Recurrent alcohol-associated hepatitis is common and is associated with increased mortality.

BACKGROUND AND AIMS: Alcohol relapse after surviving an episode of alcohol-associated hepatitis (AH) is common. However, the clinical features, risk factors, and prognostic implications of recurrent alcohol-associated hepatitis (RAH) are not well described. APPROACH AND RESULTS: A registry-based study was done of patients admitted to 28 Spanish hospitals for an episode of AH between 2014 and 2021. Baseline demographics and laboratory variables were collected. Risk factors for RAH were investigated using Cox regression analysis. We analyzed the severity of the index episodes of AH and compared it to that of RAH. Long-term survival was assessed by Kaplan-Meier curves and log-rank tests. A total of 1118 patients were included in the analysis, 125 (11%) of whom developed RAH during follow-up (median: 17 [7-36] months). The incidence of RAH in patients resuming alcohol use was 22%. The median time to recurrence was 14 (8-29) months. Patients with RAH had more psychiatric comorbidities. Risk factors for developing RAH included age <50 years, alcohol use >10 U/d, and history of liver decompensation. RAH was clinically more severe compared to the first AH (higher MELD, more frequent ACLF, and HE). Moreover, alcohol abstinence during follow-up was less common after RAH (18% vs. 45%, p <0.001). Most importantly, long-term mortality was higher in patients who developed RAH (39% vs. 21%, p = 0.026), and presenting with RAH independently predicted high mortality (HR: 1.55 [1.11-2.18]). CONCLUSIONS: RAH is common and has a more aggressive clinical course, including increased mortality. Patients surviving an episode of AH should undergo intense alcohol use disorder therapy to prevent RAH.

Anxiety and depression in patients with narcolepsy.

We analysed the co-existence of psychopathology in patients with narcolepsy at our centre. We performed an observational retrospective descriptive analysis of patients with a diagnosis of narcolepsy, with and without psychopathology, who attended our sleep disorders unit from October 2012 to October 2021. A total of 51patients with narcolepsy (mean [SD] age 41.10 [14.71] years; 23 [45.1%] males and 28 [54.90%] females) were included. In all, 27 patients (52.94%) and 24 patients (47.06%) had narcolepsy with and without cataplexy, respectively. Of the total, 18 (33.33%) had a mood disorder: 18 with anxiety disorder (33.33%). Of these patients 14 (27.45%) had major depression, two (4%) had attempted suicide, one (2%) had manic outbreak, and one (2%) had substance abuse. Of the 18 patients with anxiety and depression, 10 (55.55%) and eight (44.44%) had narcolepsy with and without cataplexy, respectively. In the comparative analysis, a statistically significant relationship was found between younger age and the presence of anxiety. The prevalence of anxiety and depression in patients with narcolepsy was triple that of the general population, especially in younger patients. Psychopathology precedes the diagnosis of narcolepsy in most patients, not being reactive to diagnosis. This high prevalence suggests a possible biological relationship between both disorders, which should be assessed with larger studies.

Cowitness identification speed affects choices from target-absent photospreads.

OBJECTIVE: Three studies examined the influence of a witness's identification speed on the identification decision of another witness. HYPOTHESES: Based on research documenting cowitness effects we expected cowitness speed to affect identification decisions from target-absent photospreads. Without prior research testing the effects of cowitness speed, we did not have a specific prediction regarding how fast (vs. slow) cowitness identification decisions would affect participant-witnesses' identification rates in Study 1. Based on the results from Study 1, in Study 2 we predicted that fast (vs. slow) cowitness decisions would increase choices from target-absent photospreads when the cowitness was known to have made a positive identification. In Study 3, cowitnesses rejected the photospread. Based on the previous studies, we hypothesized that fast (vs. slow) cowitness decisions would decrease choices from target-absent photospreads. However, because a photospread rejection is qualitatively different from an identification, this prediction was tentative. METHOD: In all three studies, participants watched one of 2 stimulus videos with a confederate cowitness. After the video, the confederate made a fast (10 s) or slow (4 min) identification. Participants then attempted an identification from a target-absent photospread. In Study 1 (N = 101), the confederate's decision from the photospread was ambiguous. In Study 2 (N = 200) the confederate announced making a positive identification. In Study 3 (N = 151) the confederate cowitness rejected the photospread. RESULTS: In all 3 studies, participants paired with a fast cowitness made more choices from the target-absent photospread than did participants paired with a slow cowitness. CONCLUSIONS: Fast cowitness identifications increased choices from the target-absent photospread regardless of whether a cowitness's decision was ambiguous (Study 1), whether they made an identification (Study 2), or rejected the photospread (Study 3). Given the effects of cowitness speed on identification decisions, it might be advisable to standardize the duration of identification procedures and inform witnesses of this standardization. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Signet ring cell carcinoma in a juvenile polyp.

