A randomized, open-label two-period crossover pilot study to evaluate the relative bioavailability in the fed state of atovaquone-proguanil (Atoguanil™) versus atovaquone-proguanil hydrochloride (Malarone®) in healthy adult participants.

Atoguanil™ is a novel complex of atovaquone (ATV) and proguanil (PG) with enhanced ATV bioavailability compared to Malarone®. This pilot study assessed whether the relative bioavailability (Frel) of ATV, PG, and the primary PG metabolite cycloguanil (CG) following a single oral dose in the fed state of Atoguanil was similar to Malarone despite a 50% lower ATV dose. This open-label, single-dose, randomized 2-period, 2-treatment, balanced crossover study was conducted between 17th November 2021 and 18th March 2022. Eligible participants (aged 18-55 years) were randomized (1:1) in period 1 to Atoguanil (ATV/PG 500/348 mg) or Malarone (ATV/PG hydrochloride 1000/400 mg) administered following a high-fat, high caloric meal. After a 24-day washout period, participants crossed treatment arms. For the doses tested, Frel was assumed similar if 90%CIs were between 80 and 125% for the geometric mean ratio of the least square mean differences for each exposure parameter. In 15 evaluable participants, Frel was similar for ATV Cmax (93.6% [90%CI 83.6, 104.9]) but not AUC0-inf (77.8% [67.4, 89.8]), for PG AUC0-inf (95.6% [92.1, 99.2]) but not Cmax (82.4% [75.8, 89.5]), and for both CG Cmax (100.8% [95.0, 107.0]) and AUC0-inf (102.9% [98.4, 107.7]). Nine adverse events occurred; all were of mild severity and not considered treatment related. At the doses tested, ATV Frel was lower following Atoguanil versus Malarone based on AUC0-inf, though when adjusted for dose Frel increased by 156%. Both drugs were well tolerated with no safety concerns. ClinicalTrials.gov: NCT04866602 (April 26th, 2021).

Stress adaptive plasticity from Aegilops tauschii introgression lines improves drought and heat stress tolerance in bread wheat (Triticum aestivum L.).

Aegilops tauchii is a D-genome donor of hexaploid wheat and is a potential source of genes for various biotic and abiotic stresses including heat and drought. In the present study, we used multi-stage evaluation technique to understand the effects of heat and drought stresses on Ae. tauschii derived introgression lines (ILs). Preliminary evaluation (during stage-I) of 369 ILs for various agronomic traits identified 59 agronomically superior ILs. In the second stage (stage-II), selected ILs (i.e., 59 ILs) were evaluated for seedling heat (at 30 °C and 35 °C) and drought (at 20% poly-ethylene glycol; PEG) stress tolerance under growth chambers (stage-II). Heat and drought stress significantly reduced the seedling vigour by 59.29 and 60.37 percent, respectively. Genotype × treatment interaction analysis for seedling vigour stress tolerance index (STI) identified IL-50, IL-56, and IL-68 as high-performing ILs under heat stress and IL-42 and IL-44 as high-performing ILs under drought stress. It also revealed IL-44 and IL-50 as the stable ILs under heat and drought stresses. Furthermore, in the third stage (stage-III), selected ILs were evaluated for heat and drought stress tolerance under field condition over two cropping seasons (viz., 2020-21 and 2021-22), which significantly reduced the grain yield by 72.79 and 48.70 percent, respectively. Stability analysis was performed to identify IL-47, IL-51, and IL-259 as the most stable ILs in stage-III. Tolerant ILs with specific and wider adaptability identified in this study can serve as the potential resources to understand the genetic basis of heat and drought stress tolerance in wheat and they can also be utilized in developing high-yielding wheat cultivars with enhanced heat and drought stress tolerance.

"The impact of orthognathic surgery on articulation proficiency and speech intelligibility in skeletal Class III malocclusion: 18 months follow up".

