Routine Conditions Research Articles

Developing Problematic Performance Value Scores: Binding Routine Activity Performance, Environmental Barriers, and Health Conditions.

Community design features, such as sidewalks and street crossings, present significant challenges for individuals with disabilities, hindering their physical performance and social integration. However, limited research has been conducted on the application of Universal Design (UD) to address these challenges, particularly concerning specific demographic groups and population cohorts. Understanding the influence of environmental features on physical performance is crucial for developing inclusive solutions like UD, which can enhance usability and social integration across diverse populations. This study aims to bridge this gap by investigating the complex relationships between environmental barriers, health conditions, and routine activity performance. An index was developed to evaluate users' UD performance based on functional capacity, providing scientifically rigorous and objectively measured evidence of UD effectiveness in creating inclusive built environments. Using data from the Problematic Activities Survey (PAS) conducted in the U.S., Canada, and Australia and targeting individuals with and without functional limitations, multinomial logit models were employed to estimate the probabilities of encountering performance problems. This analysis led to the development of the Problematic Performance Value (PPV) score. The results demonstrated significant disparities in PPVs across various health conditions, particularly concerning curb ramps. Individuals facing mobility issues in their legs/feet, arms/hands, or back/neck encounter more pronounced challenges, especially when curb ramps lack proper design elements. Similarly, individuals with vision impairments face heightened difficulties with traffic signals, particularly due to issues with audible signal systems. These findings underscore the importance of addressing micro-level environmental challenges to accommodate individuals with varying functional capacities effectively. By providing insights into the most problematic daily activities encountered by diverse populations, the PPV score serves as a valuable indicator for guiding environmental design improvements and promoting equitable space usage. This can be used to guide improved UD solutions and decide areas of concentration by providing generalized information on specific environmental features that contribute to user performance.

Whole Genome Sequencing of Mycobacterium tuberculosis under routine conditions in a high-burden area of multidrug-resistant tuberculosis in Peru.

Whole Genome Sequencing (WGS) is a promising tool in the global fight against tuberculosis (TB). The aim of this study was to evaluate the use of WGS in routine conditions for detection of drug resistance markers and transmission clusters in a multidrug-resistant TB hot-spot area in Peru. For this, 140 drug-resistant Mycobacterium tuberculosis strains from Lima and Callao were prospectively selected and processed through routine (GenoType MTBDRsl and BACTEC MGIT) and WGS workflows, simultaneously. Resistance was determined in accordance with the World Health Organization mutation catalogue. Agreements between WGS and BACTEC results were calculated for rifampicin, isoniazid, pyrazinamide, moxifloxacin, levofloxacin, amikacin and capreomycin. Transmission clusters were determined using different cut-off values of Single Nucleotide Polymorphism differences. 100% (140/140) of strains had valid WGS results for 13 anti-TB drugs. However, the availability of final, definitive phenotypic BACTEC MGIT results varied by drug with 10-17% of invalid results for the seven compared drugs. The median time to obtain results of WGS for the complete set of drugs was 11.5 days, compared to 28.6-52.6 days for the routine workflow. Overall categorical agreement by WGS and BACTEC MGIT for the compared drugs was 96.5%. Kappa index was good (0.65≤k≤1.00), except for moxifloxacin, but the sensitivity and specificity values were high for all cases. 97.9% (137/140) of strains were characterized with only one sublineage (134 belonging to "lineage 4" and 3 to "lineage 2"), and 2.1% (3/140) were mixed strains presenting two different sublineages. Clustering rates of 3.6% (5/140), 17.9% (25/140) and 22.1% (31/140) were obtained for 5, 10 and 12 SNP cut-off values, respectively. In conclusion, routine WGS has a high diagnostic accuracy to detect resistance against key current anti-TB drugs, allowing results to be obtained through a single analysis and helping to cut quickly the chain of transmission of drug-resistant TB in Peru.

Impact of seasonal malaria chemoprevention based on the number of medicines doses received on malaria burden among children aged 3-59 months in Nigeria: A propensity score-matched analysis.

