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Abstract BackgroundThe substantial increase in smartphone ownership has led to a rise in mobile health (mHealth) app use. Developing tailored features through mHealth apps creates a pathway to address the health care needs of pediatric patients with cancer and their families who have complex care needs. However, few apps are designed specifically to integrate with pediatric cancer care. ObjectiveThis study reports a systematic search and analysis of mHealth apps available on the Apple App (iOS) and Google Play (Android) stores designed for pediatric cancer through a list of features that serve (1) patients, (2) caregivers, or (3) both audiences. MethodsFollowing PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we reviewed apps for pediatric patients with cancer and caregivers available as of January 30, 2024. We searched the Apple App and Google Play stores with a list of keyword combinations focusing on pediatric cancer care. The inclusion criteria were (1) specifically apps targeted toward pediatric patients with cancer, their families, or both; (2) available in either app store; and (3) available in English. Apps were assessed using the Mobile Application Rating Scale (MARS). The MARS is a quality assessment for mHealth apps, including components of engagement, functionality, aesthetics, and informational quality (5-point Likert scale items—1: low and 5: high quality). ResultsIn total, 22 apps were identified and 17 of those apps were available on both platforms. The most popular features (n=12) were resource sharing, symptom tracking, reminders, care team connections, journaling, community support, medication tracking, data visualizations, and appointment tracking. Features and interfaces were designed for caregivers (n=9) more frequently than the patients (n=7) while a subset of apps created options for both users (n=6). A total of 16 apps received positive reviews (mean 4.4, SD 0.59; Min=3.1, Max=5.0). A small subset (n=3) achieved over 5000 downloads; however, the majority (n=15) had fewer than 500. More than half (n=12) of the apps were not available in English. Apps requested access to a range of device functionalities to operate (mean 2.72, SD 3.13; Min=0, Max=10). Out of 22, a total of 17 apps were publicly accessible. The mean MARS scores for the apps ranged from 1.71 (SD 0.75) to 4.33 (SD 0.82). Overall, apps scored high on functionality (mean 3.72, SD 0.54) but low on engagement (mean 3.02, SD 0.93). ConclusionsOur review highlights the promising yet underdeveloped potential of mHealth apps in pediatric oncology care, underscoring the need for more inclusive, comprehensive, and integrative digital health solutions. Future developments should actively involve key stakeholders from the pediatric oncology community, including patients, families, and health care professionals, to ensure the apps meet specific needs while addressing linguistic and cultural barriers.

Abstract Web‐based studies of human dimensions are increasing across environmental and socio‐ecological disciplines. However, the prevalence of fraud threatens research quality. Increased fraud rates should be expected as surveys move progressively more online, motivated by expanding reach, cost savings and/or in response to COVID‐19. Web‐based research must better account for fraud to maintain confidence in findings. Practical diagnostic tools and data quality protocols are required to detect fraud and ensure results quality. Drawing on our experience using an online participatory mapping case study, we discuss methods to detect potentially fraudulent responses—and identify some limitations. We begin by reviewing the current state of knowledge on fraudulent responses or ‘fraudsters’ and its relative absence in environmental and socio‐ecological disciplines. We then describe our research approach, the indicators and variables we used to detect and assess fraud and our decision‐making process to eliminate suspicious responses without jeopardizing research integrity. We found that despite several preventative measures, many fraudulent respondents could provide survey responses and effectively mimicked legitimate respondents at first glance. By assuming each response to be ‘potentially fraudulent’, we determined that the complete screening of each respondent, while time‐consuming, can limit the prevalence of fraud. We also determined that the most common data consistency checks (e.g. duration, trap questions and straight‐liner checks) are unlikely to guarantee valid respondents. If not acknowledged and addressed, fraud has the potential to undermine data integrity, discredit research findings and limit the utility of results for policy. This study contributes to environmental and socio‐ecological research by reviewing existing fraudster literature and using our experience with fraud to provide recommendations for researchers to address this problem. We encourage researchers implementing online qualitative research methods to thoroughly assess and report fraud, when possible, to ensure widespread knowledge of this growing threat. Read the free Plain Language Summary for this article on the Journal blog.

Same-sex sexual behaviour (SSSB) occurs in most animal clades, but published reports are largely concentrated in a few taxa. Thus, there remains a paucity of published reports for most mammalian species. We conducted a cross-sectional expert survey to better understand the underlying reasons for the lack of publications on this topic. Most respondents researched Primates (83.6%, N = 61), while the rest studied Carnivora (6.9%, N = 5), Rodentia (4.1%, N = 3), Artiodactyla (2.7%, N = 2), and Proboscidea (2.7%, N = 2). Most respondents (76.7%, N = 56) had observed SSSB in their study species, but only 48.2% (N = 27) collected data on SSSB, and few (18.5%, N = 5) had published papers on SSSB. Of the unique species identified as engaging in SSSB in the survey, 38.6% (N = 17) have no existing reports of SSSB to the knowledge of the authors. In both the survey questions and freeform responses, most respondents indicated that their lack of data collection or publication on SSSB was because the behaviours were rare, or because it was not a research priority of their lab. No respondents reported discomfort or sociopolitical concerns at their university or field site as a reason for why they did not collect data or publish on SSSB. Multiple logistic regressions were performed to assess whether taxa studied, education level, or identification within the LGBTQ+ community predicted observing, collecting data on, or publishing on SSSB, but none of these variables were significant predictors. These results provide preliminary evidence that SSSB occurs more frequently than what is available in the published record and suggest that this may be due to a publishing bias against anecdotal evidence.