Introduction: Orthognathic surgery results in the positional change of the maxilla and mandible that may affect speech. The present study evaluated the effect of combined maxillary advancement and mandibular setback surgery on articulation proficiency and speech intelligibility in patients with non-syndromic skeletal Class III malocclusion. Methods: In this prospective study, twenty-five patients with skeletal class III malocclusion and consecutively treated with Lefort-1 maxillary advancement and mandibular setback (BSSO) orthognathic surgery were included in this study. The speech sample was recorded with a digital audio tape recorder one day before surgery and at 3, 6, 9, 12 and 18 months after surgery. Three qualified and experienced speech and language pathologists evaluated articulation errors and intelligibility of speech samples. Repeated One-way analysis of variance was used to compare articulation proficiency and speech intelligibility at different time intervals. Results: The substitution, omission, distortion and addition errors showed no significant changes at 3 months and 6 months. The total articulation errors decreased to zero at 9 months and no significant increase was observed till 18 months (P < 0.05). Speech intelligibility showed statistically non-significant improvement at any time interval. Cephalometric skeletal parameters SNA and N l A°. were significantly correlated with addition and total articulation errors at 18 months follow up. Conclusions: The ortho-surgical treatment improves speech (decreases. articulation errors) in most of the patients usually 6-9 months post-surgery. Speech intelligibility is not affected by bimaxillary orthognathic surgery in skeletal class III patients. The articulation errors were correlated to changes in position of maxilla.

To Study the Outcome of Cartilage Tympanoplasty Type I in Patients with Medium and Large Perforations Using 0.5 mm Sliced Conchal Cartilage Reinforced with Temporalis Fascia Grafts with 5 Years Follow-up.

Aims: To study the outcome of cartilage tympanoplasty type I in patients with medium and large perforations using 0.5 mm sliced conchal cartilage reinforced with temporalis fascia grafts with 5 years follow-up. Study Design: Retrospective clinical study. Patients and Method: 120 patients with dry tympanic membrane perforation medium and large size and intact ossicular chain, and with no history of previous ear surgery were selected. An underlay type one tympanoplasty, using 0.5 mm sliced conchal cartilage reinforced with temporalis fascia, was performed during 2018-19. A successful anatomical outcome was considered to comprise full, intact healing of the graft without perforation these patients were evaluated for at least 5 years post-operatively till 2023. Results: In this study graft uptake rate was 95.33% for medium size and 93.66% for large perforations at 3 months and after 5 years of follow-up 92.77% medium size and large size perforations were 89.67.66% (P < 0.001). Residual perforations were there in about 7.29% in medium and 10.33% in large size perfrations. Conclusion: Sliced conchal cartilage reinforced with temporalis fascia is a reliable technique for tympanoplasty, with improved graft uptake results in medium and large perforations in the long-term, also the residual perforations is significantly lower.

Isotopic evidence of autochthonous organic matter acting as a major sink of anthropogenic heavy metals in modern lacustrine sediments.

The knowledge of major sources, sinks, and the burial fate of various pollutants added to modern aquatic ecosystems under changing environmental conditions is limited but crucial for our sustainability. In this context, the spatial distributions and causative factors of organic matter (OM) and heavy metal accumulations have been explored in modern lacustrine sediments of a large urbanized and protected wetland (ULB: Upper Lake Bhopal) in Central India. For this purpose, geochemical properties, in particular, stable isotopes (δ13C and δ15N) were measured in the ULB surficial sediments (core depth ∼0-1 cm; n = 19), and additionally collected riverbed sediments (n = 2) and atmospheric free-fall dust samples (n = 3) from the lake periphery. The major and trace element data indicate widespread mafic sediment provenance and nearly dysoxic lacustrine conditions. The riverine supply of soil OM from cropped lands and the lake productivity (algae, largely sustained by nutrients from sewage and agricultural runoff) are the major OM sources to the western and eastern lake portions, respectively. The fractional contribution from autochthonous TOC (∼0.19-0.95, mean ∼0.62) predominates that of allochthonous TOC (∼0.05-0.81, mean ∼0.38). Whereas, atmospheric dust deposition is a primary anthropogenic source of heavy metals (Pb and Zn). The lake productivity rather than soil OM or any mineral sorbent is found responsible for the anthropogenic enrichments of Pb and Zn in the ULB surficial sediments, especially on the eastern ULB portion under high anthropogenic pressure. Therefore, the settled OM (primarily autochthonous) being oxidizable acts as a temporary but major sink of anthropogenic heavy metals in modern lacustrine sediments, which are vulnerable to heavy metal efflux to the water column by sediment diagenesis.

The Lingering Effects of COVID-19: The Psychological State and Quality of Life of Patients with Persistent Loss of Smell and Taste.

The COVID-19 pandemic has resulted in a significant number of individuals experiencing the loss of smell and taste, medically known as anosmia and ageusia, respectively. While many patients recover these senses during the post-acute phase of the illness, a subset of individuals continues to suffer from anosmia and ageusia even after recovering from COVID-19. This article aims to explore the psychological state of COVID patients who have not regained their sense of smell and taste post-recovery, highlighting the potential impact on their mental health and overall well-being. To accomplish this, a comprehensive review of existing literature on the topic has been conducted, analyzing studies and reports that shed light on the psychological consequences of unrecovered anosmia and ageusia in COVID patients.