Seasonal malaria chemoprevention using sulfadoxine-pyrimethamine plus amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine on Day 1 and amodiaquine on both Day 2 and Day 3) is delivered to children aged 3-59 months in areas of highly season malaria transmission. While the overall population-level impact of seasonal malaria chemoprevention on malaria control has been documented in various countries and time periods, there is no clear evidence regarding seasonal malaria chemoprevention impact based on the number of medicine doses children receive in one cycle in routine programmatic conditions. Data were extracted from Nigeria's routinely collected seasonal malaria chemoprevention end-of-round coverage surveys (2021, 2022). We matched seasonal malaria chemoprevention-targeted children who received specific numbers of seasonal malaria chemoprevention medicines with those who did not receive any doses of seasonal malaria chemoprevention medicines (non-sulfadoxine-pyrimethamine plus amodiaquine) using multiple sets of propensity score matches. We performed multilevel logistic regression for each matched group to evaluate the association between the number of doses of seasonal malaria chemoprevention medicines and monthly confirmed malaria cases (caregiver-reported malaria infection diagnosed by rapid diagnostic test at a health facility following the penultimate cycle of seasonal malaria chemoprevention). Among 21,621 SMC-targeted children, 9.7% received non-sulfadoxine-pyrimethamine plus amodiaquine, 0.5% received only Day 1 sulfadoxine-pyrimethamine plus amodiaquine, 1.0% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and either Day 2 amodiaquine or Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine), and 88.8% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and both Day 2 and Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine). Children receiving only Day 1 sulfadoxine-pyrimethamine plus amodiaquine did not have significant lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.77, 0.42-1.42). However, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine had significantly lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.42, 95% CI 0.28-0.63). Similarly, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine also had significantly lower odds of rapid diagnostic test-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.54, 95% CI 0.47-0.62). Adherence to at least one daily dose of amodiaquine administration following receipt of Day 1 sulfadoxine-pyrimethamine plus amodiaquine by eligible children is crucial to ensure the effectiveness of seasonal malaria chemoprevention. This demonstrates the importance of enhancing caregiver awareness regarding the importance of amodiaquine and identifying barriers toward amodiaquine administration at the community level.

Unmasking Obstruction in Hypertrophic Cardiomyopathy With Postprandial Resting and Treadmill Stress Echocardiography

Latent left ventricular outflow tract obstruction (LVOTO) is an important cause of symptoms in patients with hypertrophic cardiomyopathy (HCM) but can be challenging to provoke. To examine the value of postprandial resting and stress echocardiography and utilization of invasive or enhanced drug therapies (surgical myectomy, alcohol septal ablation, disopyramide, and mavacamten) in patients with postprandial LVOTO. Consecutive HCM patients without LVOTO underwent routine and postprandial echocardiography at rest, with provocation (Valsalva and standing) and after symptom-limited treadmill stress. Among 252 patients (mean age, 58years, 39% women), postprandial LVOT gradients were higher compared with routine echocardiography at rest (median, 9.0 [0-38.0] vs 0 [0-14.0] mm Hg; P<.0001) and with provocation (18.5 [0-70.3] vs 1.5 [0-41.0] mm Hg; P<.0001). Postprandial exercise stress echocardiogram (PPXSE) gradients were higher in a subset of 44 patients who underwent both postprandial and fasting stress echocardiography (47.0 [5.3-81.0] vs 17.5 [0-46.0] mm Hg; P<.0001). In total, 49 (19.5%) patients achieved the ≥50mm Hg threshold under routine conditions (rest/provocation); 90 (35.7%) additional patients achieved postprandial gradients ≥50mm Hg (rest/provocation/exercise), 38 (15.1%) with PPXSE alone. A total of 71 patients were treated with 91 invasive or enhanced drug therapies, 32 (45.1%) of whom had gradients ≥50mm Hg only after eating (rest/provocation) and 8 (11.3%) only with PPXSE, with symptom relief in the majority. Postprandial echocardiography was useful at unmasking LVOTO in more than one-third of patients who did not have high gradients otherwise. Eating before echocardiography is a powerful provocative tool in the evaluation of patients with HCM.

