Rapid and non-invasive detection of malaria parasites using near-infrared spectroscopy and machine learning.

BACKGROUND: Novel and highly sensitive point-of-care malaria diagnostic and surveillance tools that are rapid and affordable are urgently needed to support malaria control and elimination. METHODS: We demonstrated the potential of near-infrared spectroscopy (NIRS) technique to detect malaria parasites both, in vitro, using dilutions of infected red blood cells obtained from Plasmodium falciparum cultures and in vivo, in mice infected with P. berghei using blood spotted on slides and non-invasively, by simply scanning various body areas (e.g., feet, groin and ears). The spectra were analysed using machine learning to develop predictive models for infection. FINDINGS: Using NIRS spectra of in vitro cultures and machine learning algorithms, we successfully detected low densities (<10-7 parasites/µL) of P. falciparum parasites with a sensitivity of 96% (n = 1041), a specificity of 93% (n = 130) and an accuracy of 96% (n = 1171) and differentiated ring, trophozoite and schizont stages with an accuracy of 98% (n = 820). Furthermore, when the feet of mice infected with P. berghei with parasitaemia ≥3% were scanned non-invasively, the sensitivity and specificity of NIRS were 94% (n = 66) and 86% (n = 342), respectively. INTERPRETATION: These data highlights the potential of NIRS technique as rapid, non-invasive and affordable tool for surveillance of malaria cases. Further work to determine the potential of NIRS to detect malaria in symptomatic and asymptomatic malaria cases in the field is recommended including its capacity to guide current malaria elimination strategies.

Performance evaluation of InfectID-BSI: A rapid quantitative PCR assay for detecting sepsis-associated organisms directly from whole blood.

BACKGROUND: Bloodstream infections (BSIs) (presence of pathogenic organism in blood) that progress to sepsis (life-threatening organ dysfunction caused by the body's dysregulated response to an infection) is a major healthcare issue globally with close to 50 million cases annually and 11 million sepsis-related deaths, representing about 20% of all global deaths. A rapid diagnostic assay with accurate pathogen identification has the potential to improve antibiotic stewardship and clinical outcomes. METHODS: The InfectID-Bloodstream Infection (InfectID-BSI) test is a real-time quantitative PCR assay, which detects 26 of the most prevalent BSI-causing pathogens (bacteria and yeast) directly from blood (without need for pre-culture). InfectID-BSI identifies pathogens using highly discriminatory single nucleotide polymorphisms located in conserved regions of bacterial and fungal genomes. This report details the findings of a patient study which compared InfectID-BSI with conventional blood culture at two public hospitals in Queensland, Australia, using 375 whole blood samples (from multiple anatomical sites, eg. left arm, right arm, etc.) from 203 patients that have been clinically assessed to have signs and symptoms of suspected BSI, sepsis and septic shock. FINDINGS: InfectID-BSI was a more sensitive method for microorganism detection compared with blood culture (BacT/ALERT, bioMerieux) for positivity rate (102 vs 54 detections), detection of fastidious organisms (Streptococcus pneumoniae and Aerococcus viridans) (25 vs 0), detection of low bioburden infections (measured as genome copies/0.35 mL of blood), time to result (<3 h including DNA extraction for InfectID-BSI vs 16 h-48 h for blood culture), and volume of blood required for testing (0.5 mL vs 40-60 mL). InfectID-BSI is an excellent 'rule out' test for BSI, with a negative predictive value of 99.7%. InfectID-BSI's ability to detect 'difficult to culture' microorganisms re-defines the four most prevalent BSI-associated pathogens as E. coli (28.4%), S. pneumoniae (17.6%), S. aureus (13.7%), and S. epidermidis (13.7%). INTERPRETATION: InfectID-BSI has the potential to alter the clinical treatment pathway for patients with BSIs that are at risk of progressing to sepsis.

An Extremes of Phenotype Approach Confirms Significant Genetic Heterogeneity in Patients with Ulcerative Colitis.

