations are reported from a clinical trial comparing tafenoquine (TQ) efficacy and safety versus sequential chloroquine (CQ)/primaquine (PQ) for acute Plasmodium vivax malaria. METHODS: In an active-control, double-blind study, 70 adult subjects with microscopically confirmed P. vivax malaria were randomized (2:1) to receive 400 mg TQ × 3 days or 1500 mg CQ × 3 days then 15 mg PQ × 14 days. MAIN OUTCOME MEASURES: clinically relevant changes at Day 28 and Day 90 versus baseline in the ocular examination, color vision evaluation, and corneal and retinal digital photography. RESULTS: Post-baseline keratopathy occurred in 14/44 (31.8%) patients with TQ and 0/24 with CQ/PQ (P = 0.002). Mild post-baseline retinal findings were reported in 10/44 (22.7%) patients receiving TQ and 2/24 (8.3%) receiving CQ/PQ (P = 0.15; treatment difference 14.4%, 95% CI - 5.7, 30.8). Masked evaluation of retinal photographs identified a retinal hemorrhage in one TQ patient (Day 90) and a slight increase in atrophy from baseline in one TQ and one CQ/PQ patient. Visual field sensitivity (Humphrey™ 10-2 test) was decreased in 7/44 (15.9%) patients receiving TQ and 3/24 (12.5%) receiving CQ/PQ; all cases were < 5 dB. There were no clinically relevant changes in visual acuity or macular function tests. CONCLUSIONS: There was no evidence of clinically relevant ocular toxicity with either treatment. Mild keratopathy was observed with TQ, without conclusive evidence of early retinal changes. Eye safety monitoring continues in therapeutic studies of low-dose tafenoquine (300 mg single dose). CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01290601.

Triangular test design to evaluate tinidazole in the prevention of Plasmodium vivax relapse.

BACKGROUND: There are very few drugs that prevent the relapse of Plasmodium vivax malaria in man. Tinidazole is a 5-nitroimidazole approved in the USA for the treatment of indications including amoebiasis and giardiasis. In the non-human primate relapsing Plasmodium cynomolgi/macaque malaria model, tinidazole cured one of six macaques studied with an apparent mild delay to relapse in the other five of 14-28 days compared to 11-12 days in controls. One study has demonstrated activity against P. vivax in man. Presented here are the results of a pilot phase II, randomized, open-label study conducted along the Thai-Myanmar border designed to evaluate the efficacy of tinidazole to prevent relapse of P. vivax when administered with chloroquine. METHODS: This study utilized a modified triangular test sequential analysis which allows repeated statistical evaluation during the course of enrolment while maintaining a specified power and type 1 error and minimizing recruitment of subjects. Enrolment was to be halted when a pre-specified success/failure ratio was surpassed. The study was designed to have a 5% type 1 error and 90% power to show whether tinidazole would produce a relapse rate of less than 20% or greater than 45% through Day 63 of weekly follow-up after initiation of treatment and initial parasite clearance with 3 days of an oral weight based dosing of chloroquine and five days of 2 grams/day of tinidazole. RESULTS: All subjects cleared their parasitaemia by Day 3. Six of the first seven subjects treated with tinidazole relapsed prior to Day 63 (average Day 48.3 (range 42-56)). This exceeded the upper boundary of the triangular test and enrolment to receive tinidazole was halted. A concurrent cohort of five subjects definitively treated with standard doses of primaquine and chloroquine (historically 100% effective) showed no episodes of recurrent P. vivax parasitaemia during the 63-day protocol specified follow-up period. CONCLUSIONS: Tinidazole is ineffective in preventing relapse of P. vivax at the dose used. The macaque relapsing model appeared to correctly predict outcome in humans. Use of the modified triangular test allowed minimal enrolment and limited unnecessary exposure to the study drug and reduced costs. This adds weight to the ethical and economic advantages of this study design to evaluate similarly situated drugs. TRIAL REGISTRATION: ClinicalTrials.gov NCT00811096.

A simplified intravenous artesunate regimen for severe malaria.