Pragmaticism in Cancer Clinical Trials.

Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past decades. Traditional explanatory trials, focused on establishing intervention efficacy in ideal settings, often lack generalizability and may not reflect real-world patient care scenarios. Furthermore, increasing complexity in cancer clinical trial design has led to challenges such as protocol deviations, slow enrollment leading to lengthened durations of trial, and escalating costs. By contrast, pragmatic trials aim to assess intervention effectiveness in more representative patient populations under routine clinical conditions. Here, we review the principles, methodologies, challenges, and advantages of incorporating pragmatic features (PFs) into cancer clinical trials. We illustrate the application of pragmatic trial designs in oncology and discuss the QUASAR collaborative, TAPUR study, and the ongoing PRAGMATICA-LUNG trial. Although not all oncology trials may be amenable to adopting fully pragmatic designs, integration of PFs when feasible will enhance trial generalizability and real-world applicability. Project Pragmatica and similar initiatives advocate for the integration of real-world practice with clinical trials, fostering a nuanced approach to oncology research that balances efficacy and effectiveness assessments, ultimately with a goal of improving patient outcomes.

Effectiveness of Usual-Care Cognitive-Behavioral Therapy for Children and Adolescents with Nonorganic Enuresis and Comorbid Mental Disorders

ABSTRACT Highly controlled randomized controlled trials (RCT) have provided considerable evidence for the efficacy of standard urotherapy (SU) consisting of cognitive-behavioral therapy (CBT) in patients with enuresis. However, the effectiveness of CBT under routine care conditions regarding wetting frequency and comorbid mental health problems has not been shown. Changes under routine CBT were analyzed in a sample of n = 220 clinically referred children and adolescents with enuresis (88.2% with at least one comorbid mental disorder) aged 6 to 18 years (M = 9.30; SD = 2.32) treated at a university outpatient clinic (experimental group, EG). At the start and end of treatment, wetting frequency as well as parent- and teacher-rated mental health problems were assessed and compared to a historical control group (CG) receiving a medical placebo. The EG showed a large, statistically significant pre-post reduction in wetting frequency (effect size d = 1.47). When comparing these results to the CG, a net effect size in favor of the EG emerged (d = 1.32). Furthermore, small to large, statistically significant reductions in mental health problems were found in the EG (range: d = 0.26 to d = 1.24). However, a substantial proportion of the EG remained in the clinical range at the end of treatment. The present study indicates that routine CBT for patients with enuresis may be effective, thus supporting the findings of more controlled efficacy trials. Trial registration: DRKS00028094 - Retrospectively registered, May 25, 2022, http://drks.de

Impact of Hydrocolloid Dressing and Moisturizing Cream as Facial Skin Protectants Among Health Care Workers.

During the novel coronavirus disease 2019 pandemic, health care workers experienced facial problems from prolonged use of N95 masks, including skin irritation, pigmentation changes, and contact dermatitis. We assessed the use of hydrocolloid dressing versus dimethicone cream to prevent skin breakdown among military health care workers while wearing an N95. Participants were recruited using convenience and snowball sampling in this nonblinded, randomized, cross-over study with 2 active treatments, hydrocolloid dressing and dimethicone cream, across 3 time points. The skin was assessed using photographs and subepidermal moisture scanner (SEM). N95 seal integrity was assessed using qualitative fit test. Institutional review board approval was obtained from the Madigan Army Medical Center Institutional Review Board. Among the 73 participants, wearing an N95 alone versus with dimethicone cream or hydrocolloid dressing caused more adverse skin reactions. There were no significant differences in qualitative fit test failure rate between groups. Participants experienced minimal to no dizziness, loss of energy/tiredness/fatigue, claustrophobia, shortness of breath, difficulty breathing, and dry or itchy eyes. For all interventions, wearing an N95 did not interfere with participants' concentration, verbal communication, hearing, vision, and, importantly, delivery of care. Using a skin protectant with an N95 may prevent adverse skin reactions while preserving health care workers' ability to safely and competently care for patients in routine and pandemic conditions.