Abstract Despite the availability of highly sensitive polymerase chain reaction (PCR)-based methods, the dearth of remotely deployable diagnostic tools circumvents the early and accurate detection of individuals with post-kala-azar dermal leishmaniasis (PKDL). Here, we evaluate a design-locked loop-mediated isothermal amplification (LAMP) assay to diagnose PKDL. A total of 76 snip-skin samples collected from individuals with probable PKDL (clinical presentation and a positive rK39 rapid diagnostic test (RDT)) were assessed by microscopy, qPCR, and LAMP. An equal number of age and sex-matched healthy controls were included to determine the specificity of the LAMP assay. The LAMP assay with a Qiagen DNA extraction (Q-LAMP) showed a promising sensitivity of 72.37% (95% CI: 60.91–82.01%) for identifying the PKDL cases. LAMP assay sensitivity declined when the DNA was extracted using a boil-spin method. Q-qPCR showed 68.42% (56.75–78.61%) sensitivity, comparable to LAMP and with an excellent agreement, whereas the microscopy exhibited a weak sensitivity of 39.47% (28.44–51.35%). When microscopy and/or qPCR were considered the gold standard, Q-LAMP exhibited an elevated sensitivity of 89.7% (95% CI: 78.83–96.11%) for detection of PKDL cases and Bayesian latent class modeling substantiated the excellent sensitivity of the assay. All healthy controls were found to be negative. Notwithstanding the optimum efficiency of the LAMP assay towards the detection of PKDL cases, further optimization of the boil-spin method is warranted to permit remote use of the assay.

Leprosy reaction (LR) and physical disability (PD) are the most significant clinical complications of leprosy. Herein, we assessed the circulating serum-sTREM-1 and TNF-α levels and their genetic polymorphisms in leprosy. Serum-sTREM-1 and TNF-α levels were measured in leprosy patients (LP) before treatment (n = 51) and from their household contacts (HHCs; n = 25). DNA samples were genotyped using TREM-1 rs2234246 and TNF-α rs1800629-SNP in 210 LPs and 168 endemic controls. The circulating sTREM-1 and TNF-α levels are higher in the multibacillary form. The ROC curve of the serum-sTREM-1 levels was able to differentiate LR from non-LR and PD from non-PD. Similarly, LPs with serum-sTREM-1 levels >210 pg/ml have 3-fold and 6-fold higher chances of presenting with LR and PD, respectively. Genotypes CC+CT of the TREM-1 were associated with leprosy. Taken together, our analyses indicated that sTREM-1 and TNF-α play an important role in the pathogenesis of leprosy and provide promising biomarkers to assist in the diagnosis of leprosy complications.

A rapid, cost-effective, and simple nucleic acid isolation technique coupled with a point-of-need DNA amplification assay is a desirable goal for programmatic use. For diagnosis of Visceral Leishmaniasis (VL), Recombinase Polymerase Amplification (RPA) rapid tests for the detection of Leishmania DNA are versatile and have operational advantages over qPCR. To facilitate the delivery of the RPA test at point-of-need for VL diagnosis, we compared two rapid DNA extraction methods, SwiftDx (SX) and an in-house Boil and Spin (BS) method, coupled with RPA amplification, versus more widely used methods for DNA extraction and amplification, namely Qiagen (Q) kits and qPCR, respectively. A total of 50 confirmed VL patients and 50 controls, matched for age and gender, were recruited from Mymensingh, Bangladesh, a region highly endemic for VL. Blood samples were collected from each participant and DNA was extracted using Q, SX and BS methods. Following DNA extraction, qPCR and RPA assays were performed to detect L. donovani in downstream analysis. No significant differences in sensitivity of the RPA assay were observed between DNA extraction methods, 94.00% (95% CI: 83.45–98.75%), 90% (95% CI: 78.19–96.67%), and 88% (95% CI: 75.69–95.47%) when using Q, SX, and BS, respectively. Similarly, using qPCR, no significant differences in sensitivity were obtained when using Q or SX for DNA extraction, 94.00% (95% CI: 83.45–98.75%) and 92.00% (80.77–97.78%), respectively. It is encouraging that RPA and qPCR showed excellent agreement (k: 0.919–0.980) when different extraction methods were used and that the DNA impurities using BS had no inhibitory effect on the RPA assay. Furthermore, significantly higher DNA yields were obtained using SX and BS versus Q; however, a significantly higher parasite load was detected using qPCR when DNA was extracted using Q versus SX. Considering the cost, execution time, feasibility, and performance of RPA assay, rapid extraction methods such as the Boil and Spin technique appear to have the potential for implementation in resource-limited endemic settings. Further clinical research is warranted prior to broader application.

Abstract Expert elicitation can be valuable for informing decision‐makers on conservation and wildlife management issues. To date, studies eliciting expert opinions have primarily focused on identifying and building consensus on key issues. Nonetheless, there are drawbacks of a strict focus on consensus, and it is important to understand and emphasize dissent, too. This study adopts a dissensus‐based Delphi to understand conflict among dingo experts. Twenty‐eight experts participated in three rounds of investigation. We highlight disagreement on most of the issues explored. In particular, we find that disagreement is underpinned by what we call “conflict over values” and “conflict over evidence.” We also note the broader role played by distrust in influencing such conflicts. Understanding and recognizing the different elements shaping disagreement is critical for informing and improving decision‐making and can also enable critique of dominant paradigms in current practices. We encourage greater reflexivity and open deliberation on these aspects and hope our study will inform similar investigations in other contexts.

Spin-orbit coupling in gate-defined quantum dots in silicon metal-oxide semiconductors provides a promising route for electrical control of spin qubits. Here, the authors demonstrate that intervalley spin–orbit interaction enables fast singlet–triplet qubit rotations in this platform, at frequencies exceeding 200MHz.

Objectives: The democratization of diagnostics is one of the key challenges towards containing the transmission of coronavirus disease 2019 (COVID-19) around the globe. The operational complexities of existing PCR-based methods, including sample transfer to advanced central laboratories with expensive equipment, limit their use in resource-limited settings. However, with the advent of isothermal technologies, the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is possible at decentralized facilities. Methods: In this study, two recombinase-based isothermal techniques, reverse transcription recombinase polymerase amplification (RT-RPA) and reverse transcription recombinase-aided amplification (RT-RAA), were evaluated for the detection of SARS-CoV-2 in clinical samples. A total of 76 real-time reverse transcription PCR (real-time RT-PCR) confirmed COVID-19 cases and 100 negative controls were evaluated to determine the diagnostic performance of the isothermal methods. Results: This investigation revealed equally promising diagnostic accuracy of the two methods, with a sensitivity of 76.32% (95% confidence interval 65.18–85.32%) when the target genes were RdRP and ORF1ab for RT-RPA and RT-RAA, respectively; the combination of N and RdRP in RT-RPA augmented the accuracy of the assay at a sensitivity of 85.53% (95% confidence interval 75.58–92.55%). Furthermore, high specificity was observed for each of the methods, ranging from 94.00% to 98.00% (95% confidence interval 87.40–9.76%). Conclusions: Considering the diagnostic accuracies, both RT-RPA and RT-RAA appear to be suitable assays for point-of-need deployment for the detection of the pathogen, understanding its epidemiology, case management, and curbing transmission.