Juvenile polyps are hamartomatous lesions, usually unique, which appear at an early age. They are usually located in the rectosigmoid junction and are not thought to imply a higher risk of colorectal cancer. Here we report a case of signet ring cell (SRC) carcinoma in this type of lesion.

Brain changes following mindfulness: Reduced caudate volume is associated with decreased positive urgency.

Mindfulness training has been shown to improve psychological health and general well-being. However, it is unclear which brain and personality systems may be affected by this practice for improving adaptive behavior and quality of life. The present study explores the effects of a 5-week mindfulness-based intervention (MBI) at the neuroanatomical level and its relationship with dispositional mindfulness and impulsivity. Sixty-six risky drivers were quasi-randomly assigned to a mindfulness training group (MT) or a control group (N). Participants underwent magnetic resonance imaging and completed the Five Facet Mindfulness Questionnaire (FFMQ) and the UPPS-P impulsivity scale twice, at baseline and after receiving the MBI. We observed that MBI changes dispositional mindfulness in the non-reactivity and observing facets. Further, we observed that the magnitude of change in impulsivity was associated with the change in dispositional mindfulness. Whole-brain voxel-wise analysis revealed that the volume of the right caudate nucleus of the MT group (n = 27) showed a reduction compared to that of the control group (n = 33), which increased in terms of the pre-post measurement (MT=-1.76 mm3; N = 6.31 mm3). We also observed that reduced caudate nucleus volume correlated with decreased positive urgency in the MT group. Taken together, our results show that MBI improves the skills of observing and non-reactivity to inner experience, while producing changes in the structure of the caudate nucleus. These structural changes are associated with a reduction in impulsivity levels, decreasing the tendency to act rashly in situations that generate positive emotions and thus facilitating more adaptive behavior.

Genome scanning of Amazonian Plasmodium falciparum shows subtelomeric instability and clindamycin-resistant parasites.

Here, we fully characterize the genomes of 14 Plasmodium falciparum patient isolates taken recently from the Iquitos region using genome scanning, a microarray-based technique that delineates the majority of single-base changes, indels, and copy number variants distinguishing the coding regions of two clones. We show that the parasite population in the Peruvian Amazon bears a limited number of genotypes and low recombination frequencies. Despite the essentially clonal nature of some isolates, we see high frequencies of mutations in subtelomeric highly variable genes and internal var genes, indicating mutations arising during self-mating or mitotic replication. The data also reveal that one or two meioses separate different isolates, showing that P. falciparum clones isolated from different individuals in defined geographical regions could be useful in linkage analyses or quantitative trait locus studies. Through pairwise comparisons of different isolates we discovered point mutations in the apicoplast genome that are close to known mutations that confer clindamycin resistance in other species, but which were hitherto unknown in malaria parasites. Subsequent drug sensitivity testing revealed over 100-fold increase of clindamycin EC(50) in strains harboring one of these mutations. This evidence of clindamycin-resistant parasites in the Amazon suggests that a shift should be made in health policy away from quinine + clindamycin therapy for malaria in pregnant women and infants, and that the development of new lincosamide antibiotics for malaria should be reconsidered.

Autistic adults' perspectives on appropriate empathic responses to others' emotions.