Harmonizing tumor mutational burden analysis: Insights from a multicenter study using in silico reference data sets in clinical whole-exome sequencing (WES).

Tumor mutational burden (TMB) is a significant biomarker for predicting immune checkpoint inhibitor response, but the clinical performance of whole-exome sequencing (WES)-based TMB estimation has received less attention compared to panel-based methods. This study aimed to assess the reliability and comparability of WES-based TMB analysis among laboratories under routine testing conditions. A multicenter study was conducted involving 24 laboratories in China using in silico reference data sets. The accuracy and comparability of TMB estimation were evaluated using matched tumor-normal data sets. Factors such as accuracy of variant calls, limit of detection (LOD) of WES test, size of regions of interest (ROIs) used for TMB calculation, and TMB cutoff points were analyzed. The laboratories consistently underestimated the expected TMB scores in matched tumor-normal samples, with only 50% falling within the ±30% TMB interval. Samples with low TMB score (<2.5) received the consensus interpretation. Accuracy of variant calls, LOD of the WES test, ROI, and TMB cutoff points were important factors causing interlaboratory deviations. This study highlights real-world challenges in WES-based TMB analysis that need to be improved and optimized. This research will aid in the selection of more reasonable analytical procedures to minimize potential methodologic biases in estimating TMB in clinical exome sequencing tests. Harmonizing TMB estimation in clinical testing conditions is crucial for accurately evaluating patients' response to immunotherapy.

AMP, ADP, and ATP Concentrations Differentially Affected by Meat Processing, Manufacturing, and Nonmeat Ingredients

Given its presence in a wide spectrum of soils relevant to food process hygiene, the biological metabolite adenosine triphosphate (ATP) is used as a target for surface hygiene assessments in food processing facilities. Yet, ample evidence demonstrates that ATP is depleted into adenosine di- (ADP) and monophosphate (AMP) homologs resulting in a loss of sensitivity for ATP-based hygiene assays. Yet, there are few studies that denote the degree of these shifts under routine processing conditions such as those encountered during various meat processing steps that may likely alter redox potential and adenosine profiles (e.g., tissue/cellular disruption, application of reducing additives, fermentation, or thermal treatment steps). In this study, meat samples were collected from homogenized beef tissue treated with nonmeat ingredients (sodium chloride, sodium nitrite, sodium erythorbate, natural smoke condensate, and sodium acid pyrophosphate) during manufacture at predetermined steps, and from retail meat products purchased from local markets. Concentrations of ATP, ADP, AMP, and AXP (sum concentration of all homologs) in a lab setting and in situ meat processing venues were determined and compared. Greater differences in AXP were seen during manufacture, where ADP generally comprised ∼90% as a mole fraction of AXP across all treatments, with the exception of the final cook step where AMP predominated. ATP concentrations averaged 2 log values lower than ADP and AMP. Adenosine profiles in retail samples followed similar trends with minimal ATP concentrations with ADP predominant in uncooked samples and AMP predominant in cooked samples. Resultingly, meat processing steps during product manufacture will alter AXP-reliant test sensitivities which should be considered when such technologies are utilized for hygiene verification in meat processing.

Enhance U(VI) reduction on natural pyrite surfaces by gamma irradiation

Pyrite with acid-washed surfaces is chemically inert toward aqueous U(VI) at routine conditions. Given that there is a strong radiation field in the nuclear waste repository, the impact of gamma irradiation on the interaction between aqueous U(VI) and natural pyrite was investigated. Three different natural pyrites, namely Si-, Pb-, and As-pyrites, were used for reactions with uranyl nitrate and uranyl acetate, and the focus was set on Si-pyrite. With an initial pH of ∼ 4.5 and ∼ 6.5, results showed that the solution pH increased mainly due to the reduction of nitrate or the decomposition of acetate caused by the gamma irradiation, while it decreased for the reaction with an initial pH of ∼ 9.0 after gamma irradiation due to the oxidation of aqueous Fe2+. Meanwhile, significant amounts of U(IV)/U(V) were formed on pyrite surfaces at these three pH conditions, demonstrating that gamma irradiation can greatly enhance the U(VI) reduction by pyrite. We proposed that the oxidizing ·OH radical generated by water radiolysis could react with pyrite, leaving the concomitant eaq− and ·H radicals to be effective reductants for aqueous U(VI) or the U(VI)-precipitate formed on pyrite surfaces. Conversely, the impact of gamma irradiation on the U(VI) reduction is insignificant at pH ∼ 3.0, mainly due to the quenching effect of eaq− by H+. Besides, carbonate has an inhibitive effect, because it is a quencher of eaq− and can form anionic complexes with U(VI). The presence of pyrite can also protect UO2 from γ-irradiation-induced oxidation.