BACKGROUND: We compared a conventional empirically derived regimen with a simplified regimen for parenteral artesunate in severe malaria. METHODS: This was a randomized, double-blind, placebo-controlled comparison to assess the noninferiority of a simplified 3-dose regimen (given at 0, 24, and 48 hours) compared with the conventional 5-dose regimen of intravenous artesunate (given at 0, 12, 24, 48, and 72 hours) in African children with Plasmodium falciparum malaria with a prespecified delta of 0.2. The total dose of artesunate in each group was 12 mg/kg. The primary end point was the proportion of children clearing ≥ 99% of their admission parasitemia at 24 hours. Safety data, secondary efficacy end points, and pharmacokinetics were also analyzed. RESULTS: In 171 children (per protocol), 78% of the recipients (95% confidence interval [CI], 69%-87%) in the 3-dose group achieved ≥ 99% parasite clearance 24 hours after the start of treatment, compared with 85% (95% CI, 77%-93%) of those receiving the conventional regimen (treatment difference, -7.2%; 95% CI, -18.9% to 4.4%). Dihydroartemisinin was cleared slightly more slowly in those children receiving the higher 3-dose regimen (7.4 vs 8.8 L/h for a 13-kg child; P 5 .008). CONCLUSIONS: Pharmacodynamic analysis suggests that 3 doses of artesunate were not inferior to 5 doses for the treatment of severe malaria in children. CLINICAL TRIALS REGISTRATION: NCT00522132.

Modelling to inform next-generation medical interventions for malaria prevention and treatment.

Global progress against malaria has stagnated and novel medical interventions to prevent malaria are needed to fill gaps in existing tools and improve protection against infection and disease. Candidate selection for next-generation interventions should be supported by the best available evidence. Target product profiles and preferred product characteristics play a key role in setting selection criteria requirements and early endorsement by health authorities. While clinical evidence and expert opinion often inform product development decisions, integrating modelling evidence early and iteratively into this process provides an opportunity to link product characteristics with expected public health outcomes. Population models of malaria transmission can provide a better understanding of which, and at what magnitude, key intervention characteristics drive public health impact, and provide quantitative evidence to support selection of use-cases, transmission settings, and deployment strategies. We describe how modelling evidence can guide and accelerate development of new malaria vaccines, monoclonal antibodies, and chemoprevention.

Prolonged protection provided by a single dose of atovaquone-proguanil for the chemoprophylaxis of Plasmodium falciparum malaria in a human challenge model.

BACKGROUND: We conducted a randomized, placebo-controlled, double-blind trial to establish the efficacy of atovaquone-proguanil to prevent malaria with the goal of simulating weekly dosing in a human Plasmodium falciparum challenge model. METHODS: Thirty volunteers randomly received 1 of the following dose regimens: (1) 250 milligrams of atovaquone and 100 milligrams of proguanil (250/100 milligrams) 1 day prior to infectious mosquito challenge (day -1), (2) 250/100 milligrams on day 4 after challenge, (3) 250/100 milligrams on day -7, (4) 500 milligrams of atovaquone and 200 milligrams of proguanil (500/200 milligrams) on day -7 or, (5) 1000 milligrams of atovaquone and 400 milligrams of proguanil (1000/400 milligrams) on day -7. All regimens included matching placebo such that all volunteers received identical pill numbers. Six volunteers served as open-label infectivity controls. Volunteers underwent mosquito sporozoite challenge with P. falciparum 3D7 strain. Follow-up consisted of serial microscopy and close clinical monitoring for 90 days. RESULTS: Six of 6 infectivity controls developed parasitemia as expected. Two of 5 evaluable volunteers receiving 250/100 milligrams 7 days prior to challenge and 1 of 6 volunteers receiving 1000/400 milligrams 7 days prior to challenge were microscopically diagnosed with malaria. All other volunteers were protected. Atovaquone exposure (area under the curve) during liver stage development was low in 2 of 3 volunteers with prophylactic failure (423 and 199 ng/mL × days compared with a mean for protected volunteers of 1903 ng/mL × days), as was peak concentration (165 and 81 ng/mL compared with a mean of 594 ng/mL in volunteers with prophylactic success). Elimination half-life was short in volunteers with prophylactic failure (2.4, 2.0, and 3.3 days compared with a mean of 4.1 days in volunteers with prophylactic success). CONCLUSIONS: Single-dose atovaquone-proguanil provides effective malaria chemoprophylaxis against P. falciparum challenge at dosing intervals supportive of weekly dosing. Postexposure prophylaxis 4 days after challenge was 100% effective.

