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(1) Background: Musculoskeletal disorders (MSDs), discomfort, fatigue, pain, and other acute and chronic work-related injuries are common among dental clinicians. Hand instruments constitute a primary risk factor for these conditions. The overall goal of this study was to compare in dental hygienists with healthy hands, and in those with MSDs, the effect of three different handle designs on instrumentation-related muscle work, comfort, fatigue, and quality of tactile feedback. (2) Methods: Clinicians tested three periodontal curettes: one with a novel adaptive silicone handle, another with a rigid resin handle, and the third with a rigid silicone handle. Ten hygienists-five with MSDs and five without-each scaled three typodonts using the three different curettes. Statistical analysis was performed using a General Linear Model (GLIM) and Tukeys post hoc test, and a significance level of p < 0.05 was implemented. (3) Results: On average, mean comfort and fatigue across all instruments were significantly worse in testers with MSDs, who also expended significantly more work to complete the same task. In all testers, a novel adaptive handle design was associated with significantly reduced total muscle work and post-instrumentation fatigue, as well as better comfort than conventional rigid handle designs. (4) Conclusions: An adaptive curette handle design demonstrated significantly better ergonomic outcomes than conventional rigid curette handle designs. Hygienists with MSDs expend significantly more muscle work during dental instrumentation.

BACKGROUND: Amyloidosis, a rare multisystem condition, often requires complex, multidisciplinary care. Its low prevalence underscores the importance of efforts to ensure the availability of high-quality patient education materials for better outcomes. ChatGPT (OpenAI) is a large language model powered by artificial intelligence that offers a potential avenue for disseminating accurate, reliable, and accessible educational resources for both patients and providers. Its user-friendly interface, engaging conversational responses, and the capability for users to ask follow-up questions make it a promising future tool in delivering accurate and tailored information to patients. OBJECTIVE: We performed a multidisciplinary assessment of the accuracy, reproducibility, and readability of ChatGPT in answering questions related to amyloidosis. METHODS: In total, 98 amyloidosis questions related to cardiology, gastroenterology, and neurology were curated from medical societies, institutions, and amyloidosis Facebook support groups and inputted into ChatGPT-3.5 and ChatGPT-4. Cardiology- and gastroenterology-related responses were independently graded by a board-certified cardiologist and gastroenterologist, respectively, who specialize in amyloidosis. These 2 reviewers (RG and DCK) also graded general questions for which disagreements were resolved with discussion. Neurology-related responses were graded by a board-certified neurologist (AAH) who specializes in amyloidosis. Reviewers used the following grading scale: (1) comprehensive, (2) correct but inadequate, (3) some correct and some incorrect, and (4) completely incorrect. Questions were stratified by categories for further analysis. Reproducibility was assessed by inputting each question twice into each model. The readability of ChatGPT-4 responses was also evaluated using the Textstat library in Python (Python Software Foundation) and the Textstat readability package in R software (R Foundation for Statistical Computing). RESULTS: ChatGPT-4 (n=98) provided 93 (95%) responses with accurate information, and 82 (84%) were comprehensive. ChatGPT-3.5 (n=83) provided 74 (89%) responses with accurate information, and 66 (79%) were comprehensive. When examined by question category, ChatGTP-4 and ChatGPT-3.5 provided 53 (95%) and 48 (86%) comprehensive responses, respectively, to general questions (n=56). When examined by subject, ChatGPT-4 and ChatGPT-3.5 performed best in response to cardiology questions (n=12) with both models producing 10 (83%) comprehensive responses. For gastroenterology (n=15), ChatGPT-4 received comprehensive grades for 9 (60%) responses, and ChatGPT-3.5 provided 8 (53%) responses. Overall, 96 of 98 (98%) responses for ChatGPT-4 and 73 of 83 (88%) for ChatGPT-3.5 were reproducible. The readability of ChatGPT-4s responses ranged from 10th to beyond graduate US grade levels with an average of 15.5 (SD 1.9). CONCLUSIONS: Large language models are a promising tool for accurate and reliable health information for patients living with amyloidosis. However, ChatGPTs responses exceeded the American Medical Associations recommended fifth- to sixth-grade reading level. Future studies focusing on improving response accuracy and readability are warranted. Prior to widespread implementation, the technologys limitations and ethical implications must be further explored to ensure patient safety and equitable implementation.