Digital colloid-enhanced Raman spectroscopy by single-molecule counting.

Quantitative detection of various molecules at very low concentrations in complex mixtures has been the main objective in many fields of science and engineering, from the detection of cancer-causing mutagens and early disease markers to environmental pollutants and bioterror agents1-5. Moreover, technologies that can detect these analytes without external labels or modifications are extremely valuable and often preferred6. In this regard, surface-enhanced Raman spectroscopy can detect molecular species in complex mixtures on the basis only of their intrinsic and unique vibrational signatures7. However, the development of surface-enhanced Raman spectroscopy for this purpose has been challenging so far because of uncontrollable signal heterogeneity and poor reproducibility at low analyte concentrations8. Here, as a proof of concept, we show that, using digital (nano)colloid-enhanced Raman spectroscopy, reproducible quantification of a broad range of target molecules at very low concentrations can be routinely achieved with single-molecule counting, limited only by the Poisson noise of the measurement process. As metallic colloidal nanoparticles that enhance these vibrational signatures, including hydroxylamine-reduced-silver colloids, can be fabricated at large scale under routine conditions, we anticipate that digital (nano)colloid-enhanced Raman spectroscopy will become the technology of choice for the reliable and ultrasensitive detection of various analytes, including those of great importance for human health.

Digital treatments for affective disorders: an integrated overview

AbstractAffective disorders represent a category of psychiatric syndromes with high prevalence and associated disability. While effective, both pharmacological and psychosocial, treatments are available for depression and bipolar disorder, the many therapeutic needs of affected patients are far from being properly addressed under routine conditions. Along the past decade, several digital treatments, tools and approaches have been developed and tested in clinical settings, showing an highly promising potential to fill the treatment gap of affective psychopathology. In more detail, reviewed here will be telepsychiatry solutions for affective disorders, also encompassing the available officially approved digital therapies for major depression and bipolar disorder. Furthermore, the impact of artificial intelligence, serious gaming, social media and virtual/augmented reality in the treatment of mood disorders will be also discussed, in the light of the most recent research evidence on these topics.Disclosure of InterestNone Declared

Using Inundation Extents to Predict Microbial Contamination in Private Wells after Flooding Events.

Disaster recovery poses unique challenges for residents reliant on private wells. Flooding events are drivers of microbial contamination in well water, but the relationship observed between flooding and contamination varies substantially. Here, we investigate the performance of different flood boundaries─the FEMA 100 year flood hazard boundary, height above nearest drainage-derived inundation extents, and satellite-derived extents from the Dartmouth Flood Observatory─in their ability to identify well water contamination following Hurricane Florence. Using these flood boundaries, we estimated about 2600 wells to 108,400 private wells may have been inundated─over 2 orders of magnitude difference based on boundary used. Using state-generated routine and post-Florence testing data, we observed that microbial contamination rates were 7.1-10.5 times higher within the three flood boundaries compared to routine conditions. However, the ability of the flood boundaries to identify contaminated samples varied spatially depending on the type of flooding (e.g., riverine, overbank, coastal). While participation in testing increased after Florence, rates were overall still low. With <1% of wells tested, there is a critical need for enhanced well water testing efforts. This work provides an understanding of the strengths and limitations of inundation mapping techniques, which are critical for guiding postdisaster well water response and recovery.