Although the ability of autistic adults to recognize others' emotions has been extensively studied, less attention has been given to how they respond to these emotions. We examined two aspects of autistic and non-autistic adults' responsiveness to the emotional expressions of non-autistic actors: their perspectives on the appropriate way of responding to others' emotions and their awareness of others' perceptions of the likely appropriateness of such responses. Autistic (N = 63) and non-autistic (N = 67) adult samples viewed videos of 74 dyadic social interactions displaying different examples of 12 emotions expressed by one actor in response to the behavior of the other. After each video, participants (a) nominated the emotion expressed by the first actor, (b) offered their perspective on what would constitute an appropriate empathic response by the second actor, and (c) indicated their confidence in that response. Although the autistic group provided fewer appropriate empathic responses-operationalized via a panel's interpretations of normative responses-than the non-autistic group, within-group variability was marked, and the effect was weak and largely confined to basic emotions. Autistic individuals were, however, considerably less confident in their responses. Examination of the relationships between confidence in and the appropriateness of empathic responses provided no indication in either group of reliable discrimination of appropriate from inappropriate empathic responses or finely tuned metacognitive awareness of variations in appropriateness. In sum, autistic adults' perspectives on the appropriate empathic reactions to non-autistic adults' emotions were not unilaterally or markedly different to those of non-autistic adults.

Detecting dodgy behaviour: The role of autism, autistic traits and theory of mind.

LAY ABSTRACT: Difficulties in reading others' minds make it difficult to anticipate their future behaviour. It has often been argued that such difficulties contribute to autistic individuals becoming enmeshed in criminal activity. However, supportive scientific evidence is virtually non-existent. We compared the ability of groups of autistic and non-autistic adults of similar intellectual ability to detect dodgy or suspicious behaviour across a wide range of scenarios. Although the autistic group performed more poorly than the non-autistic group on an established measure of mindreading, there were no group differences in the ability to detect dodginess. Nor did we find any evidence that detecting dodgy behaviour was associated with the degree of autistic traits reported by individual participants. However, when we combined the two groups, difficulty reading the minds of others was indeed associated with poorer detection of dodginess, thus highlighting a characteristic of individuals that may well increase the likelihood of becoming involved in crime or exploited for autistic and non-autistic individuals alike.

Genetic diversity and population structure of genes encoding vaccine candidate antigens of Plasmodium vivax.

BACKGROUND: A major concern in malaria vaccine development is genetic polymorphisms typically observed among Plasmodium isolates in different geographical areas across the world. Highly polymorphic regions have been observed in Plasmodium falciparum and Plasmodium vivax antigenic surface proteins such as Circumsporozoite protein (CSP), Duffy-binding protein (DBP), Merozoite surface protein-1 (MSP-1), Apical membrane antigen-1 (AMA-1) and Thrombospondin related anonymous protein (TRAP). METHODS: Genetic variability was assessed in important polymorphic regions of various vaccine candidate antigens in P. vivax among 106 isolates from the Amazon Region of Loreto, Peru. In addition, genetic diversity determined in Peruvian isolates was compared to population studies from various geographical locations worldwide. RESULTS: The structured diversity found in P. vivax populations did not show a geographic pattern and haplotypes from all gene candidates were distributed worldwide. In addition, evidence of balancing selection was found in polymorphic regions of the trap, dbp and ama-1 genes. CONCLUSIONS: It is important to have a good representation of the haplotypes circulating worldwide when implementing a vaccine, regardless of the geographic region of deployment since selective pressure plays an important role in structuring antigen diversity.

Facing up to others' emotions: No evidence of autism-related deficits in metacognitive awareness of emotion recognition.

Emotion recognition difficulties are considered to contribute to social-communicative problems for autistic individuals and awareness of such difficulties may be critical for the identification and pursuit of strategies that will mitigate their adverse effects. We examined metacognitive awareness of face emotion recognition responses in autistic (N = 63) and non-autistic (N = 67) adults across (a) static, dynamic and social face emotion stimuli, (b) free- and forced-report response formats, and (c) four different sets of the six "basic" and six "complex" emotions. Within-individual relationships between recognition accuracy and post-recognition confidence provided no indication that autistic individuals were poorer at discriminating correct from incorrect recognition responses than non-autistic individuals, although both groups exhibited marked inter-individual variability. Although the autistic group was less accurate and slower to recognize emotions, confidence-accuracy calibration analyses provided no evidence of reduced sensitivity on their part to fluctuations in their emotion recognition performance. Across variations in stimulus type, response format and emotion, increases in accuracy were associated with progressively higher confidence, with similar calibration curves for both groups. Calibration curves for both groups were, however, characterized by overconfidence at the higher confidence levels (i.e., overall accuracy less than the average confidence level), with the non-autistic group contributing more decisions with 90%-100% confidence. Comparisons of slow and fast responders provided no evidence of a "hard-easy" effect-the tendency to exhibit overconfidence during hard tasks and underconfidence during easy tasks-suggesting that autistic individuals' slower recognition responding may reflect a strategic difference rather than a processing speed limitation. LAY SUMMARY: It is generally considered that autistic individuals may have difficulty recognizing other people's facial emotions. However, little is known about their awareness of any emotion recognition difficulties they may experience. This study indicates that, although there is considerable individual variability, autistic adults were as sensitive to variations in the accuracy of their recognition of others' emotions as their non-autistic peers.