BACKGROUND AND AIMS: Ulcerative colitis [UC] is a major form of inflammatory bowel disease globally. Phenotypic heterogeneity is defined by several variables including age of onset and disease extent. The genetics of disease severity remains poorly understood. To further investigate this, we performed a genome wide association [GWA] study using an extremes of phenotype strategy. METHODS: We conducted GWA analyses in 311 patients with medically refractory UC [MRUC], 287 with non-medically refractory UC [non-MRUC] and 583 controls. Odds ratios [ORs] were calculated for known risk variants comparing MRUC and non-MRUC, and controls. RESULTS: MRUC-control analysis had the greatest yield of genome-wide significant single nucleotide polymorphisms [SNPs] [2018], including lead SNP = rs111838972 [OR = 1.82, p = 6.28 × 10-9] near MMEL1 and a locus in the human leukocyte antigen [HLA] region [lead SNP = rs144717024, OR = 12.23, p = 1.7 × 10-19]. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC [p < 9.0 × 10-6]. No SNPs reached significance in the non-MRUC-control analysis (top SNP, rs7680780 [OR 2.70, p = 5.56 × 10-8). We replicate findings for rs4151651 in the Complement Factor B [CFB] gene and demonstrate significant changes in CFB gene expression in active UC. Detailed HLA analyses support the strong associations with MHC II genes, particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1 in MRUC. CONCLUSIONS: Our MRUC subgroup replicates multiple known UC risk variants in contrast to non-MRUC and demonstrates significant differences in effect sizes compared to those published. Non-MRUC cases demonstrate lower ORs similar to those published. Additional risk and prognostic loci may be identified by targeted recruitment of individuals with severe disease.

A Method Using Longitudinal Laboratory Data to Predict Future Intestinal Complication in Patients with Crohn's Disease.

BACKGROUND: Stenosis, fistulization, and perforation of the bowel are severe outcomes which can occur in patients with Crohn's disease. Accurate prediction of these events may enable clinicians to alter treatment strategies and avoid these outcomes. AIMS: To study the correlation between longitudinal laboratory testing and subsequent intestinal complications in patients with Crohn's disease. METHODS: An observational cohort of patients with Crohn's disease at a single center were analyzed between 01/01/1994 and 06/30/2016. A complication was defined as the development of an intestinal fistula, stenosis, or perforation. Exploratory analysis using Cox regression was performed to select the best statistical method to represent longitudinal laboratory data. Cox regression was used to identify laboratory variables independently associated with the development of a subsequent complication. A clinical scoring tool was designed. RESULTS: In 246 patients observed over a median of 5.72 years, 134 complications occurred. Minimum or maximum value in a preceding window period of one year was most strongly associated with subsequent complication. A Longitudinal Laboratory score of ≥ 2 (maximum albumin level < 39 g/L = 1, maximum mean cell volume < 88 fL = 1, minimum platelet count > 355 × 109/L = 1, minimum C reactive protein > 5 mg/L = 1) was 62% sensitive and 91% specific in identifying patients who develop a subsequent complication. CONCLUSION: A consistent reduction in serum albumin and mean cell volume, and a consistent increase in platelet count and C reactive protein were associated with a subsequent complication in patients with Crohn's disease. Longitudinal laboratory tests may be used as described in this paper to provide a rational for earlier escalation of therapy.

First Report of the Detection of DENV1 in Human Blood Plasma with Near-Infrared Spectroscopy.