Update on rapid diagnostic testing for malaria.

To help mitigate the expanding global impact of malaria, with its associated increasing drug resistance, implementation of prompt and accurate diagnosis is needed. Malaria is diagnosed predominantly by using clinical criteria, with microscopy as the current gold standard for detecting parasitemia, even though it is clearly inadequate in many health care settings. Rapid diagnostic tests (RDTs) have been recognized as an ideal method for diagnosing infectious diseases, including malaria, in recent years. There have been a number of RDTs developed and evaluated widely for malaria diagnosis, but a number of issues related to these products have arisen. This review highlights RDTs, including challenges in assessing their performance, internationally available RDTs, their effectiveness in various health care settings, and the selection of RDTs for different health care systems.

Efficacy of hydroxychloroquine for post-exposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among adults exposed to coronavirus disease (COVID-19): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Primary Objective • To test the efficacy of Hydroxychloroquine (HCQ) (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection Secondary objectives • To determine the safety and tolerability of HCQ as SARS-CoV-2 Post-exposure Prophylaxis (PEP) in adults • To test the efficacy of HCQ (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection 2 weeks after completing therapy, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection • To test the efficacy of HCQ to shorten the duration of SARS-CoV-2 shedding among those with SARS-CoV-2 infection in the HCQ PEP group • To test the efficacy of HCQ to prevent incident COVID-19 TRIAL DESIGN: This is a randomized, multi-center, placebo-equivalent (ascorbic acid) controlled, blinded study of HCQ PEP for the prevention of SARS-CoV-2 infection in adults exposed to the virus. PARTICIPANTS: This study will enroll up to 2000 asymptomatic adults 18 to 80 years of age (inclusive) at baseline who are close contacts of persons with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 or clinically suspected COVID-19 and a pending SARS-CoV-2 PCR test. This multisite trial will be conducted at seven sites in Seattle (UW), Los Angeles (UCLA), New Orleans (Tulane), Baltimore (UMB), New York City (NYU), Syracuse (SUNY-Upstate), and Boston (BMC). Inclusion criteria Participants are eligible to be included in the study only if all of the following criteria apply: 1.Men or women 18 to 80 years of age inclusive, at the time of signing the informed consent2.Willing and able to provide informed consent3.Had a close contact of a person (index) with known PCR-confirmed SARS-CoV-2 infection or index who is currently being assessed for COVID-19 Close contact is defined as: a.Household contact (i.e., residing with the index case in the 14 days prior to index diagnosis or prolonged exposure within a residence/vehicle/enclosed space without maintaining social distance)b.Medical staff, first responders, or other care persons who cared for the index case without personal protection (mask and gloves)4.Less than 4 days since last exposure (close contact with a person with SARS-CoV-2 infection) to the index case5.Access to device and internet for Telehealth visits6.Not planning to take HCQ in addition to the study medication Exclusion criteria Participants are excluded from the study if any of the following criteria apply: 1.Known hypersensitivity to HCQ or other 4-aminoquinoline compounds2.Currently hospitalized3.Symptomatic with subjective fever, cough, or shortness of breath4.Current medications exclude concomitant use of HCQ5.Concomitant use of other anti-malarial treatment or chemoprophylaxis, including chloroquine, mefloquine, artemether, or lumefantrine.6.History of retinopathy of any etiology7.Psoriasis8.Porphyria9.Known bone marrow disorders with significant neutropenia (polymorphonuclear leukocytes <1500) or thrombocytopenia (<100 K)10.Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifen11.Known moderate or severe liver disease12.Known long QT syndrome13.Severe renal impairment14.Use of any investigational or non-registered drug or vaccine within 30 days preceding the first dose of the study drugs or planned use during the study period INTERVENTION AND COMPARATOR: Households will be randomized 1:1 (at the level of household), with close contact participants receiving one of the following therapies: •HCQ 400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days •Placebo-like control (ascorbic acid) 500 mg orally daily for 3 days then 250 mg orally daily for 11 days MAIN OUTCOMES: The primary outcome of the study is the incidence of SARS-CoV-2 infection through day 14 among participants who are SARS-CoV-2 negative at baseline by randomization group. RANDOMISATION: Participants will be randomized in a 1:1 ratio to HCQ or ascorbic acid at the level of the household (all eligible participants in 1 household will receive the same intervention). The randomization code and resulting allocation list will be generated and maintained by the Study Statistician. The list will be blocked and stratified by site and contact type (household versus healthcare worker). BLINDING (MASKING): This is a blinded study. HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be bitter and ascorbic acid will be sour. The participants will be blinded to their randomization group once assigned. Study team members, apart from the Study Pharmacist and the unblinded statistical staff, will be blinded. Laboratory staff are blinded to the group allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size for the study is N=2 000 participants randomized 1:1 to either HCZ (n=1 000) and ascorbic acid (n=1 000). TRIAL STATUS: Protocol version: 1.2 05 April 2020 Recruitment is ongoing, started March 31 and anticipated end date is September 30, 2020. TRIAL REGISTRATION: ClinicalTrials.gov, Protocol Registry Number: NCT04328961 Date of registration: April 1, 2020, retrospectively registered FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Antimicrobial susceptibilities of geographically diverse clinical human isolates of Leptospira.