Background: Several studies suggest that chronic stress may be associated with increased risk of cancer mortality. Our study sought to determine the association between allostatic load (AL), a measure of cumulative stress, and risk of cancer death; and whether these associations varied by race/ethnicity. Methods: We performed retrospective analysis using National Health and Nutrition Examination Survey (NHANES) years 1988 through 2010 linked with the National Death Index through December 31, 2019. We fit Fine & Gray Cox proportional hazards models to estimate sub-distribution hazard ratios (SHRs) of cancer death between high and low AL status (models adjusted for age, sociodemographics, and comorbidities). Results: In fully adjusted models, high AL was associated with a 14% increased risk of cancer death (adjusted (SHR): 1.14, 95% CI: 1.04–1.26) among all participants and a 18% increased risk of cancer death (SHR:1.18, 95% CI: 1.03–1.34) among Non-Hispanic White (NH-White) adults. When further stratified by age (participants aged

Abstract Deleterious effects of habitat loss and fragmentation on biodiversity have been demonstrated in numerous taxa. Although parasites represent a large part of worldwide biodiversity, they are mostly neglected in this context. We investigated the effects of various anthropogenic environmental changes on gastrointestinal parasite infections in four small mammal hosts inhabiting two landscapes of fragmented dry forest in northwestern Madagascar. Coproscopical examinations were performed on 1,418 fecal samples from 903 individuals of two mouse lemur species, Microcebus murinus (n = 199) and M. ravelobensis (n = 421), and two rodent species, the native Eliurus myoxinus (n = 102) and the invasive Rattus rattus (n = 181). Overall, sixteen parasite morphotypes were detected and significant prevalence differences between host species regarding the most common five parasites may be explained by parasite–host specificity or host behavior, diet, and socioecology. Ten host‐ and habitat‐related ecological variables were evaluated by generalized linear mixed modeling for significant impacts on the prevalence of the most abundant gastrointestinal parasites and on gastrointestinal parasite species richness (GPSR). Forest maturation affected homoxenous parasites (direct life cycle) by increasing Lemuricola, but decreasing Enterobiinae gen. sp. prevalence, while habitat fragmentation and vegetation clearance negatively affected the prevalence of parasites with heterogenic environment (i.e., Strongyloides spp.) or heteroxenous (indirect cycle with intermediate host) cycles, and consequently reduced GPSR. Forest edges and forest degradation likely change abiotic conditions which may reduce habitat suitability for soil‐transmitted helminths or required intermediate hosts. The fragility of complex parasite life cycles suggests understudied and potentially severe effects of decreasing habitat quality by fragmentation and degradation on hidden ecological networks that involve parasites. Since parasites can provide indispensable ecological services and ensure stability of ecosystems by modulating animal population dynamics and nutrient pathways, our study underlines the importance of habitat quality and integrity as key aspects of conservation.

Abstract Background Edge effects can influence species composition and community structure as a result of changes in microenvironment and edaphic variables. We investigated effects of habitat edges on vegetation structure, abundance and body mass of one vulnerable Microcebus species in northwestern Madagascar. We trapped mouse lemurs along four 1000-m transects (total of 2424 trap nights) that ran perpendicular to the forest edge. We installed 16 pairs of 20 m2 vegetation plots along each transect and measured nine vegetation parameters. To determine the responses of the vegetation and animals to an increasing distance to the edge, we tested the fit of four alternative mathematical functions (linear, power, logistic and unimodal) to the data and derived the depth of edge influence (DEI) for all parameters. Results Logistic and unimodal functions best explained edge responses of vegetation parameters, and the logistic function performed best for abundance and body mass of M. ravelobensis. The DEI varied between 50 m (no. of seedlings, no. of liana, dbh of large trees [dbh ≥ 10 cm]) and 460 m (tree height of large trees) for the vegetation parameters, whereas it was 340 m for M. ravelobensis abundance and 390 m for body mass, corresponding best to the DEI of small tree [dbh

Abstract Diagnostic testing for M. tuberculosis infection has advanced with QuantiFERON and GeneXpert, but simple cost-effective alternatives for widespread TB screening has remained elusive and purified protein derivative (PPD)-based tuberculin skin testing (TST) remains the most widely used method. PPD-based tests have reduced performance, however, in BCG vaccinees and in individuals with immune deficiencies. We compared the performance of skin testing with the recombinant DPPD protein against that of a standard PPD-based skin test. Our data indicates similar performance of DPPD and PPD (r2 = 0.7689) among HIV-negative, active TB patients, all of whom presented greater than 10 mm induration following administration. In contrast to results demonstrating that PPD induced indurations greater than 5 mm (i.e., the recommended threshold for positive results in this population) in only half (19 of 38) of the HIV positive TB patients, 89.5% (34 of 38) of these participants developed indurations greater than 5 mm when challenged with DPPD. Importantly, none of the patients that were positive following PPD administration were negative following DPPD administration, indicating markedly improved sensitivity of DPPD among HIV-infected individuals. Our data indicate that DPPD has superior performance in skin testing than the current TST standard.

The leishmaniases are a collection of vector-borne parasitic diseases caused by a number of different Leishmania species that are distributed worldwide. Clinical and laboratory research have together revealed several important immune components that control Leishmania infection and indicate the potential of immunization to prevent leishmaniasis. In this review we introduce previous and ongoing experimental research efforts to develop vaccines against Leishmania species. First, second and third generation vaccine strategies that have been proposed to counter cutaneous and visceral leishmaniasis (CL and VL, respectively) are summarized. One of the major bottlenecks in development is the transition from results in animal model studies to humans, and we highlight that although American tegumentary leishmaniasis (ATL; New World CL) can progress to destructive and disfiguring mucosal lesions, most research has been conducted using mouse models and Old World Leishmania species. We conclude that assessment of vaccine candidates in ATL settings therefore appears merited.