OBJECTIVES: The objective of this research was to generate psychometric evidence supporting the myasthenia gravis (MG) symptoms patient-reported outcome (PRO) scales as a fit-for-purpose measure of severity of core symptoms of MG and provide information allowing their meaningful interpretation using data from a phase 3 study in MG. METHODS: Data from the MycarinG study, a phase 3 study of rozanolixizumab in patients with generalized MG who experience moderate to severe symptoms (ClinicalTrials.gov Identifier: NCT03971422) were analyzed with both classical test theory (CTT) and Rasch measurement theory (RMT). Meaningful within-individual change and group-level meaningful change were estimated for three MG Symptoms PRO scales using anchor- and distribution-based methods. Anchor-based methods used patient global impression of severity (PGIS) and change (PGIC) in MG symptoms as anchors. RESULTS: Good measurement properties of the MG Symptoms PRO scales were shown in the sample of 200 participants: good to excellent reliability (test-retest and internal consistency reliability) and validity (associations between items and scores within the MG Symptoms PRO scales and between the MG Symptoms PRO scores and other clinical outcomes-MG ADL, QMG score, MGC score, and MGFA classes-were as expected); and the items showed good coverage of the continuum and fit to the Rasch model. Triangulation of the anchor- and distribution-based method results led to the definition of clinically meaningful within-patient improvement in scores for Muscle Weakness Fatigability (-16.67), Physical Fatigue (-20.00), and Bulbar Muscle Weakness (-20.00), with associated ranges. Benchmarks are also proposed for the interpretation of group-level results. CONCLUSION: The strong psychometric performance of the MG Symptoms PRO scales and the information generated to guide its interpretation supports its use in clinical trials for demonstrating the clinical benefits of new treatments targeting core symptoms of MG (muscle weakness fatigability, physical fatigue, bulbar muscle weakness, respiratory muscle weakness, and ocular muscle weakness).

OBJECTIVE: To describe the protocol of a prospective study to test the validity of intermuscular coherence (IMC) as a diagnostic tool and biomarker of upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). METHODS: This is a multicenter, prospective study. IMC of muscle pairs in the upper and lower limbs is gathered in ∼650 subjects across three groups using surface electrodes and conventional electromyography (EMG) machines. The following subjects will be tested: 1) neurotypical controls; 2) patients with symptomatology suggestive for early ALS but not meeting probable or definite ALS by Awaji Criteria; 3) patients with a known ALS mimic. The recruitment period is between 3/31/2021 and 12/31/2025. Written consent will be sought from the subject or the subjects legally authorized representative during enrollment. RESULTS: The endpoints of this study include: 1) whether adding IMC to the Awaji ALS criteria improve its sensitivity in early ALS and can allow for diagnosis earlier; 2) constructing a database of IMC across different ages, genders, and ethnicities. SIGNIFICANCE: This study may validate a new inexpensive, painless, and widely available tool for the diagnosis of ALS.

BackgroundTo compare fatigue, comfort, and muscle work associated with the use of two periodontal curettes during scaling: one with a novel adaptive design, the other with a conventional non-adaptive design.MethodsTwelve hygienists scaled a typodont using two Universal Barnhart 5/6 curettes: (1) a prototype featuring an adaptive silicone-covered handle (Curette A), and (2) a stainless-steel curette (Curette B). Surface Electromyography (sEMG) traced muscle work. Hand positions, fatigue, comfort, pinch, and grasp strength were recorded. Paired t-tests and a repeated measures ANOVA with covariates were tested for differences. The significance level was set at p < 0.05.ResultsCurette A performed significantly better in all categories. Pinch and grasp strength and fatigue were significantly reduced post-instrumentation for Curette B. Curette A required significantly less (i) total muscle work and (ii) work in individual muscles. Comfort, correct grasp, and blade adaptation were significantly better using Curette A.ConclusionsA curette featuring a novel adaptive handle design demonstrated significantly improved ergonomic performance. Additional clinical studies are needed to solidify our understanding of the potential short- and long-term benefits of the novel curette handle design.Practical implicationsA novel adaptive curette handle design that enables the clinician to adapt the instrument across the index finger may reduce musculoskeletal burden and fatigue, as well as improve comfort during periodontal instrumentation.