Although antimicrobial therapy of leptospirosis has been studied in a few randomized controlled clinical studies, those studies were limited to specific regions of the world and few have characterized infecting strains. A broth microdilution technique for the assessment of antibiotic susceptibility has been developed at Brooke Army Medical Center. In the present study, we assessed the susceptibilities of 13 Leptospira isolates (including recent clinical isolates) from Egypt, Thailand, Nicaragua, and Hawaii to 13 antimicrobial agents. Ampicillin, cefepime, azithromycin, and clarithromycin were found to have MICs below the lower limit of detection (0.016 microg/ml). Cefotaxime, ceftriaxone, imipenem-cilastatin, penicillin G, moxifloxacin, ciprofloxacin, and levofloxacin had MIC(90)s between 0.030 and 0.125 microg/ml. Doxycycline and tetracycline had the highest MIC(90)s: 2 and 4 microg/ml, respectively. Doxycycline and tetracycline were noted to have slightly higher MICs against isolates from Egypt than against strains from Thailand or Hawaii; otherwise, the susceptibility patterns were similar. There appears to be possible variability in susceptibility to some antimicrobial agents among strains, suggesting that more extensive testing to look for geographic variability should be pursued.

Therapeutic efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Bangladesh.

Bangladesh faces increasing levels of chloroquine resistance, and drug sensitivity to sulfadoxine-pyremethamine is already compromised. Therefore, the Ministry of Health recently changed the national treatment guidelines to artemisinin-based combination therapies. The purpose of this study was to determine the baseline therapeutic efficacy of artemether-lumefantrine used as a six-dose regimen for the treatment of uncomplicated Plasmodium falciparum malaria. Sixty-seven patients were enrolled in the study; the cure rate in a 42-day follow-up after an adjustment by polymerase chain reaction was 94.3%. The treatment led to rapid fever (mean +/- SD = 25.82 +/- 12.14 hours) and parasite (30.36 +/- 19.43 hours) clearance. These data suggest that artemether-lumefantrine is a highly efficacious and well-tolerated treatment for uncomplicated P. falciparum malaria in Bangladesh.

A randomized, double-blind, active-control trial to evaluate the efficacy and safety of a three day course of tafenoquine monotherapy for the treatment of Plasmodium vivax malaria.