Evaluation of magnetic resonance imaging to detect cholesteatoma in clinical healthcare

Background Non-Echo-Planar Diffusion Weighed Magnetic Resonance Imaging (non-EPI DW MRI) plays a role in the planning of cholesteatoma surgery. Objectives To outline the usage of Non-EPI DW MRI in cholesteatoma diagnostics and to determine its accuracy, using otosurgery diagnostics as reference standard. Material and Methods A retrospective descriptive study. All subjects operated, with suspicion of cholesteatoma as indication, that had a preceding examination with non-EPI DW MRI, between October 2010 and March 2019. Calculating sensitivity, specificity, predicative values, and likelihood ratios, using non-EPI DW MRI as index test and diagnosis from otosurgery as reference standard. Results Fifty-two subject episodes were included. Non-EPI DW MRI had a sensitivity of 0.50, specificity of 0.75, positive and negative predictive values of 0.74 and 0.52 and, positive and negative likelihood ratios of 2.0 and 0.67 respectively. Conclusions and Significance There is a clear annual trend with increased numbers of executed examinations during the study period. The diagnostic accuracy of non-EPI DW MRI does not reach acceptable levels in the existing everyday routine practice conditions. The accuracy of the examination increases when interpreted by an experienced radiologist and when using the definition of cholesteatoma recommended by EAONO/JOS.

Rapid detection of tomato spotted wilt virus by real-time RT-LAMP and in-field application

Tomato spotted wilt virus (TSWV) is considered one of the most threatening viruses worldwide for different economically important agricultural crops. In this scenario, it is important to perform an early detection by laboratory tests to prevent TSWV spread. A rapid and sensitive TSWV detection protocol based on real time reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed in this work, also using cost-effective and simplified sample preparation procedure, to assess the suitability of the RT-LAMP assay in field conditions on tomato and pepper samples. A set of six primers was designed within the nucleotide sequence region coding for the nucleocapsid protein (N) of segment S, targeting a 220-nucleotide sequence. Sensitivity, specificity, accuracy, and in-field application of the real-time RT-LAMP assay were evaluated. The developed real-time RT-LAMP assay proved to be one thousand and one hundred times more sensitive than end-point RT-PCR and real-time RT-PCR methods, respectively, detecting a total of 9.191 × 101 genome copies as minimum target, and no cross-reactivity were detected with other viruses belonging to Tospoviridae and Bromoviridae families used as outgroup. In addition, the in-field application of the assay using the rapid sample preparation gave adequate and reliable results within 60 minutes, with an acceptable reaction delay when compared to canonical RNA extraction. The in-field analyses showed an increase of TSWV-positive samples (37%) detection compared with end-point RT-PCR and real-time RT-PCR (32% and 29%, respectively), particularly on asymptomatic samples, confirming that the real-time RT-LAMP assay can be implemented as a routine test both in-field and laboratory conditions as a rapid and sensitive technique for TSWV detection.

The histone deacetylase Hda1 affects oxidative and osmotic stress response as well as mycoparasitic activity and secondary metabolite biosynthesis in Trichoderma atroviride.