Deciphering the genetic landscape of seedling drought stress tolerance in wheat (Triticum aestivum L.) through genome-wide association studies.

Wheat is an important cereal crop constrained by several biotic and abiotic stresses including drought stress. Understating the effect of drought stress and the genetic basis of stress tolerance is important to develop drought resilient, high-yielding wheat cultivars. In this study, we investigated the effects of drought stress on seedling characteristics in an association panel consisting of 198 germplasm lines. Our findings revealed that drought stress had a detrimental effect on all the seedling characteristics under investigation with a maximum effect on shoot length (50.94% reduction) and the minimum effect on germination percentage (7.9% reduction). To gain a deeper understanding, we conducted a genome-wide association analysis using 12,511 single nucleotide polymorphisms (SNPs), which led to the identification of 39 marker-trait associations (MTAs). Of these 39 MTAs, 13 were particularly noteworthy as they accounted for >10% of the phenotypic variance with a LOD score >5. These high-confidence MTAs were further utilized to extract 216 candidate gene (CGs) models within 1 Mb regions. Gene annotation and functional characterization identified 83 CGs with functional relevance to drought stress. These genes encoded the WD40 repeat domain, Myb/SANT-like domain, WSD1-like domain, BTB/POZ domain, Protein kinase domain, Cytochrome P450, Leucine-rich repeat domain superfamily, BURP domain, Calmodulin-binding protein60, Ubiquitin-like domain, etc. Findings from this study hold significant promise for wheat breeders as they provide direct assistance in selecting lines harboring favorable alleles for improved drought stress tolerance. Additionally, the identified SNPs and CGs will enable marker-assisted selection of potential genomic regions associated with enhanced drought stress tolerance in wheat.

Targeted Protein Degraders- The Druggability Perspective.

Targeted Protein degraders (TPDs) show promise in harnessing cellular machinery to eliminate disease-causing proteins, even those previously considered undruggable. Especially if protein turnover is low, targeted protein removal bestows lasting therapeutic effect over typical inhibition. The demonstrated safety and efficacy profile of clinical candidates has fueled the surge in the number of potential candidates across different therapeutic areas. As TPDs often do not comply with Lipinski's rule of five, developing novel TPDs and unlocking their full potential requires overcoming solubility, permeability and oral bioavailability challenges. Tailored in-vitro assays are key to precise profiling and optimization, propelling breakthroughs in targeted protein degradation.

Prospective Evaluation of AI Triage of Pulmonary Emboli on CT Pulmonary Angiograms.

Background Artificial intelligence (AI) algorithms have shown high accuracy for detection of pulmonary embolism (PE) on CT pulmonary angiography (CTPA) studies in academic studies. Purpose To determine whether use of an AI triage system to detect PE on CTPA studies improves radiologist performance or examination and report turnaround times in a clinical setting. Materials and Methods This prospective single-center study included adult participants who underwent CTPA for suspected PE in a clinical practice setting. Consecutive CTPA studies were evaluated in two phases, first by radiologists alone (n = 31) (May 2021 to June 2021) and then by radiologists aided by a commercially available AI triage system (n = 37) (September 2021 to December 2021). Sixty-two percent of radiologists (26 of 42 radiologists) interpreted studies in both phases. The reference standard was determined by an independent re-review of studies by thoracic radiologists and was used to calculate performance metrics. Diagnostic accuracy and turnaround times were compared using Pearson χ2 and Wilcoxon rank sum tests. Results Phases 1 and 2 included 503 studies (participant mean age, 54.0 years ± 17.8 [SD]; 275 female, 228 male) and 1023 studies (participant mean age, 55.1 years ± 17.5; 583 female, 440 male), respectively. In phases 1 and 2, 14.5% (73 of 503) and 15.9% (163 of 1023) of CTPA studies were positive for PE (P = .47). Mean wait time for positive PE studies decreased from 21.5 minutes without AI to 11.3 minutes with AI (P < .001). The accuracy and miss rate, respectively, for radiologist detection of any PE on CTPA studies was 97.6% and 12.3% without AI and 98.6% and 6.1% with AI, which was not significantly different (P = .15 and P = .11, respectively). Conclusion The use of an AI triage system to detect any PE on CTPA studies improved wait times but did not improve radiologist accuracy, miss rate, or examination and report turnaround times. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Murphy and Tee in this issue.