INTRODUCTION: Accurate measurement of myasthenia gravis (MG) severity is required for appropriate clinical monitoring of patients with MG and assessment of the benefit of new treatments in clinical trials. Our objective was to explore how MG severity can be measured and to determine how the newly developed MG Symptoms Patient-Reported Outcome (PRO) instrument complements the available measures of MG severity. METHODS: The conceptual coverage of the Quantitative MG (QMG), MG Composite (MGC), MG-Activities of Daily Living (MG-ADL), and MG Symptoms PRO was scrutinized against core symptoms of MG: muscle weakness in three muscle groups (ocular, bulbar, and respiratory), muscle weakness fatigability, and physical fatigue. Post hoc analyses of the MG0002 study, a Phase 2a clinical trial of rozanolixizumab in adults with moderate to severe generalized MG, included correlation and Rasch model analyses. RESULTS: The qualitative appraisal highlighted that only the MG Symptoms PRO captured physical fatigue. Data from 541 assessments (43 unique patients) were used for the analyses. Correlations ranged between 0.56 and 0.74 for the MG-ADL, QMG, MGC, and MG Symptoms PRO Muscle Weakness Fatigability score, and between 0.20 and 0.71 for the MG Symptoms PRO scores focusing on independent muscle groups. Analyses with the Rasch model estimated a meaningful continuum of severity of MG, including all items, except ocular muscles, from the four instruments. The QMG and MG Symptoms PRO had the broadest coverage of the MG severity continuum. Muscle fatigability and physical fatigue were more characteristic of low severity while bulbar weakness indicated more severe MG. CONCLUSION: The severity of MG can be reflected in a meaningful continuum underpinned by the MG-specific outcome measures. Only ocular muscle manifestations were shown to reflect a possibly different facet of MG severity. With its modular nature and comprehensive content, the MG Symptoms PRO provides complementary information to the outcome measures widely used in MG. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03052751.

An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised.

An increasing number of clinical trials are enrolling patients with myasthenia gravis (MG). A lack of standardization in the performance of outcome measures leads to confusion among site research teams and is a source of variability in clinical trial data. MGNet, the NIH-supported Rare Disease Clinical Research Network for MG, views standardization of MG outcome measures as a critical need. To address this issue, a group of experts summarized key outcome measures used in MG clinical trials and a symposium was convened to address issues contributing to outcome measure variability. Consensus recommendations resulted in changes to outcome measure instructions and, in some cases, modifications to specific instruments. Recommended changes were posted for public commentary before finalization. Changes to the MG-Activities of Daily Living, MG-Quality of Life-15r, and MG-Impairment Index were limited to adding details to the administration instructions. Recommendations for proper positioning of participants and how to score items that could not be performed because of non-MG reasons were provided for the MG Composite. The Quantitative MG (QMG) score required the most attention, and changes were made both to the instructions and the performance of certain items resulting in the QMG-Revised. The Postintervention Status was believed to have a limited role in clinical trials, except for the concept of minimal manifestation status. As a next step, training materials and revised source documents, which will be freely available to study teams, will be created and posted on the MGNet website. Further studies are needed to validate changes made to the QMG-Revised.

In recent years, there has been an increasing concern regarding the impact of pesticide exposure on pollinators, particularly honeybees (Apis mellifera L.). This concern arises from their crucial role in maintaining ecological balance and global food production. Therefore, an extensive investigation has been conducted to explore the intricate relationship between pesticides and the biological development of honey bees in the Rahim Yar Khan region. This study assessed the impact of four pesticides (Emamectin benzoate, Chlorpyrifos, Imidacloprid, and Acetamiprid) on honey bee eggs, larvae, and adult bees under controlled laboratory conditions. The pesticides were applied at concentrations of 10%, 30%, and 50%, as per regional agricultural recommendations. A zero-toxicity control was also included for comparison. Toxicity evaluations were conducted through contact exposure, and Probit and regression analyses were performed using SPSS software to comprehensively assess the toxicity profiles. The study revealed significant adverse effects on the immediate behavioral responses of A. mellifera following pesticide exposure. These effects included heightened agitation, narcotic-like symptoms, audible hovering, crawling, ceased food-sharing behavior, and reduced proboscis extension. Chlorpyrifos exhibited the highest toxicity against adult bees, while Emamectin Benzoate had the least toxicity. Regarding honey bee eggs, Chlorpyrifos, Imidacloprid, and Acetamiprid were notably more toxic, whereas Emamectin Benzoate exhibited the least toxicity. The impact on larvae varied across developmental stages and pesticides, with Imidacloprid, Chlorpyrifos, and Acetamiprid causing significant mortality, while Emamectin Benzoate showed lower toxicity. The study highlights that Emamectin Benzoate demonstrates lower toxicity compared to other insecticides. This emphasizes the importance of balancing effective pest management with the preservation of pollinator health. The findings underscore the need for informed and sustainable approaches to pesticide use, taking into consideration the potential repercussions on honeybee development and behavior.