The mycoparasitic fungus Trichoderma atroviride is applied in agriculture as a biostimulant and biologic control agent against fungal pathogens that infest crop plants. Secondary metabolites are among the main agents determining the strength and progress of the mycoparasitic attack. However, expression of most secondary metabolism-associated genes requires specific cues, as they are silent under routine laboratory conditions due to their maintenance in an inactive heterochromatin state. Therefore, histone modifications are crucial for the regulation of secondary metabolism. Here, we functionally investigated the role of the class II histone deacetylase encoding gene hda1 of T. atroviride by targeted gene deletion, phenotypic characterization, and multi-omics approaches. Deletion of hda1 did not result in obvious phenotypic alterations but led to an enhanced inhibitory activity of secreted metabolites and reduced mycoparasitic abilities of T. atroviride against the plant-pathogenic fungi Botrytis cinerea and Rhizoctonia solani. The ∆hda1 mutants emitted altered amounts of four volatile organic compounds along their development, produced different metabolite profiles upon growth in liquid culture, and showed a higher susceptibility to oxidative and osmotic stress. Moreover, hda1 deletion affected the expression of several notable gene categories such as polyketide synthases, transcription factors, and genes involved in the HOG MAPK pathway.IMPORTANCEHistone deacetylases play crucial roles in regulating chromatin structure and gene transcription. To date, classical-Zn2+ dependent-fungal histone deacetylases are divided into two classes, of which each comprises orthologues of the two sub-groups Rpd3 and Hos2 and Hda1 and Hos3 of yeast, respectively. However, the role of these chromatin remodelers in mycoparasitic fungi is poorly understood. In this study, we provide evidence that Hda1, the class II histone deacetylases of the mycoparasitic fungus Trichoderma atroviride, regulates its mycoparasitic activity, secondary metabolite biosynthesis, and osmotic and oxidative stress tolerance. The function of Hda1 in regulating bioactive metabolite production and mycoparasitism reveals the importance of chromatin-dependent regulation in the ability of T. atroviride to successfully control fungal plant pathogens.

Low body mass index as a predictor of sputum culture conversion and treatment outcomes among patients receiving treatment for multidrug-resistant tuberculosis in Lesotho

ABSTRACT Background A low body mass index (BMI) at the start of treatment for rifampicin- or multidrug-resistant tuberculosis (MDR/RR-TB) is associated with poor treatment outcomes and may contribute to delayed sputum culture conversion, thereby prolonging the period of potential transmission to others. Whether the relative importance of low BMI in predicting treatment outcomes differs by HIV status is unclear. Objectives We evaluated the association between low BMI and two dependent variables, sputum culture conversion and end-of-treatment outcome, among patients receiving treatment for MDR/RR-TB in Lesotho, a setting with a high prevalence of HIV infection. Methods Secondary data from a prospective cohort of patients initiating a longer (18–20 months) treatment containing bedaquiline and/or delamanid under routine programmatic conditions in Lesotho were analysed. Risk ratios and differences were adjusted for potential confounders using multivariable logistic regression, and estimates were stratified by HIV status. Results Of 264 patients, 105 and 250 were eligible for culture conversion and end-of-treatment analyses, respectively. Seventy-one per cent of patients (74/105) experienced culture conversion within six months, while 74% (184/250) experienced a favourable end-of-treatment outcome. Low BMI was associated with a lower frequency of culture conversion at six months among those who were not living with HIV (relative risk [RR]: 0.50 [95% CI: 0.21, 0.79]); this association was attenuated among those living with HIV (RR: 0.88 [95% CI: 0.68, 1.23]). A low BMI was moderately associated with a lower frequency of treatment success (RR = 0.89 [95% CI: 0.77, 1.03]), regardless of HIV status. Conclusions Low BMI was common and associated with the frequency of six-month culture conversion and end-of-treatment outcomes. The association with culture conversion was more pronounced among those not living with HIV. Addressing the myriad factors that drive low BMI in this setting could hasten culture conversion and improve end-of-treatment outcomes. This will require a multipronged approach focused on alleviating food insecurity and enabling prompt diagnosis and treatment of HIV and TB.

Diagnostic accuracy of Xpert MTB/RIF Ultra for childhood tuberculosis in West Africa – a multicenter pragmatic study

ObjectiveTo evaluate the performance of Xpert Mycobacterium Tuberculosis/rifampicin (MTB/RIF) Ultra (Ultra) for diagnosis of childhood tuberculosis (TB) within public health systems. MethodsIn this cross-sectional study, children aged <15 years with presumptive pulmonary TB were consecutively recruited and evaluated for TB at tertiary-level hospitals in Benin, Mali, and Ghana. Bivariate random-effects models were used to determine the pooled sensitivity and specificity of Ultra against culture. We also estimated its diagnostic yield against a composite microbiological reference standard (cMRS) of positive culture or Ultra. ResultsOverall, 193 children were included in the analyses with a median (interquartile range) age of 4.0 (1.1-9.2) years, 88 (45.6%) were female, and 36 (18.7%) were HIV-positive. Thirty-one (16.1%) children had confirmed TB, 39 (20.2%) had unconfirmed TB, and 123 (63.7%) had unlikely TB. The pooled sensitivity and specificity of Ultra verified by culture were 55.0% (95% confidence interval [CI]: 28.0–79.0%) and 95.0% (95% CI: 88.0–98.0%), respectively. Against the cMRS, the diagnostic yield of Ultra and culture were 67.7% (95% CI: 48.6–83.3%) and 70.9% (95% CI: 51.9–85.8%), respectively. ConclusionUltra has suboptimal sensitivity in children with TB that were investigated under routine conditions in tertiary-level hospitals in three West African countries.