BACKGROUND: Tafenoquine is an investigational 8-aminoquinoline for the prevention of Plasmodium vivax relapse. Tafenoquine has a long half-life and the potential for more convenient dosing, compared with the currently recommended 14-day primaquine regimen. METHODS: This randomized, active-control, double-blind trial was conducted in Bangkok, Thailand. Seventy patients with microscopically confirmed P. vivax were randomized (2:1) to tafenoquine 400 mg once daily for 3 days or 2500 mg total dose chloroquine phosphate (1500 mg chloroquine base) given over 3 days plus primaquine 15 mg daily for 14 days. Patients were followed to day 120. RESULTS: Day 28 adequate clinical response rate in the per-protocol population was 93% (40/43) (90%CI 83-98%) with tafenoquine, and 100% (22/22) (90%CI 87-100%) with chloroquine/primaquine. Day 120 relapse prevention was 100% (35/35) with tafenoquine (90%CI 92-100%), and 95% (19/20) (90%CI 78-100%) with chloroquine/primaquine. Mean (SD) parasite, gametocyte and fever clearance times with tafenoquine were 82.5 h (32.3), 49.1 h (33.0), and 41.1 h (31.4) versus 40.0 h (15.7), 22.7 h (16.4), and 24.7 h (17.7) with chloroquine/primaquine, respectively. Peak methemoglobin was 1.4-25.6% (median 7.4%, mean 9.1%) in the tafenoquine arm, and 0.5-5.9% (median 1.5%, mean 1.9%) in the chloroquine/primaquine arm. There were no clinical symptoms of methemoglobinemia in any patient. DISCUSSION: Although there was no difference in efficacy in this study, the slow rate of parasite, gametocyte and fever clearance indicates that tafenoquine should not be used as monotherapy for radical cure of P. vivax malaria. Also, monotherapy increases the potential risk of resistance developing to this long-acting agent. Clinical trials of single-dose tafenoquine 300 mg combined with standard 3-day chloroquine or artemisinin-based combination therapy are ongoing. TRIAL REGISTRATION: Clinicaltrials.gov NCT01290601.

Sensitivity and specificity of an antigen detection ELISA for malaria diagnosis.

Enzyme-linked immunosorbent assays (ELISAs) allow for the testing of large numbers of samples within a short time frame. We tested the sensitivity and specificity of a histidine-rich protein 2 (HRP2)-based, commercially available ELISA antigen detection assay for Plasmodium falciparum (Malaria Antigen CELISA; Cellabs, Sydney, Australia). A total of 700 whole blood samples obtained from symptomatic outpatients of malaria clinics along the Thai-Myanmar border were tested relative to blinded duplicate expert microscopy adjusted with species-specific polymerase chain reaction (PCR). PCR-adjusted microscopy showed that 79 (11.3%) were infected with P. falciparum, 118 (16.9%) with P. vivax, 1 (0.1%) with P. malariae, 7 (1.0%) with mixed infections (P. falciparum and P. vivax), and 495 (70.7%) were negative. The geometric mean parasite density for P. falciparum was 7547/muL (range: 12-363,810/muL). The overall sensitivity of the HRP2 ELISA for P. falciparum malaria was 98.8% (95% CI, 93.6-100%) and the specificity was 100% (95% CI, 99.5-100%). The positive and negative predictive values for the ELISA were 100% (95% CI, 96.5-100%) and 99.8% (95% CI, 99.1-100%), respectively. The results for P. falciparum were clearly superior to expert microscopy alone, particularly in mixed infections. Microscopy combined with ELISA reaches a sensitivity and specificity similar to PCR-adjusted microscopy for the diagnosis of P. falciparum while being considerably less expensive and faster. We conclude that ELISA serves as an excellent tool to augment microscopy as the gold standard for P. falciparum diagnosis in research settings and should be further evaluated for screening in blood banks.

Effective treatment of uncomplicated Plasmodium falciparum malaria with azithromycin-quinine combinations: a randomized, dose-ranging study.

Azithromycin, the most potent antimalarial macrolide antibiotic, is synergistic with quinine against Plasmodium falciparum in vitro. We assessed combinations of azithromycin and quinine against uncomplicated P. falciparum malaria at the Armed Forces Research Institute of Medical Sciences-Kwai River Clinical Center along the Thailand-Myanmar border, an area with a high prevalence of multidrug-resistant P. falciparum. Four regimens were assessed in an open-label dose-ranging design involving 61 volunteers. All received oral quinine (Q; 30 mg/kg/day divided every 8 hours for 3 days) with oral azithromycin (Az; 500 mg twice a day for 3 days, 500 mg twice a day for 5 days, or 500 mg three times a day for 3 days). A comparator group received quinine and doxycycline (Dx; 100 mg twice a day for 7 days). Study observation was 28 days per protocol. Sixty volunteers completed the study. Seven days of QDx cured 100% of the volunteers. One failure occurred in the lowest QAz regimen (on day 28) and none occurred in either of the two higher Az regimens. Cinchonism occurred in nearly all subjects. Overall, the azithromycin regimens were well tolerated, and no volunteers discontinued therapy. Three- and five-day azithromycin-quinine combination therapy appears safe, well tolerated, and effective in curing drug-resistant P. falciparum malaria. Further evaluation, especially in pediatric and obstetric populations, is warranted.