Speed and accuracy of emotion recognition in autistic adults: The role of stimulus type, response format, and emotion.

Emotion recognition difficulties are considered to contribute to social-communicative problems for autistic individuals. Prior research has been dominated by a focus on forced-choice recognition response accuracy for static face presentations of basic emotions, often involving small samples. Using free-report and multiple-choice response formats, we compared emotion recognition in IQ-matched autistic (N = 63) and nonautistic (N = 67) adult samples using 12 face emotion stimuli presented in three different stimulus formats (static, dynamic, social) that varied the degree of accompanying contextual information. Percent agreement with normative recognition responses (usually labeled "recognition accuracy") was slightly lower for autistic adults. Both groups displayed marked inter-individual variability and, although there was considerable overlap between groups, a very small subset of autistic individuals recorded lower percent agreement than any of the nonautistic sample. Overall, autistic individuals were significantly slower to respond and less confident. Although stimulus type, response format, and emotion affected percent agreement, latency and confidence, their interactions with group were nonsignificant and the associated effect sizes extremely small. The findings challenge notions that autistic adults have core deficits in emotion recognition and are more likely than nonautistic adults to be overwhelmed by increasingly dynamic or complex emotion stimuli and to experience difficulties recognizing specific emotions. Suggested research priorities include clarifying whether longer recognition latencies reflect fundamental processing limitations or adjustable strategic influences, probing age-related changes in emotion recognition across adulthood, and identifying the links between difficulties highlighted by traditional emotion recognition paradigms and real-world social functioning. LAY SUMMARY: It is generally considered that autistic individuals are less accurate than nonautistic individuals at recognizing other people's facial emotions. Using a wide array of emotions presented in various contexts, this study suggests that autistic individuals are, on average, only slightly less accurate but at the same time somewhat slower when classifying others' emotions. However, there was considerable overlap between the two groups, and great variability between individuals. The differences between groups prevailed regardless of how stimuli were presented, the response required or the particular emotion.

Spatiotemporal dynamics of Plasmodium falciparum histidine-rich protein 2 and 3 deletions in Peru.

Peru was the first country where pfhrp2 and pfhrp3 gene deletions were detected despite the fact that rapid diagnostics tests are not commonly used for confirmatory malaria diagnosis. This context provides a unique scenario to study the dynamics of pfhrp2 and pfhrp3 gene deletions without apparent RDTs selection pressure. In this study we characterized the presence of pfhrp2 and pfhrp3 genes on 325 P. falciparum samples collected in Iquitos and surrounding communities between 2011 and 2018 in order to understand the dynamics of gene deletion prevalence, potential associations with clinical symptomatology and parasite genetic background. P. falciparum presence was confirmed by microscopy and PCR of 18 s rRNA, pfmsp1 and pfmsp2. Gene deletions were assessed by amplification of exon1 and exon2 of pfhrp2 and pfhrp3 using gene specific PCRs. Confirmation of absence of HRP2 expression was assessed by ELISA of HRP2 and pLDH. Genotyping of 254 samples were performed using a panel of seven neutral microsatellite markers. Overall, pfhrp2 and pfhrp3 dual gene deletions were detected in 67% (217/324) parasite samples. Concordance between pfhrp2 deletion and negligible HRP2 protein levels was observed (Cohen's Kappa = 0.842). Prevalence of gene deletions was heterogeneous across study sites (adjusted p < 0.005) but there is an overall tendency towards increase through time in the prevalence of dual pfhrp2/3-deleted parasites between 2011 (14.3%) and 2016 (88.39%) stabilizing around 65% in 2018. Dual deletions increase was associated with dominance of a single new parasite haplotype (H8) which rapidly spread to all study sites during the 8 study years. Interestingly, participants infected with dual pfhrp2/3-deleted parasites had a significantly lower parasitemias than those without gene deletions in this cohort. Our study showed the increase of pfhrp2/3 deletions in the absence of RDTs pressure and a clonal replacement of circulating lines in the Peruvian Amazon basin. These results suggest that other factors linked to the pfhrp2/3 deletion provide a selective advantage over non-deleted strains and highlight the need for additional studies and continuing surveillance.