Dengue virus (DENV) is the world's most common arboviral infection, with an estimated 3.9 million people at risk of the infection, 100 million symptomatic cases and 10,000 deaths per year. Current diagnosis for DENV includes the use of molecular methods, such as polymerase chain reaction, which can be costly for routine use. The near-infrared spectroscopy (NIR) technique is a high throughput technique that involves shining a beam of infrared light on a biological sample, collecting a reflectance spectrum, and using machine learning algorithms to develop predictive algorithms. Here, we used NIR to detect DENV1 artificially introduced into whole blood, plasma, and serum collected from human donors. Machine learning algorithms were developed using artificial neural networks (ANN) and the resultant models were used to predict independent samples. DENV in plasma samples was detected with an overall accuracy, sensitivity, and specificity of 90% (N = 56), 88.5% (N = 28) and 92.3% (N = 28), respectively. However, a predictive sensitivity of 33.3% (N = 16) and 80% (N = 10) and specificity of 46.7% (N = 16) and 32% (N = 10) was achieved for detecting DENV1 in whole blood and serum samples, respectively. DENV1 peaks observed at 812 nm and 819 nm represent C-H stretch, peaks at 1130-1142 nm are related to methyl group and peaks at 2127 nm are related to saturated fatty groups. Our findings indicate the potential of NIR as a diagnostic tool for DENV, however, further work is recommended to assess its sensitivity for detecting DENV in people naturally infected with the virus and to determine its capacity to differentiate DENV serotypes and other arboviruses.

Nudix hydrolase 15 (NUDT15) loss-of-function variants in an Australian inflammatory bowel disease population.

BACKGROUND: Thiopurine-related adverse events such as leukopenia, liver dysfunction and pancreatitis are associated with variants in the NUDT15 gene. Loss-of-function (low or no enzyme activity) alleles are more common in Asian and Hispanic populations. The prevalence of these variants in the Australian inflammatory bowel disease (IBD) population has not yet been reported. AIM: To evaluate the presence of NUDT15 loss-of-function alleles *2,*3,*9 in the Australian IBD population. METHODS: The NUDT15 screening cohort included 423 IBD patients from Brisbane, Australia. Study patients were recruited by: (i) retrospective review of clinical charts for thiopurine-related severe adverse events; (ii) pathology data (white blood cell (WBC) and neutrophil counts). NUDT15 genotyping was performed using polymerase chain reaction (PCR)-high-resolution melt (HRM), TaqMan genotyping and Sanger sequencing. RESULTS: NUDT15 mutation R139C (allele *3) was identified in 8 of 423 (1.9%) IBD patients. Seven of eight patients were R139C heterozygous (C/T) and one patient was R139C homozygous (T/T). One of the C/T group and the T/T patient developed thiopurine-induced myelosuppression (TIM) within 60 days of dosing. One patient in the C/T group developed TIM after 60 days of thiopurine dosing. The remaining five patients in the C/T group did not show TIM; however, other thiopurine-related events could not be ruled out and therefore careful monitoring over a long period is recommended. CONCLUSIONS: This is the first study to report the frequency of NUDT15 haplotypes *2,*3,*9 in an Australian IBD population. The most common variant detected was the R139C mutation. PCR and Sanger sequencing are efficient and cost-effective approaches for NUDT15 genotyping.

Markers of Systemic Inflammation in Acute Attacks of Ulcerative Colitis: What Level of C-reactive Protein Constitutes Severe Colitis?

BACKGROUND AND AIMS: The erythrocyte sedimentation rate [ESR] as a component of the Truelove and Witts Criteria [TWC] is the traditional inflammatory marker used for the assessment of ulcerative colitis [UC] activity. However, the C-reactive protein [CRP] is preferentially used in contemporary clinical practice. We aimed to determine the equivalent CRP cut-off for an ESR of  >30 mm/h in patients presenting with acute severe UC. METHODS: Clinical and pathological data were prospectively collected from 163 presentations of severe UC. A CRP cut-off corresponding to an ESR of  >30 mm/h was determined using confusion matrices. A validation cohort of 128 presentations was prospectively collected and analysed. RESULTS: A CRP cut-off of ≥12 mg/L generated an 85% positive predictive value [PPV] with a sensitivity of 95% and an accuracy of 82% for having a paired ESR of  >30 mm/h. There were no statistically significant differences between groups determined by the traditional ESR versus the new CRP-based criterion in the presenting faecal calprotectin, Mayo endoscopic subscore, or the rates of intravenous corticosteroid therapy failure and colectomy-by-discharge. Applying the CRP  ≥12 mg/L criterion to a validation cohort of 128 presentations generated a PPV of 83% and a sensitivity of 94%. CONCLUSIONS: The proposed CRP  ≥12 mg/L cut-off is an inclusive, sensitive, and very practical alternative to ESR as part of the TWC for defining UC presentation severity. It demonstrated similar performance characteristics to the classical ESR criterion when used for the assessment of acute UC disease activity. These findings were confirmed in a validation cohort.