Leishmania parasites cause a variety of discrete clinical diseases that present in regions where their specific sand fly vectors sustain transmission. Clinical and laboratory research indicate the potential of immunization to prevent leishmaniasis and a wide array of vaccine candidates have been proposed. Unfortunately, multiple factors have precluded advancement of more than a few Leishmania targeting vaccines to clinical trial. The recent maturation of RNA vaccines into licensed products in the context of COVID-19 indicates the likelihood of broader use of the technology. Herein, we discuss the potential benefits provided by RNA technology as an approach to address the bottlenecks encountered for Leishmania vaccines. Further, we outline a variety of strategies that could be used to more efficiently evaluate Leishmania vaccine efficacy, including controlled human infection models and initial use in a therapeutic setting, that could prioritize candidates before evaluation in larger, longer and more complicated field trials.

Abstract Background Leprosy is is still considered a public health issue and in Colombia 7–10% of new cases are found in children, indicating both active transmission and social inequality. We hypothesized that circulating antibodies against Natural Octyl Disaccharide-Leprosy IDRI Diagnostic (NDO-LID) (a combination of Mycobacterium leprae antigens) could reveal the social and environmental aspects associated with higher frequencies of M. leprae infection among children and adolescents in Colombia. Methods An observational cross-sectional study was conducted involving sampling from 82 children and adolescents (younger than 18 years of age) who had household contact with index leprosy patients diagnosed in the last 5 years. Data were analyzed through bivariate analysis made by applying a Pearson x2 test for qualitative variables, while quantitative variables, depending on their distribution, were analyzed using either a Student’s t-test or Mann-Whitney U test. Multivariate analysis was performed using a multiple regression and binomial logistic approach. Results A bivariate analysis demonstrated that antibody titers against NDO-LID were significantly greater in children and adolescents with a low socioeconomic status that had: lived in vulnerable areas of the UAChR shared region; eaten armadillo meat; exposure of over 10 years to an index case and; not received BCG immunization. Moreover, a multivariate analysis showed that residing in the UAChR region has a strong association with a greater possibility of M. leprae infection. Conclusions M. leprae transmission persists among young Colombians, and this is associated with social and environmental conditions. An intensification of efforts to identify new leprosy cases in vulnerable and forgotten populations where M. leprae transmission continues therefore appears necessary.

With reduced prevalence of visceral leishmaniasis (VL) in the Indian subcontinent (ISC), direct and field deployable diagnostic tests are needed to implement an effective diagnostic and surveillance algorithm for post-elimination VL control. In this regard, here we investigated the diagnostic efficacies of a loop-mediated isothermal amplification (LAMP) assay (Loopamp™ Leishmania Detection Kit, Eiken Chemical CO., Ltd, Japan), a real-time quantitative PCR assay (qPCR) and the Leishmania antigen ELISA (CLIN-TECH, UK) with different sampling techniques and evaluated their prospect to incorporate into post-elimination VL control strategies. Eighty clinically and rK39 rapid diagnostic test confirmed VL cases and 80 endemic healthy controls were enrolled in the study. Peripheral blood and dried blood spots (DBS) were collected from all the participants at the time of diagnosis. DNA was extracted from whole blood (WB) and DBS via silica columns (QIAGEN) and boil & spin (B&S) methods and tested with qPCR and Loopamp. Urine was collected from all participants at the time of diagnosis and was directly subjected to the Leishmania antigen ELISA. 41 patients were followed up and urine samples were collected at day 30 and day 180 after treatment and ELISA was performed. The sensitivities of the Loopamp-WB(B&S) and Loopamp-WB(QIA) were 96.2% (95% CI 89·43-99·22) and 95% (95% CI 87·69-98·62) respectively. The sensitivity of Loopamp-DBS(QIA) was 85% (95% CI 75·26- 92·00). The sensitivities of the qPCR-WB(QIA) and qPCR-DBS(QIA) were 93.8% (95% CI 86·01-97·94) and 72.5% (95% CI 61·38-81·90) respectively. The specificity of all molecular assays was 100%. The sensitivity and specificity of the Leishmania antigen ELISA were 97.5% (95% CI 91·47-99·70) and 91.95% (95% CI 84·12-96·70) respectively. The Leishmania antigen ELISA depicted clinical cure at day 180 in all the followed-up cases. Efficacy and sustainability identify the Loopamp-WB(B&S) and the Leishmania antigen ELISA as promising and minimally invasive VL diagnostic tools to support VL diagnostic and surveillance activities respectively in the post-elimination era.

In many freshwater habitats, green algae form intracellular symbioses with a variety of heterotrophic host taxa including several species of freshwater sponge. These sponges perform important ecological roles in their habitats, and the poriferan:green algae partnerships offers unique opportunities to study the evolutionary origins and ecological persistence of endosymbioses. We examined the association between Ephydatia muelleri and its chlorophyte partner to identify features of host cellular and genetic responses to the presence of intracellular algal partners. Chlorella-like green algal symbionts were isolated from field-collected adult E. muelleri tissue harboring algae. The sponge-derived algae were successfully cultured and subsequently used to reinfect aposymbiotic E. muelleri tissue. We used confocal microscopy to follow the fate of the sponge-derived algae after inoculating algae-free E. muelleri grown from gemmules to show temporal patterns of symbiont location within host tissue. We also infected aposymbiotic E. muelleri with sponge-derived algae, and performed RNASeq to study differential expression patterns in the host relative to symbiotic states. We compare and contrast our findings with work in other systems (e.g., endosymbiotic Hydra) to explore possible conserved evolutionary pathways that may lead to stable mutualistic endosymbioses. Our work demonstrates that freshwater sponges offer many tractable qualities to study features of intracellular occupancy and thus meet criteria desired for a model system.

We use the magnitude and centroid period of Rayleigh wave along with the amplitude of fluctuations of water level in a well to calculate effective porosity of a karst aquifer at the site scale. The radial and vertical displacements of Rayleigh wave are first related to the confining pressure of rock, which is then related to fluid pressure via the Gassmann equation. Three seismograms recorded at station 633A of the USARRAY and the induced responses of Well J-17 in the Edwards Aquifer (Texas) allow the calculation of an effective porosity between 17.0 and 24.4 percent, the average of which is close to the total porosity of core samples determined by geophysical well logs. This paper provides an innovative method to measure effective porosity in aquifers. Because of the long wavelengths of Rayleigh wave, the interdisciplinary approach is advantageous in that the resulting effective porosity is at the site scale which includes large conduits or voids.