Drug resistance and population structure of Plasmodium falciparum and Plasmodium vivax in the Peruvian Amazon.

Malaria is a major health problem in Peru despite substantial progress achieved by the ongoing malaria elimination program. This study explored the population genetics of 63 Plasmodium falciparum and 170 P. vivax cases collected in the Peruvian Amazon Basin between 2015 and 2019. Microscopy and PCR were used for malaria detection and positive samples were genotyped at neutral and drug resistance-associated regions. The P. falciparum population exhibited a low nucleotide diversity (π = 0.02) whereas the P. vivax population presented a higher genetic diversity (π = 0.34). All P. falciparum samples (n = 63) carried chloroquine (CQ) resistant mutations on Pfcrt. Most P. falciparum samples (53 out of 54) carried sulfadoxine (SD) resistant mutations on Pfdhfr and Pfdhps. No evidence was found of artemisinin resistance mutations on kelch13. Population structure showed that a single cluster accounted for 93.4% of the P. falciparum samples whereas three clusters were found for P. vivax. Our study shows a low genetic diversity for both species with significant differences in genetic sub-structuring. The high prevalence of CQ-resistance mutations could be a result of indirect selection pressures driven by the P. vivax treatment scheme. These results could be useful for public health authorities to safeguard the progress that Peru has achieved towards malaria elimination.

There Is More to Mindfulness Than Emotion Regulation: A Study on Brain Structural Networks.

Dispositional mindfulness and emotion regulation are two psychological constructs closely interrelated, and both appear to improve with the long-term practice of mindfulness meditation. These constructs appear to be related to subcortical, prefrontal, and posterior brain areas involved in emotional processing, cognitive control, self-awareness, and mind wandering. However, no studies have yet discerned the neural basis of dispositional mindfulness that are minimally associated with emotion regulation. In the present study, we use a novel brain structural network analysis approach to study the relationship between structural networks and dispositional mindfulness, measured with two different and widely used instruments [Mindfulness Attention Awareness Scale (MAAS) and Five Facet Mindfulness Questionnaire (FFMQ)], taking into account the effect of emotion regulation difficulties. We observed a number of different brain regions associated with the different scales and dimensions. The total score of FFMQ and MAAS overlap with the bilateral parahippocampal and fusiform gyri. Additionally, MAAS scores were related to the bilateral hippocampus and the FFMQ total score to the right insula and bilateral amygdala. These results indicate that, depending on the instrument used, the characteristics measured could differ and could also involve different brain systems. However, it seems that brain areas related to emotional reactivity and semantic processing are generally related to Dispositional or trait mindfulness (DM), regardless of the instrument used.

Cilastatin attenuates cisplatin-induced proximal tubular cell damage.

A major area in cancer therapy is the search for protective strategies against cisplatin-induced nephrotoxicity. We investigated the protective effect of cilastatin on cisplatin-induced injury to renal proximal tubular cells. Cilastatin is a specific inhibitor of renal dehydrodipeptidase I (DHP-I), which prevents hydrolysis of imipenem and its accumulation in the proximal tubule. Primary cultures of proximal cells were treated with cisplatin (1-30 microM) in the presence or absence of cilastatin (200 microg/ml). Apoptosis and mitochondrial injury were assessed by different techniques. Cisplatin uptake and DNA binding were measured by inductively coupled plasma spectrometry. HeLa cells were used to control the effect of cilastatin on the tumoricidal activity of cisplatin. Cisplatin increased cell death, apoptotic-like morphology, caspase activation, and mitochondrial injury in proximal tubular cells in a dose- and time-dependent way. Concomitant treatment with cilastatin reduced cisplatin-induced changes. Cilastatin also reduced the DNA-bound platinum but did not modify cisplatin-dependent up-regulation of death receptors (Fas) or ligands (tumor necrosis factor alpha, Fas ligand). In contrast, cilastatin did not show any effects on cisplatin-treated HeLa cells. Renal DHP-I was virtually absent in HeLa cells. Cilastatin attenuates cisplatin-induced cell death in proximal tubular cells without reducing the cytotoxic activity of cisplatin in tumor cells. Our findings suggest that the affinity of cilastatin for renal dipeptidase makes this effect specific for proximal tubular cells and may be related to a reduction in intracellular drug accumulation. Therefore, cilastatin administration might represent a novel strategy in the prevention of cisplatin-induced acute renal injury.