Intestinal ultrasound as first-line investigation in low-risk gastrointestinal symptoms: a new model of care.

BACKGROUND: Functional gut disorders (FGD) are common. Diagnosis is symptom based, although symptoms may be indistinguishable from inflammatory bowel disease. As a result of this, investigations are common, diagnostic yield is low. A streamlined novel model of care may reduce costly investigations. AIM: To compare a new model of care for patients with low-risk gastrointestinal symptoms to a matched historical cohort. METHODS: Data were prospectively collected over 12 months. General practitioner referrals for low-risk abdominal symptoms were triaged to a new multidisciplinary clinic structure utilising intestinal ultrasound. Outcomes were compared to the historical model in the preceding 12 months. Duration of care (time from referral to discharge), number of contact episodes and investigations ordered were reviewed. RESULTS: Thirty-seven patients meeting strict inclusion criteria completed their care. Compared with the historical cohort, colonoscopies reduced from 0.7 to 0.05 per patient (P < 0.0001). Gastroenterology consults reduced from 1.5 to 1.2 (P = 0.303) and dietitian review increased from 0.8 to 1.5 (P < 0.0001). Total contact episodes reduced from 3.2 to 1.8 (P < 0.0001). Duration of care reduced from a median of 252 days to 130 days (interquartile ranges (IQR) 287 and 69, respectively; P < 0.0001). Time from first consultation to discharge reduced from 125 to 42 days (IQR 188 and 63; P < 0.0001). CONCLUSION: This multidisciplinary approach to care of low-risk abdominal symptoms significantly reduced contact episodes, time in care and invasive investigations. It decreased costly gastroenterology consultation and increased allied health exposure. It demonstrates improved health service outcomes.

Dietary intake of patients with inflammatory bowel disease aligns poorly with traditional Mediterranean diet principles.

AIM: Previous research has shown that individuals with inflammatory bowel disease avoid specific food items, such as fibre rich foods, in order to manage symptoms. Dietary fibre and the traditional Mediterranean diet are both associated with reduced mucosal and systemic inflammation, gut barrier integrity, and microbiota diversity. There is limited data on the diet composition of individuals with inflammatory bowel disease. The aim of this study was to evaluate how it compares to the traditional Mediterranean diet and national dietary guidelines. METHODS: Outpatients with inflammatory bowel disease were recruited to the study between February and August 2019. Demographic and medical information was obtained for consenting participants. All participants completed a dietary assessment of usual intake (24-h diet recall and 17-point ready reckoner) from which a Mediterranean diet adherence score was calculated. Dietary intake of core food groups was compared to the recommended number of serves outlined in the Australian Guide to Healthy Eating. RESULTS: 100 participants were recruited. The mean Mediterranean diet adherence score was 5.1 ± 1.3 (maximum 14 points), 4% of participants scored ≥9 (commonly agreed criteria for Mediterranean diet adherence). Participants also consumed considerably less grains and vegetables than national dietary guidelines recommendations. CONCLUSIONS: The diet of outpatients with inflammatory bowel disease did not align with Mediterranean diet characteristics. Participants consumed significantly less grains and vegetables than national guidelines, suggesting a low fibre intake. These findings suggest that dietary interventions focusing on improving the diet of individuals with inflammatory bowel disease to align with Mediterranean diet characteristics are warranted.