Therapeutic efficacy of quinine plus sulfadoxine-pyremethamine for the treatment of uncomplicated falciparum malaria in Bangladesh.

In terms of drug resistance Bangladesh acts as an important gateway to the Indian Subcontinent. However, little is known about the current status of drug resistance in this country. The aim of this study was therefore to determine the therapeutic efficacy as well as in vitro drug sensitivity of quinine for 3 days plus a single dose of sulfadoxine/pyrimethamine (Q3F), an affordable alternative to the previously used chloroquine, for the treatment of uncomplicated falciparum malaria. Sixty-three patients were enrolled in the study; the overall cure rate in a 42-day follow-up after PCR adjustment was 87.3% (95% CI: 77.6-94.1). One patient was classified as early treatment failure (1.7%, 95% CI: 0.0-8.9%); 6 patients (10%; 95% CI: 3.8-20.5%) had late treatment failures within a median time of 27 days. HRP2 in vitro drug sensitivity tests were performed on all samples. Significantly higher (P = 0.008) in vitro IC(50)s for pyrimethamine in treatment failures reflect the somewhat compromised drug sensitivity to this drug. These data suggest that the combination of 3 days of quinine with a single dose of sulfadoxine/pyrimethamine is an interesting and affordable alternative as long as or whenever ACT is not available.

Simple and Procedural Reaction Time for Mild Traumatic Brain Injury in a Hyperbaric Oxygen Clinical Trial.

Simple reaction time (SRT) and procedural reaction time (PRT) are speed-of-processing tasks in the Automated Neuropsychological Assessment Metrics (ANAM) that may be sensitive to mild traumatic brain injury (mTBI). The investigators measured SRT and PRT throughput (correct responses per minute) at baseline, 6 weeks, and 13 weeks in military personnel with mTBI randomized to local care or 40 chamber sessions (sham-1.2 atmospheres absolute [ATA] air, hyperbaric oxygen-1.5 ATA O2). Scores were assessed at baseline using univariate analysis of variance and across time with repeated measures methods. Data reported as throughput standard scores (mean = 100, SD = 15). Seventy-two participants with ongoing symptoms after mTBI enrolled in the study (three female, median age 31 years, mean three lifetime concussion events, most recent mTBI 23 months prior). Sixty-four had Automated Neuropsychological Assessment Metrics data at 13 weeks. SRT and PRT throughput standard scores were comparable across groups at baseline. Over time, SRT scores did not change in the hyperbaric oxygen or sham groups and decreased in the local care group. PRT throughput standard scores increased from baseline to mid-intervention and decreased from mid-intervention to postintervention in all groups. Repeated measures change over time in SRT (p = 0.23), and PRT (p = 0.17) scores were not different among groups. This study may be underpowered to detect statistically significant change.

Measuring allelic heterogeneity in Plasmodium falciparum by a heteroduplex tracking assay.

We developed a novel Plasmodium falciparum genotyping strategy based on the heteroduplex tracking assay (HTA) method commonly used to genotype viruses. Because it can detect both sequence and size polymorphisms, we hypothesized that HTA is more sensitive than current methods. To test this hypothesis, we compared the ability of HTA and a nested polymerase chain reaction (PCR) to detect genetic diversity in 17 Thai samples. The HTA detected more MSP1 sequence variants in eight isolates (47%), less sequence variants in three isolates (18%), and an equal number of sequence variants in six isolates (35%), suggesting that HTA is equal to or more sensitive than the nested PCR. This study is a proof of concept that HTA is a sensitive allelic discrimination method able to determine genetic diversity in P. falciparum and warrants its use in studies of antimalarial drug efficacy.