The colonic mucus layer, comprised of highly O-glycosylated mucins, is vital to mediating host-gut microbiota interactions, yet the impact of dietary changes on colonic mucin O-glycosylation and its associations with the gut microbiota remains unexplored. Here, we used an array of omics techniques including glycomics to examine the effect of dietary fiber consumption on the gut microbiota, colonic mucin O-glycosylation and host physiology of high-fat diet-fed C57BL/6J mice. The high-fat diet group had significantly impaired glucose tolerance and altered liver proteome, gut microbiota composition, and short-chain fatty acid production compared to normal chow diet group. While dietary fiber inclusion did not reverse all high fat-induced modifications, it resulted in specific changes, including an increase in the relative abundance of bacterial families with known fiber digesters and a higher propionate concentration. Conversely, colonic mucin O-glycosylation remained similar between the normal chow and high-fat diet groups, while dietary fiber intervention resulted in major alterations in O-glycosylation. Correlation network analysis revealed previously undescribed associations between specific bacteria and mucin glycan structures. For example, the relative abundance of the bacterium Parabacteroides distasonis positively correlated with glycan structures containing one terminal fucose and correlated negatively with glycans containing two terminal fucose residues or with both an N-acetylneuraminic acid and a sulfate residue. This is the first comprehensive report of the impact of dietary fiber on the colonic mucin O-glycosylation and associations of these mucosal glycans with specific gut bacteria.

There is little evidence that current control strategies for canine leishmaniosis (CanL), the veterinary disease caused by L. infantum infection, are having a positive impact. This is of critical importance because dogs are a primary reservoir for L. infantum and a significant source of parasite transmission to humans. Drugs intended primarily for human use are prohibited for the treatment of CanL because of concerns over the propagation of resistant parasites. Although allopurinol effectively decreases parasite burden in CanL the treatment needs to be maintained for life. We hypothesized that during the allopurinol-induced parasite reduction dogs may become capable of developing a more robust immune response that may permit more effective control of parasites. To test this, we investigated the clinical and parasitological impact of short-term treatment with allopurinol, either alone or in combination with a defined subunit vaccine, on dogs naturally infected with L. infantum. A total of 28 dogs were distributed as follows: untreated; oral allopurinol alone (20 mg/kg, once each day for 90 days); or allopurinol with immunization with the Leish-F2 antigen formulated with the Toll-like receptor (TLR) 4 agonist Second generation Lipid Adjuvant (SLA) in stable emulsion (SE; SLA-SE). Dogs that did not receive treatment had a progressive decline in their clinical condition and an increase in their infection levels, while treatment with allopurinol alone alleviated the clinical symptoms of CanL but did not generate sustained reduction in parasites. Concomitant immunization with Leish-F2 + SLA-SE, however, improved clinical condition while also providing long-term clearance of L. infantum from lymphoid tissues and systemic organs. These results have important implications for both the management of CanL and for limiting L. infantum transmission to humans. Keywords: Canine visceral leishmaniasis, Vaccine, Parasite, Drug, Clinical signs

Kevin

Kevin

As the performance of silicon-based qubits has improved, there has been increasing focus on developing designs that are compatible with industrial processes. Here, Jock et al. exploit spin-orbit coupling to demonstrate full, all-electrical control of a metal-oxide-semiconductor electron spin qubit.

In recent years, vaccine development using ribonucleic acid (RNA) has become the most promising and studied approach to produce safe and effective new vaccines, not only for prophylaxis but also as a treatment. The use of messenger RNA (mRNA) as an immunogenic has several advantages to vaccine development compared to other platforms, such as lower coast, the absence of cell cultures, and the possibility to combine different targets. During the COVID-19 pandemic, the use of mRNA as a vaccine became more relevant; two out of the four most widely applied vaccines against COVID-19 in the world are based on this platform. However, even though it presents advantages for vaccine application, mRNA technology faces several pivotal challenges to improve mRNA stability, delivery, and the potential to generate the related protein needed to induce a humoral- and T-cell-mediated immune response. The application of mRNA to vaccine development emerged as a powerful tool to fight against cancer and non-infectious and infectious diseases, for example, and represents a relevant research field for future decades. Based on these advantages, this review emphasizes mRNA and self-amplifying RNA (saRNA) for vaccine development, mainly to fight against COVID-19, together with the challenges related to this approach.

In silicon, quantum information can be stored in donors or quantum dots, each with its advantages and limitations—particularly in terms of fabrication. Here the authors coherently couple a phosphorous donor’s electron spin to a quantum dot, encoding information in the hybrid two-electron system’s state.

Leishmaniasis: Improved vaccine candidate demonstrates protection A research collaboration between the United States and Bangladesh has improved its own vaccine candidate and demonstrated it to be effective. The vaccine’s target, visceral leishmaniasis, is a deadly parasitic disease transmitted via the bites of sandflies. The collaboration, led by Steven Reed of the United States’ Infectious Disease Research Institute, previously developed a vaccine that presents two parasite-derived proteins (antigens) to a host’s immune system, allowing it to build a defense. The new vaccine candidate contains three antigens and has shown to confer disease resistance to hamsters who were subsequently exposed to infected sandflies. This is the first time a vaccine for visceral leishmaniasis has stood up in tests where the host has been infected through natural methods, which inspires confidence in the vaccine’s capacity to work in the wild.

Brain microvascular endothelial cells (BMECs) are an essential component of the blood-brain barrier (BBB) that shields the brain against toxins and immune cells. While BBB dysfunction exists in neurological disorders, including Huntington’s disease (HD), it is not known if BMECs themselves are functionally compromised to promote BBB dysfunction. Further, the underlying mechanisms of BBB dysfunction remain elusive given limitations with mouse models and post-mortem tissue to identify primary deficits. We undertook a transcriptome and functional analysis of human induced pluripotent stem cell (iPSC)-derived BMECs (iBMEC) from HD patients or unaffected controls. We demonstrate that HD iBMECs have intrinsic abnormalities in angiogenesis and barrier properties, as well as in signaling pathways governing these processes. Thus, our findings provide an iPSC-derived BBB model for a neurodegenerative disease and demonstrate autonomous neurovascular deficits that may underlie HD pathology with implications for therapeutics and drug delivery.