Rapid and Non-Invasive Detection of Aedes aegypti Co-Infected with Zika and Dengue Viruses Using Near Infrared Spectroscopy.

The transmission of dengue (DENV) and Zika (ZIKV) has been continuously increasing worldwide. An efficient arbovirus surveillance system is critical to designing early-warning systems to increase preparedness of future outbreaks in endemic countries. The Near Infrared Spectroscopy (NIRS) is a promising high throughput technique to detect arbovirus infection in Ae. aegypti with remarkable advantages such as cost and time effectiveness, reagent-free, and non-invasive nature over existing molecular tools for similar purposes, enabling timely decision making through rapid detection of potential disease. Our aim was to determine whether NIRS can differentiate Ae. aegypti females infected with either ZIKV or DENV single infection, and those coinfected with ZIKV/DENV from uninfected ones. Using 200 Ae. aegypti females reared and infected in laboratory conditions, the training model differentiated mosquitoes into the four treatments with 100% accuracy. DENV-, ZIKV-, and ZIKV/DENV-coinfected mosquitoes that were used to validate the model could be correctly classified into their actual infection group with a predictive accuracy of 100%, 84%, and 80%, respectively. When compared with mosquitoes from the uninfected group, the three infected groups were predicted as belonging to the infected group with 100%, 97%, and 100% accuracy for DENV-infected, ZIKV-infected, and the co-infected group, respectively. Preliminary lab-based results are encouraging and indicate that NIRS should be tested in field settings to evaluate its potential role to monitor natural infection in field-caught mosquitoes.

Malaria absorption peaks acquired through the skin of patients with infrared light can detect patients with varying parasitemia.

To eliminate malaria, scalable tools that are rapid, affordable, and can detect patients with low parasitemia are required. Non-invasive diagnostic tools that are rapid, reagent-free, and affordable would also provide a justifiable platform for testing malaria in asymptomatic patients. However, non-invasive surveillance techniques for malaria remain a diagnostic gap. Here, we show near-infrared Plasmodium absorption peaks acquired non-invasively through the skin using a miniaturized hand-held near-infrared spectrometer. Using spectra from the ear, these absorption peaks and machine learning techniques enabled non-invasive detection of malaria-infected human subjects with varying parasitemia levels in less than 10 s.

Diagnostic accuracy of narrow-band imaging endoscopy with targeted biopsies compared with standard endoscopy with random biopsies in patients with Barrett's esophagus: A systematic review and meta-analysis.

BACKGROUND AND AIM: Endoscopic surveillance for dysplasia in Barrett's esophagus (BE) with random biopsies is the primary diagnostic tool for monitoring clinical progression into esophageal adenocarcinoma. As an alternative, narrow-band imaging (NBI) endoscopy offers targeted biopsies that can improve dysplasia detection. This study aimed to evaluate NBI-guided targeted biopsies' diagnostic accuracy for detecting dysplasia in patients undergoing endoscopic BE surveillance compared with the widely used Seattle protocol. METHODS: Cochrane DTA Register, MEDLINE/PubMed, EMBASE, OpenGrey, and bibliographies of identified papers were searched until 2018. Two independent investigators resolved discrepancies by consensus, study selection, data extraction, and quality assessment. Data on sensitivity, specificity, and predictive values were pooled and analyzed using a random-effects model. RESULTS: Of 9528 identified articles, six studies comprising 493 participants were eligible for quantitative synthesis. NBI-targeted biopsy showed high diagnostic accuracy in detection of dysplasia in BE with a sensitivity of 76% (95% confidence interval [CI]: 0.61-0.91), specificity of 99% (95% CI: 0.99-1.00), positive predictive value of 97% (95% CI: 0.96-0.99), and negative predictive value of 84% (95% CI: 0.69-0.99) for detection of all grades of dysplasia. The receiver-operating characteristic curve for NBI model performance was 0.8550 for detecting all dysplasia. CONCLUSION: Narrow-band imaging-guided biopsy demonstrated high diagnostic accuracy and might constitute a valid substitute for random biopsies during endoscopic surveillance for dysplasia in BE.