Autism Screening in Early Childhood: Discriminating Autism From Other Developmental Concerns.

Early identification of autism, followed by appropriate intervention, has the potential to improve outcomes for autistic individuals. Numerous screening instruments have been developed for children under 3 years of age. Level 1 screeners are used in large-scale screening to detect at-risk children in the general population; Level 2 screeners are concerned with distinguishing children with signs of autism from those with other developmental problems. The focus here is evaluation of Level 2 screeners. However, given the contributions of Level 1 screeners and the necessity to understand how they might interface with Level 2 screeners, we briefly review Level 1 screeners and consider instrument characteristics and system variables that may constrain their effectiveness. The examination of Level 2 screeners focuses on five instruments associated with published evaluations in peer-reviewed journals. Key criteria encompass the traditional indices of test integrity such as test reliability (inter-rater, test-retest) and construct validity, including concurrent and predictive validity, sensitivity (SE), and specificity (SP). These evaluations reveal limitations, including inadequate sample sizes, reliability issues, and limited involvement of independent researchers. Also lacking are comparative test evaluations under standardized conditions, hindering interpretation of differences in discriminative performance across instruments. Practical considerations constraining the use of such instruments-such as the requirements for training in test administration and test administration time-are canvassed. Published Level 2 screener short forms are reviewed and, as a consequence of that evaluation, future directions for assessing the discriminative capacity of items and measures are suggested. Suggested priorities for future research include targeting large and diverse samples to permit robust appraisals of Level 2 items and scales across the 12-36 month age range, a greater focus on precise operationalization of items and response coding to enhance reliability, ongoing exploration of potentially discriminating items at the younger end of the targeted age range, and trying to unravel the complexities of developmental trajectories in autistic infants. Finally, we emphasize the importance of understanding how screening efficacy is dependent on clinicians' and researchers' ability not only to develop screening tests but also to negotiate the complex organizational systems within which screening procedures must be implemented.

Repeat Traffic Offenders Improve Their Performance in Risky Driving Situations and Have Fewer Accidents Following a Mindfulness-Based Intervention.

Risky decision-making is highly influenced by emotions and can lead to fatal consequences. Attempts to reduce risk-taking include the use of mindfulness-based interventions (MBI), which have shown promising results for both emotion regulation (ER) and risk-taking. However, it is still unclear whether improved emotion regulation is the mechanism responsible for reduced risk-taking. In the present study, we explore the effect of a 5-week MBI on risky driving in a group of repeat traffic offenders by comparing them with non-repeat offenders and repeat offenders without training. We evaluated the driving behavior of the participants through a driving simulation, and self-reported emotion regulation, both before and after the intervention. At baseline, poor emotion regulation was related to a more unstable driving behavior, and speeding. The group that received mindfulness training showed improved performance during risky driving situations and had fewer accidents, although their overall driving behavior remained largely unchanged. The observed trend toward improved emotion regulation was not significant. We discuss whether other effects of MBI - such as self-regulation of attention - could underlie the observed reduction in risky driving in the initial stages. Nonetheless, our findings still confirm the close relationship between emotion regulation skills and risky driving.

Dynamics of malaria drug resistance patterns in the Amazon basin region following changes in Peruvian national treatment policy for uncomplicated malaria.