IntroductionTo sustain the achievement of kala-azar elimination program (KEP), early detection and treatment of the visceral leishmaniasis (VL) cases and associated modalities such as treatment failure (TF), relapse VL (RVL), and Post-kala-azar dermal leishmaniasis (PKDL) is the cornerstone. A predictive biomarker for VL development and related complications could also play a crucial role in curtailing disease incidence and transmission. Investigations to find a biomarker with prospective capabilities are, however, scarce. Using samples and known clinical outcomes generated within two previous longitudinal cohort studies, we aimed to determine if fluctuations in serum anti-rK39 antibody levels could provide such predictive value.Materials and MethodsSerum samples collected at four different time points (Baseline, 12, 18, and 24 months) from 16 patients who had developed VL within the monitoring period and 15 of their asymptomatic healthy controls counterparts were investigated. To investigate potential prediction of VL related complications, serum samples of 32 PKDL, 10 RVL, 07 TF, and 38 cured VL from a single dose AmBisome trial were analyzed. Of this second panel, all patients were monitored for 5 years and sera were collected at four time points (Baseline then 1, 6, and 12 months after treatment). The level of anti-rK39 antibodies in archived samples was measured by a semi-quantitative ELISA.ResultsThe mean antibody level was significantly higher in VL patients compared to their asymptomatic healthy counterparts at each time point. Likewise, we observed a trend toward elevations in antibody levels for PKDL, RVL, TF relative to the reducing levels observed in cured VL. Receiver operating characteristic (ROC) analysis found a promising predictive power of rK39 antibody levels to reveal progression from asymptomatic Leishmania donovani infection stage to VL, defined as 87.5% sensitive and 95% specific. Following treatment, rk39 antibody notably showed 100% sensitivity and 95% specificity in predicting TF.ConclusionOur data indicate that the relative quantity of serum anti-rK39 antibody has promise within either a predictive or prognostic algorithm for VL and VL-related modalities. These could enable VL control programs to implement more effective measures to eliminate the disease. Further research is, however, imperative to standardize the rK39 antibody ELISA between sites prior to broader use.

Canonical and non-canonical Wnt signaling, as well as the Pax/Six gene network, are involved in patterning the freshwater sponge aquiferous system. Using computational approaches to identify transcription factor binding motifs in a freshwater sponge genome, we located putative PaxB binding sites near a Secreted Frizzled Related Protein (SFRP) gene in Ephydatia muelleri. EmSFRP is expressed throughout development, but with highest levels in juvenile sponges. In situ hybridization and antibody staining show EmSFRP expression throughout the pinacoderm and choanoderm in a subpopulation of amoeboid cells that may be differentiating archeocytes. Knockdown of EmSFRP leads to ectopic oscula formation during development, suggesting that EmSFRP acts as an antagonist of Wnt signaling in E. muelleri. Our findings support a hypothesis that regulation of the Wnt pathway by the Pax/Six network as well as the role of Wnt signaling in body plan morphogenesis was established before sponges diverged from the rest of the metazoans.

BACKGROUND:Leprosy is a treatable infectious disease caused by Mycobacterium leprae. However, there is additional morbidity from leprosy-associated pathologic immune reactions, reversal reaction (RR) and erythema nodosum leprosum (ENL), which occur in 1 in 3 people with leprosy, even with effective treatment of M. leprae. There is currently no predictive marker in use to indicate which people with leprosy will develop these debilitating immune reactions. Our peripheral blood mononuclear cell (PBMC) transcriptome analysis revealed that activation of the classical complement pathway is common to both RR and ENL. Additionally, differential expression of immunoglobulin receptors and B cell receptors during RR and ENL support a role for the antibody-mediated immune response during both RR and ENL. In this study, we investigated B-cell immunophenotypes, total and M. leprae-specific antibodies, and complement levels in leprosy patients with and without RR or ENL. The objective was to determine the role of these immune mediators in pathogenesis and assess their potential as biomarkers of risk for immune reactions in people with leprosy. METHODOLOGY/FINDINGS:We followed newly diagnosed leprosy cases (n = 96) for two years for development of RR or ENL. They were compared with active RR (n = 35), active ENL (n = 29), and healthy household contacts (n = 14). People with leprosy who subsequently developed ENL had increased IgM, IgG1, and C3d-associated immune complexes with decreased complement 4 (C4) at leprosy diagnosis. People who developed RR also had decreased C4 at leprosy diagnosis. Additionally, elevated anti-M. leprae antibody levels were associated with subsequent RR or ENL. CONCLUSIONS:Differential co-receptor expression and immunoglobulin levels before and during immune reactions intimate a central role for humoral immunity in RR and ENL. Decreased C4 and elevated anti-M. leprae antibodies in people with new diagnosis of leprosy may be risk factors for subsequent development of leprosy immune reactions.

Leprosy is a chronic disease caused by M. leprae infection that can cause severe neurological complications and physical disabilities. A leprosy-specific vaccine would be an important component within control programs but is still lacking. Given that multifunctional CD4 T cells [i.e., those capable of simultaneously secreting combinations of interferon (IFN)-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)] have now been implicated in the protective response to several infections, we tested the hypothesis if a recombinant M. leprae antigen-specific multifunctional T cells differed between leprosy patients and their healthy contacts. We used whole blood assays and peripheral blood mononuclear cells to characterize the antigen-specific T cell responses of 39 paucibacillary (PB) and 17 multibacillary (MB) leprosy patients and 31 healthy household contacts (HHC). Cells were incubated with either crude mycobacterial extracts (M. leprae cell sonicate–MLCS) and purified protein derivative (PPD) or recombinant ML2028 protein, the homolog of M. tuberculosis Ag85B. Multiplex assay revealed antigen-specific production of IFN-γ and IL-2 from cells of HHC and PB, confirming a Th1 bias within these individuals. Multiparameter flow cytometry then revealed that the population of multifunctional ML2028-specific T cells observed in HHC was larger than that observed in PB patients. Taken together, our data suggest that these multifunctional antigen-specific T cells provide a more effective response against M. leprae infection that prevents the development of leprosy. These data further our understanding of M. leprae infection/leprosy and are instructive for vaccine development.