High throughput estimates of Wolbachia, Zika and chikungunya infection in Aedes aegypti by near-infrared spectroscopy to improve arbovirus surveillance.

Deployment of Wolbachia to mitigate dengue (DENV), Zika (ZIKV) and chikungunya (CHIKV) transmission is ongoing in 12 countries. One way to assess the efficacy of Wolbachia releases is to determine invasion rates within the wild population of Aedes aegypti following their release. Herein we evaluated the accuracy, sensitivity and specificity of the Near Infrared Spectroscopy (NIRS) in estimating the time post death, ZIKV-, CHIKV-, and Wolbachia-infection in trapped dead female Ae. aegypti mosquitoes over a period of 7 days. Regardless of the infection type, time post-death of mosquitoes was accurately predicted into four categories (fresh, 1 day old, 2-4 days old and 5-7 days old). Overall accuracies of 93.2, 97 and 90.3% were observed when NIRS was used to detect ZIKV, CHIKV and Wolbachia in dead Ae. aegypti female mosquitoes indicating NIRS could be potentially applied as a rapid and cost-effective arbovirus surveillance tool. However, field data is required to demonstrate the full capacity of NIRS for detecting these infections under field conditions.

Ileal Pouch-Anal Anastomosis for Ulcerative Colitis: An Australian Institution's Experience.

PURPOSE: We report outcomes and evaluate patient factors and the impact of surgical evolution on outcomes in consecutive ulcerative colitis patients who had restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) at an Australian institution over 26 years. METHODS: Data including clinical characteristics, preoperative medical therapy, and surgical outcomes were collected. We divided eligible patients into 3 period arms (period 1, 1990 to 1999; period 2, 2000 to 2009; period 3, 2010 to 2016). Outcomes of interest were IPAA leak and pouch failure. RESULTS: A total of 212 patients were included. Median follow-up was 50 (interquartile range, 17 to 120) months. Rates of early and late complications were 34.9% and 52.0%, respectively. Early complications included wound infection (9.4%), pelvic sepsis (8.0%), and small bowel obstruction (6.6%) while late complications included small bowel obstruction (18.9%), anal stenosis (16.8%), and pouch fistula (13.3%). Overall, IPAA leak rate was 6.1% and pouch failure rate was 4.8%. Eighty-three patients (42.3%) experienced pouchitis. Over time, we observed an increase in patient exposure to thiopurine (P=0.0025), cyclosporin (P=0.0002), and anti-tumor necrosis factor (P<0.00001) coupled with a shift to laparoscopic technique (P<0.00001), stapled IPAA (P<0.00001), J pouch configuration (P<0.00001), a modified 2-stage procedure (P=0.00012), and a decline in defunctioning ileostomy rate at time of IPAA (P=0.00002). Apart from pouchitis, there was no significant difference in surgical and chronic inflammatory pouch outcomes with time. CONCLUSION: Despite greater patient exposure to immunomodulatory and biologic therapy before surgery coupled with a significant change in surgical techniques, surgical and chronic inflammatory pouch outcome rates have remained stable.

Near-Infrared Spectroscopy Evaluations for the Differentiation of Carbapenem-Resistant from Susceptible Enterobacteriaceae Strains.