Replication of a neuroimaging biomarker for striatal dysfunction in psychosis.

To bring biomarkers closer to clinical application, they should be generalizable, reliable, and maintain performance within the constraints of routine clinical conditions. The functional striatal abnormalities (FSA), is among the most advanced neuroimaging biomarkers in schizophrenia, trained to discriminate diagnosis, with post-hoc analyses indicating prognostic properties. Here, we attempt to replicate its diagnostic capabilities measured by the area under the curve (AUC) in receiver operator characteristic curves discriminating individuals with psychosis (n = 101) from healthy controls (n = 51) in the Human Connectome Project for Early Psychosis. We also measured the test-retest (run 1 vs 2) and phase encoding direction (i.e., AP vs PA) reliability with intraclass correlation coefficients (ICC). Additionally, we measured effects of scan length on classification accuracy (i.e., AUCs) and reliability (i.e., ICCs). Finally, we tested the prognostic capability of the FSA by the correlation between baseline scores and symptom improvement over 12 weeks of antipsychotic treatment in a separate cohort (n = 97). Similar analyses were conducted for the Yeo networks intrinsic connectivity as a reference. The FSA had good/excellent diagnostic discrimination (AUC = 75.4%, 95% CI = 67.0-83.3%; in non-affective psychosis AUC = 80.5%, 95% CI = 72.1-88.0%, and in affective psychosis AUC = 58.7%, 95% CI = 44.2-72.0%). Test-retest reliability ranged between ICC = 0.48 (95% CI = 0.35-0.59) and ICC = 0.22 (95% CI = 0.06-0.36), which was comparable to that of networks intrinsic connectivity. Phase encoding direction reliability for the FSA was ICC = 0.51 (95% CI = 0.42-0.59), generally lower than for networks intrinsic connectivity. By increasing scan length from 2 to 10 min, diagnostic classification of the FSA increased from AUC = 71.7% (95% CI = 63.1-80.3%) to 75.4% (95% CI = 67.0-83.3%) and phase encoding direction reliability from ICC = 0.29 (95% CI = 0.14-0.43) to ICC = 0.51 (95% CI = 0.42-0.59). FSA scores did not correlate with symptom improvement. These results reassure that the FSA is a generalizable diagnostic - but not prognostic - biomarker. Given the replicable results of the FSA as a diagnostic biomarker trained on case-control datasets, next the development of prognostic biomarkers should be on treatment-response data.

Does Universal SEL Promote Academic Success? Examining Learner Outcomes Under Routine Conditions in First-Grade Classrooms

Although proponents suggest that universal social-emotional learning (SEL) programs promote academic achievement, few studies have directly tested these outcomes under routine conditions in schools. Forty first-grade classrooms participated in an effectiveness trial in which schools (N = 13) were randomly assigned to implementation of a universal SEL program (SSIS SEL CIP) or control (business-as-usual practices) conditions within sites/regions. Teachers in the treatment condition prepared for and implemented the program in accordance with their typical local practices. There were no statistically significant main effects on teacher-rated student engagement, motivation, and academic skills. Effect sizes, however, were medium to large and positive for academic engaged time and math achievement. Students with lower teacher-rated academic motivation at pretest also were more likely to improve after program exposure. These findings help identify considerations for further studying the potential academic outcomes resulting from implementing universal SEL under typical conditions.