para-Aminosalicylic acid (PAS) is a second-line anti-tubercular drug that is used for the treatment of drug-resistant tuberculosis (TB). PAS efficacy in the treatment of TB is limited by its lower potency against Mycobacterium tuberculosis relative to many other drugs in the TB treatment arsenal. It is known that intrinsic metabolites, such as, para-aminobenzoic acid (PABA) and methionine, antagonize PAS and structurally related anti-folate drugs. While the basis for PABA-mediated antagonism of anti-folates is understood, the mechanism for methionine-based antagonism remains undefined. In the present study, we used both targeted and untargeted approaches to identify factors associated with methionine-mediated antagonism of PAS activity. We found that synthesis of folate precursors as well as a putative amino acid transporter, designated MetM, play crucial roles in this process. Disruption of metM by transposon insertion resulted in a ≥30-fold decrease in uptake of methionine in M. bovis BCG, indicating that metM is the major facilitator of methionine transport. We also discovered that intracellular biotin confers intrinsic PAS resistance in a methionine-independent manner. Collectively, our results demonstrate that methionine-mediated antagonism of anti-folate drugs occurs through sustained production of folate precursors.

Abstract: An integrative literature review was conducted to synthesize available publications regarding the potential use of serological tests in leprosy programs. We searched the databases Literatura Latino-Americana e do Caribe em Ciências da Saúde, Índice Bibliográfico Espanhol em Ciências da Saúde, Acervo da Biblioteca da Organização Pan-Americana da Saúde, Medical Literature Analysis and Retrieval System Online, Hanseníase, National Library of Medicine, Scopus, Ovid, Cinahl, and Web of Science for articles investigating the use of serological tests for antibodies against phenolic glycolipid-I (PGL-I), ML0405, ML2331, leprosy IDRI diagnostic-1 (LID-1), and natural disaccharide octyl-leprosy IDRI diagnostic-1 (NDO-LID). From an initial pool of 3.514 articles, 40 full-length articles fulfilled our inclusion criteria. Based on these papers, we concluded that these antibodies can be used to assist in diagnosing leprosy, detecting neuritis, monitoring therapeutic efficacy, and monitoring household contacts or at-risk populations in leprosy-endemic areas. Thus, available data suggest that serological tests could contribute substantially to leprosy management.

Nine-banded armadillos (Dasypus novemcinctus) are naturally infected with Mycobacterium leprae and have been implicated in zoonotic transmission of leprosy. Early studies found this disease mainly in Texas and Louisiana, but armadillos in the southeastern United States appeared to be free of infection. We screened 645 armadillos from 8 locations in the southeastern United States not known to harbor enzootic leprosy for M. leprae DNA and antibodies. We found M. leprae–infected armadillos at each location, and 106 (16.4%) animals had serologic/PCR evidence of infection. Using single-nucleotide polymorphism variable number tandem repeat genotyping/genome sequencing, we detected M. leprae genotype 3I-2-v1 among 35 armadillos. Seven armadillos harbored a newly identified genotype (3I-2-v15). In comparison, 52 human patients from the same region were infected with 31 M. leprae types. However, 42.3% (22/52) of patients were infected with 1 of the 2 M. leprae genotype strains associated with armadillos. The geographic range and complexity of zoonotic leprosy is expanding.

This paper demonstrates the first single optical fibre tip probe for concurrent detection of both hydrogen peroxide (H2O2) concentration and pH of a solution. The sensor is constructed by embedding two fluorophores: carboxyperoxyfluor-1 (CPF1) and seminaphtharhodafluor-2 (SNARF2) within a polymer matrix located on the tip of the optical fibre. The functionalised fibre probe reproducibly measures pH, and is able to accurately detect H2O2 over a biologically relevant concentration range. This sensor offers potential for non-invasive detection of pH and H2O2 in biological environments using a single optical fibre.

Leprosy inflammatory episodes [type 1 (T1R) and type 2 (T2R) reactions] represent the major cause of irreversible nerve damage. Leprosy serology is known to be influenced by the patient’s bacterial index (BI) with higher positivity in multibacillary patients (MB) and specific multidrug therapy (MDT) reduces antibody production. This study evaluated by ELISA antibody responses to leprosy Infectious Disease Research Institute diagnostic-1 (LID-1) fusion protein and phenolic glycolipid I (PGL-I) in 100 paired serum samples of 50 MB patients collected in the presence/absence of reactions and in nonreactional patients before/after MDT. Patients who presented T2R had a median BI of 3+, while MB patients with T1R and nonreactional patients had median BI of 2.5+ (p > 0.05). Anti-LID-1 and anti-PGL-I antibodies declined in patients diagnosed during T1R (p < 0.05). Anti-LID-1 levels waned in MB with T2R at diagnosis and nonreactional MB patients (p < 0.05). Higher anti-LID-1 levels were seen in patients with T2R at diagnosis (vs. patients with T1R at diagnosis, p = 0.008; vs. nonreactional patients, p = 0.020) and in patients with T2R during MDT (vs. nonreactional MB, p = 0.020). In MB patients, high and persistent anti-LID-1 antibody levels might be a useful tool for clinicians to predict which patients are more susceptible to develop leprosy T2R.

To detect Post-kala-azar leishmaniasis (PKDL) cases, several molecular methods with promising diagnostic efficacy have been developed that involve complicated and expensive DNA extraction methods, thus limiting their application in resource-poor settings. As an alternative, we evaluated two rapid DNA extraction methods and determined their impact on the detection of the parasite DNA using our newly developed recombinase polymerase amplification (RPA) assay. Skin samples were collected from suspected PKDL cases following their diagnosis through national guidelines. The extracted DNA from three skin biopsy samples using three different extraction methods was subjected to RPA and qPCR. The qPCR and RPA assays exhibited highest sensitivities when reference DNA extraction method using Qiagen (Q) kit was followed. In contrast, the sensitivity of the RPA assay dropped to 76.7% and 63.3%, respectively, when the boil & spin (B&S) and SpeedXtract (SE) rapid extraction methods were performed. Despite this compromised sensitivity, the B&S-RPA technique yielded an excellent agreement with both Q-qPCR (k = 0.828) and Q-RPA (k = 0.831) techniques. As expected, the reference DNA extraction method was found to be superior in terms of diagnostic efficacy. Finally, to apply the rapid DNA extraction methods in resource-constrained settings, further methodological refinement is warranted to improve DNA yield and purity through rigorous experiments.