Antimicrobial Resistance (AMR) caused by Carbapenem-Resistant Enterobacteriaceae (CRE) is a global threat. Accurate identification of these bacterial species with associated AMR is critical for their management. While highly accurate methods to detect CRE are available, they are costly, timely and require expert skills, making their application infeasible in low-resource settings. Here, we investigated the potential of Near-Infrared Spectroscopy (NIRS) for a range of applications: (i) the detection and differentiation of isolates of two pathogenic Enterobacteriaceae species, Klebsiella pneumoniae and Escherichia coli, and (ii) the differentiation of carbapenem resistant and susceptible K. pneumoniae. NIRS has successfully differentiated between K. pneumoniae and E. coli isolates with a predictive accuracy of 89.04% (95% CI; 88.7-89.4%). K. pneumoniae isolates harbouring carbapenem-resistance determinants were differentiated from susceptible K. pneumoniae strains with an accuracy of 85% (95% CI; 84.2-86.1%). To our knowledge, this is the largest proof of concept demonstration for the utility and feasibility of NIRS to rapidly differentiate between K. pneumoniae and E. coli as well as carbapenem-resistant K. pneumoniae from susceptible strains.

Heart Rate Variability as an Index of Differential Brain Dynamics at Rest and After Acute Stress Induction.

The brain continuously receives input from the internal and external environment. Using this information, the brain exerts its influence on both itself and the body to facilitate an appropriate response. The dynamic interplay between the brain and the heart and how external conditions modulate this relationship deserves attention. In high-stress situations, synchrony between various brain regions such as the prefrontal cortex and the heart may alter. This flexibility is believed to facilitate transitions between functional states related to cognitive, emotional, and especially autonomic activity. This study examined the dynamic temporal functional association of heart rate variability (HRV) with the interaction between three main canonical brain networks in 38 healthy male subjects at rest and directly after a psychosocial stress task. A sliding window approach was used to estimate the functional connectivity (FC) among the salience network (SN), central executive network (CEN), and default mode network (DMN) in 60-s windows on time series of blood-oxygen-level dependent (BOLD) signal. FC between brain networks was calculated by Pearson correlation. A multilevel linear mixed model was conducted to examine the window-by-window association between the root mean square of successive differences between normal heartbeats (RMSSD) and FC of network-pairs across sessions. Our findings showed that the minute-by-minute correlation between the FC and RMSSD was significantly stronger between DMN and CEN than for SN and CEN in the baseline session [b = 4.36, t(5025) = 3.20, p = 0.006]. Additionally, this differential relationship between network pairs and RMSSD disappeared after the stress task; FC between DMN and CEN showed a weaker correlation with RMSSD in comparison to baseline [b = -3.35, t(5025) = -3.47, p = 0.006]. These results suggest a dynamic functional interplay between HRV and the functional association between brain networks that varies depending on the needs created by changing conditions.

Local glutamate in cingulate cortex subregions differentially correlates with affective network activations during face perception.

The cingulate cortex is involved in emotion recognition/perception and regulation. Rostral and caudal subregions belong to different brain networks with distinct roles in affective perception. Despite recent accounts of the relevance of cingulate cortex glutamate (Glu) on blood-oxygen-level-dependent (BOLD) responses, the specificity of the subregional Glu levels during emotional tasks remains unclear. Seventy-two healthy participants (age = 27.33 ± 6.67, 32 women) performed an affective face-matching task and underwent magnetic resonance spectroscopy (MRS) at 7 Tesla. Correlations between the BOLD response during emotion perception and Glu concentration in the pregenual anterior cingulate cortex (pgACC) and anterior midcingulate cortex (aMCC) were compared on a whole-brain level. Post hoc specificity of the association with an affect was assessed. Lower Glu in the pgACC correlated with stronger activation differences between negative and positive faces in the left inferior and superior frontal gyrus (L IFG and L SFG). In contrast, lower Glu in the aMCC correlated with BOLD contrasts in the posterior cingulate cortex (PCC). Furthermore, negative face detection was associated with prolonged response time (RT). Our results demonstrate a subregion-specific involvement of cingulate cortex Glu in interindividual differences during viewing of affective facial expressions. Glu levels in the pgACC were correlated with frontal area brain activations, whereas Glu in the salience network component aMCC modulated responses in the PCC-precuneus. We show that region-specific metabolite mapping enables specific activation of different BOLD signals in the brain underlying emotional perception.