Monitoring changes in the frequencies of drug-resistant and -sensitive genotypes can facilitate in vivo clinical trials to assess the efficacy of drugs before complete failure occurs. Peru changed its national treatment policy for uncomplicated malaria to artesunate (ART)-plus-mefloquine (MQ) combination therapy in the Amazon basin in 2001. We genotyped isolates collected in 1999 and isolates collected in 2006 to 2007 for mutations in the Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes, multidrug resistance gene 1 (Pfmdr-1), the chloroquine (CQ) resistance transporter gene (Pfcrt), and the Ca(2+) ATPase gene (PfATP6); these have been shown to be involved in resistance to sulfadoxine-pyrimethamine (SP), MQ, CQ, and possibly ART, respectively. Microsatellite haplotypes around the Pfdhfr, Pfdhps, Pfcrt, and Pfmdr-1 loci were also determined. There was a significant decline in the highly SP resistant Pfdhfr and Pfdhps genotypes from 1999 to 2006. In contrast, a CQ-resistant Pfcrt genotype increased in frequency during the same period. Among five different Pfmdr-1 allelic forms noted in 1999, two genotypes increased in frequency while one genotype decreased by 2006. We also noted previously undescribed polymorphisms in the PfATP6 gene as well as an increase in the frequency of a deletion mutant during this period. In addition, microsatellite analysis revealed that the resistant Pfdhfr, Pfdhps, and Pfcrt genotypes have each evolved from a single founder haplotype, while Pfmdr-1 genotypes have evolved from at least two independent haplotypes. Importantly, this study demonstrates that the Peruvian triple mutant Pfdhps genotypes are very similar to those found in other parts of South America.

A defined mechanistic correlate of protection against Plasmodium falciparum malaria in non-human primates.

Malaria vaccine design and prioritization has been hindered by the lack of a mechanistic correlate of protection. We previously demonstrated a strong association between protection and merozoite-neutralizing antibody responses following vaccination of non-human primates against Plasmodium falciparum reticulocyte binding protein homolog 5 (PfRH5). Here, we test the mechanism of protection. Using mutant human IgG1 Fc regions engineered not to engage complement or FcR-dependent effector mechanisms, we produce merozoite-neutralizing and non-neutralizing anti-PfRH5 chimeric monoclonal antibodies (mAbs) and perform a passive transfer-P. falciparum challenge study in Aotus nancymaae monkeys. At the highest dose tested, 6/6 animals given the neutralizing PfRH5-binding mAb c2AC7 survive the challenge without treatment, compared to 0/6 animals given non-neutralizing PfRH5-binding mAb c4BA7 and 0/6 animals given an isotype control mAb. Our results address the controversy regarding whether merozoite-neutralizing antibody can cause protection against P. falciparum blood-stage infections, and highlight the quantitative challenge of achieving such protection.

Genetic diversity of vaccine candidate antigens in Plasmodium falciparum isolates from the Amazon basin of Peru.

BACKGROUND: Several of the intended Plasmodium falciparum vaccine candidate antigens are highly polymorphic and could render a vaccine ineffective if their antigenic sites were not represented in the vaccine. In this study, characterization of genetic variability was performed in major B and T-cell epitopes within vaccine candidate antigens in isolates of P. falciparum from Peru. METHODS: DNA sequencing analysis was completed on 139 isolates of P. falciparum collected from endemic areas of the Amazon basin in Loreto, Peru from years 1998 to 2006. Genetic diversity was determined in immunological important regions in circumsporozoite protein (CSP), merozoite surface protein-1 (MSP-1), apical membrane antigen-1 (AMA-1), liver stage antigen-1 (LSA-1) and thrombospondin-related anonymous protein (TRAP). Alleles identified by DNA sequencing were aligned with the vaccine strain 3D7 and DNA polymorphism analysis and FST study-year pairwise comparisons were done using the DnaSP software. Multilocus analysis (MLA) was performed and average of expected heterozygosity was calculated for each loci and haplotype over time. RESULTS: Three different alleles for CSP, seven for MSP-1 Block 2, one for MSP-1 Block 17, three for AMA-1 and for LSA-1 each and one for TRAP were identified. There were 24 different haplotypes in 125 infections with complete locus typing for each gene. CONCLUSION: Characterization of the genetic diversity in Plasmodium isolates from the Amazon Region of Peru showed that P. falciparum T and B cell epitopes in these antigens have polymorphisms more similar to India than to Africa. These findings are helpful in the formulation of a vaccine considering restricted repertoire populations.