The rapid generation of strong T cell responses is highly desirable and viral vectors can have potent CD8+ T cell-inducing activity. Immunity to leishmaniasis requires selective T cell responses, with immunization schemes that raise either CD4 or CD8 T cell responses being protective in small animal models. We have defined the leishmaniasis vaccine candidate recombinant fusion antigens, LEISH-F2 and LEISH-F3+, that when formulated in a stable emulsion with a Toll-like receptor (TLR) 4 agonist, induce protective CD4+ T cell responses in animal models as well as providing therapeutic efficacy in canine leishmaniasis and in clinical trials in leishmaniasis patients. We used the genetic sequences of these validated vaccine antigens to design RNA vaccine constructs. Immunization of mice with the RNA replicons induced potent, local innate responses that were surprisingly independent of TLR7 and activated antigen-presenting cells (APC) to prime for extremely potent antigen-specific T helper 1 type responses upon heterologous boosting with either of the subunit vaccines (recombinant antigen with second generation glucopyranosyl lipid A in stable oil-in-water emulsion; SLA-SE). Inclusion of RNA in the immunization schedule also generated MHCI-restricted T cell responses. Immunization with LEISH-F2-expressing RNA vaccine followed later by subunit vaccine afforded protection against challenge with Leishmania donovani. Together, these data indicate the utility of heterologous prime-boost immunization schemes for the induction of potent antigen-specific CD4 and CD8 T cell responses for protection against intracellular pathogens.

There is growing public interest in the use of fiber supplements as a way of increasing dietary fiber intake and potentially improving the gut microbiota composition and digestive health. However, currently there is limited research into the effects of commercially available fiber supplements on the gut microbiota. Here we used an in vitro human digestive and gut microbiota model system to investigate the effect of three commercial fiber products; NutriKane™, Benefiber® and Psyllium husk (Macro) on the adult gut microbiota. The 16S rRNA gene amplicon sequencing results showed dramatic fiber-dependent changes in the gut microbiota structure and composition. Specific bacterial OTUs within the families Bacteroidaceae, Porphyromonadaceae, Ruminococcaceae, Lachnospiraceae, and Bifidobacteriaceae showed an increase in the relative abundances in the presence of one or more fiber product(s), while Enterobacteriaceae and Pseudomonadaceae showed a reduction in the relative abundances upon addition of all fiber treatments compared to the no added fiber control. Fiber-specific increases in SCFA concentrations showed correlation with the relative abundance of potential SCFA-producing gut bacteria. The chemical composition, antioxidant potential and polyphenolic content profiles of each fiber product were determined and found to be highly variable. Observed product-specific variations could be linked to differences in the chemical composition of the fiber products. The general nature of the fiber-dependent impact was relatively consistent across the individuals, which may demonstrate the potential of the products to alter the gut microbiota in a similar, and predictable direction, despite variability in the starting composition of the individual gut microbiota.

BACKGROUND Leprosy remains a health problem in many countries, with difficulties in diagnosis resulting in delayed treatment and more severe disabilities. Antibodies against several Mycobacterium leprae antigens have, however, shown value as diagnostic and/or prognostic markers. OBJECTIVES The objective of this study was to evaluate serum immunoglobulin (Ig) IgM and IgG subclass reactivity against three M. leprae specific antigens: NDO-HSA, a conjugate formed by natural octyl disaccharide bound to human serum albumin; LID-1, the fusion protein product of the ml0405 and ml2331 genes; and NDO-LID, a combination of LID-1 and NDO. METHODS Sera from healthy controls, paucibacillary (PB) and multibacillary (MB) leprosy patients, and their respective household contacts, were evaluated for the presence of antigen-specific IgM, IgG, and IgG subclass antibodies by enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity of each ELISA were evaluated by receiver operating characteristic (ROC) curve analysis. FINDINGS Our data confirm that serum IgM antibodies against NDO-HSA and IgG antibodies against LID-1, as well as IgG/M antibodies against NDO-LID, are markedly increased in MB patients. For the first time, our data reveal a selective increase in IgG1 and IgG3 antibodies against LID-1 and NDO-LID in MB patients, demonstrating that these antibody isotypes are suitable for differentiation between MB and PB patients. ROC curve analysis indicates an improved capacity for diagnosing MB leprosy patients using the detection of IgG antibodies, particularly the IgG1 isotype, specific to LID-1 and NDO-LID over the performance levels attained with NDO-HSA. CONCLUSIONS Our findings indicate that serological tests based on the detection of antigen-specific IgG1 antibodies are a useful tool to differentiate MB from PB patients, and indicate the enhanced performance of the LID-1 and NDO-LID antigens in the serodiagnosis of leprosy.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease that affects children and adolescents as well as adults. The etiology has not been established. While many pediatricians and other health-care providers are aware of ME/CFS, they often lack essential knowledge that is necessary for diagnosis and treatment. Many young patients experience symptoms for years before receiving a diagnosis. This primer, written by the International Writing Group for Pediatric ME/CFS, provides information necessary to understand, diagnose, and manage the symptoms of ME/CFS in children and adolescents. ME/CFS is characterized by overwhelming fatigue with a substantial loss of physical and mental stamina. Cardinal features are malaise and a worsening of symptoms following minimal physical or mental exertion. These post-exertional symptoms can persist for hours, days, or weeks and are not relieved by rest or sleep. Other symptoms include cognitive problems, unrefreshing or disturbed sleep, generalized or localized pain, lightheadedness, and additional symptoms in multiple organ systems. While some young patients can attend school, on a full or part-time basis, many others are wheelchair dependent, housebound, or bedbound. Prevalence estimates for pediatric ME/CFS vary from 0.1 to 0.5%. Because there is no diagnostic test for ME/CFS, diagnosis is purely clinical, based on the history and the exclusion of other fatiguing illnesses by physical examination and medical testing. Co-existing medical conditions including orthostatic intolerance (OI) are common. Successful management is based on determining the optimum balance of rest and activity to help prevent post-exertional symptom worsening. Medications are helpful to treat pain, insomnia, OI and other symptoms. The published literature on ME/CFS and specifically that describing the diagnosis and management of pediatric ME/CFS is very limited. Where published studies are lacking, recommendations are based on the clinical observations and practices of the authors.