Pharmacokinetics and Ex Vivo Antimalarial Activity of Artesunate-Amodiaquine plus Methylene Blue in Healthy Volunteers.

High rates of artemisinin-based combination therapy (ACT) failures in the treatment of Plasmodium falciparum malaria in Southeast Asia have led to triple-drug strategies to extend the useful life of ACTs. In this study, we determined whether methylene blue [MB; 3,7-bis(dimethylamino)phenothiazin-5-ium chloride hydrate] alters the pharmacokinetics of artesunate-amodiaquine (ASAQ) and enhances the ex vivo antimalarial activity of ASAQ. In an open-label, randomized crossover design, a single oral dose of ASAQ (200 mg AS/540 mg AQ) alone or with MB (325 mg) was administered to 15 healthy Vietnamese volunteers. Serial blood samples were collected up to 28 days after dosing. Pharmacokinetic properties of the drugs were determined by noncompartmental analysis. After drug administration, plasma samples from seven participants were assessed for ex vivo antimalarial activity against the artemisinin-sensitive MRA1239 and the artemisinin-resistant MRA1240 P. falciparum lines, in vitro MB significantly increased the mean area under the curve of the active metabolite of AS, dihydroartemisinin (1,246 ± 473 versus 917 ± 405 ng·h/ml, P = 0.009) but did not alter the pharmacokinetics of AQ, AS, or desethylamodiaquine. Comparing the antimalarial activities of the plasma samples from the participants collected up to 48 h after ASAQ plus MB (ASAQ+MB) and ASAQ dosing against the MRA1239 and MRA1240 lines, MB significantly enhanced the blood schizontocidal activity of ASAQ by 2.0-fold and 1.9-fold, respectively. The ring-stage survival assay also confirmed that MB enhanced the ex vivo antimalarial activity of ASAQ against MRA1240 by 2.9-fold to 3.8-fold, suggesting that the triple-drug combination has the potential to treat artemisinin-resistant malaria and for malaria elimination. (This study has been registered in the Australian New Zealand Clinical Trials Registry [https://anzctr.org.au/] under registration number ACTRN12612001298808.).

A validated risk stratification tool for detecting high-risk small bowel Crohn's disease.

BACKGROUND: Delays in Crohn's disease (CD) diagnosis are positively associated with ileal location and an increased risk of complications. AIM: To develop a simple risk assessment tool to enable primary care physicians to recognise potential ileal CD earlier, shortening the delay to specialist investigation METHODS: Three cohorts were acquired for this study. Cohort 1 included 61 patients retrospectively identified with ileal CD between 2000 and 2010 and 78 matched controls drawn from a cohort referred for investigation of abdominal symptoms. Cohort 2 included 42 individuals diagnosed with ileal CD and 57 controls identified prospectively. Cohort 3 included an additional 84 individuals with ileal CD and 495 without CD referred for colonoscopy. Clinical symptoms and serological biomarkers were acquired and used to develop a risk prediction algorithm. The algorithm was trained independently on each of the three cohorts and tested on the latter two cohorts. RESULTS: Altered bowel habit with abdominal pain combined with derangements in white cell count (WCC), albumin and platelet counts were important features in predicting ileal CD (AUC = 0.92, 95% CI = 0.89-0.92). This was validated in cohorts 2 (AUC = 0.96, 95% CI = 0.95-0.98) and 3 (AUC = 0.94, 95% CI = 0.92-0.96). C-reactive protein was independently associated with ileal CD but non-signficant in a multivariate model. CONCLUSION: A web-based risk stratification tool for ileal CD has been developed from objective and symptom-based criteria. This tool enables primary care physicians to more confidently request urgent specialist assessment for patients identified as at high risk for ileal CD.