INTRODUCTION: Social determinants of health (SDOH) are important contributors to health outcomes, and better understanding their impact on individuals diagnosed with rare, chronic diseases with high burden and unmet need is critical. Characterizing SDOH burden can help improve the design of patient support programs (PSPs), using targeted approaches to remove barriers to access. METHODS: This study used a mixed-methods strategy employing a quantitative survey, which was designed based on qualitative interviews, to understand the unmet needs and awareness/utilization of PSPs among individuals living with generalized myasthenia gravis (gMG) and experiencing SDOH barriers. The survey was completed by 38 individuals living with gMG, of which the majority were non-White/Caucasian, unemployed, low income, and enrolled in public insurance. Common SDOH challenges, awareness/utilization of available PSPs, and unmet needs were identified. RESULTS: Financial and mental health concerns were the most common among individuals living with gMG and experiencing SDOH barriers throughout diagnosis, accessing treatment, initiating treatment, and continuing treatment. Awareness and utilization of existing support services were low, especially when accessing treatment. Educational, financial, and personalized support with high human touch were commonly perceived as the most valuable resources. IMPLICATIONS: To better serve the needs of individuals with gMG experiencing SDOH barriers, PSPs should use a targeted approach to offer services tailored to harder-to-reach populations. Further, providers, advocacy groups, manufacturers, and public organizations in the gMG ecosystem should strengthen collaborations with PSPs to enable individuals living with gMG to access the services they need to improve their health outcomes.

Potato farming is a vital component of food security and the economic stability especially in the under developing countries but it faces many challenges in production, blackleg disease caused by Pectobacterium atrosepticum (Pa) is one of the main reason for damaging crop yield of the potato. Effective management strategies are essential to control these losses and to get sustainable potato crop yield. This study was focused on characterizing the Pa and the investigating new chemical options for its management. The research was involved a systematic survey across the three district of Punjab, Pakistan (Khanewal, Okara, and Multan) to collect samples exhibiting the black leg symptoms. These samples were analyzed in the laboratory where gram-negative bacteria were isolated and identified through biochemical and pathogenicity tests for Pa. DNA sequencing further confirmed these isolates of Pa strains. Six different chemicals were tested to control blackleg problem in both vitro and vivo at different concentrations. In vitro experiment, Cordate demonstrated the highest efficacy with a maximum inhibition zones of 17.139 mm, followed by Air One (13.778 mm), Profiler (10.167 mm), Blue Copper (7.7778 mm), Spot Fix (7.6689 mm), and Strider (7.0667 mm). In vivo, Cordate maintained its effectiveness with the lowest disease incidence of 14.76%, followed by Blue Copper (17.49%), Air One (16.98%), Spot Fix (20.67%), Profiler (21.45%), Strider (24.99%), and the control group (43.00%). The results highlight Cordate’s potential as a most effective chemical against Pa, offering promising role for managing blackleg disease in potato and to improve overall productivity.

Drought stress poses a significant threat to Brassica napus (L.), impacting its growth, yield, and profitability. This study investigates the effects of foliar application of individual and interactive pharmaceutical (Paracetamol; 0 and 250 mg L−1) and amino acid (0 and 4 ml/L) on the growth, physiology, and yield of B. napus under drought stress. Seedlings were subjected to varying levels of drought stress (100% field capacity (FC; control) and 50% FC). Sole amino acid application significantly improved chlorophyll content, proline content, and relative water contents, as well as the activities of antioxidative enzymes (such as superoxide dismutase and catalase) while potentially decreased malondialdehyde and hydrogen peroxide contents under drought stress conditions. Pearson correlation analysis revealed strong positive correlations between these parameters and seed yield (R2 = 0.8–1), indicating their potential to enhance seed yield. On the contrary, sole application of paracetamol exhibited toxic effects on seedling growth and physiological aspects of B. napus. Furthermore, the combined application of paracetamol and amino acids disrupted physio-biochemical functions, leading to reduced yield. Overall, sole application of amino acids proves to be more effective in ameliorating the negative effects of drought on B. napus.

IntroductionAnthracnose is a significant fungal disease that affects tree growth and development, with Colletotrichum spp. exhibiting host non-specificity and targeting various organs, making disease control challenging.MethodsThis study aimed to identify the pathogenic species causing anthracnose in Ilex macrocarpa in Nanchong, Sichuan Province, and screen effective fungicides, particularly biological ones. The pathogen was identified as Colletotrichum fioriniae through morphological observation, pathogenicity assays, and molecular biological methods. Three biological and five chemical fungicides were evaluated for their effects on the mycelial growth and spore germination rate of the pathogen.ResultsThe results indicated that prochloraz was the most effective chemical fungicide, while the cell-free supernatant (CFS) of Bacillus velezensis had the most significant inhibitory effect among the biological fungicides. Transcriptome analysis revealed that the CFS of B. velezensis significantly reduced the expression of genes associated with ribosomes, genetic information processing, membrane lipid metabolism, and sphingolipid biosynthesis in C. fioriniae. Additionally, the glutathione pathway’s expression of various genes, including key genes such as GST, GFA, Grx, TRR, and POD, was induced. Furthermore, the expression of 17 MFS transporters and 9 ABC transporters was increased. Autophagy-related ATGs were also affected by the B. velezensis CFS.DiscussionThese findings suggest that the B. velezensis CFS may inhibit C. fioriniae through interference with ribosomes, genetic information processing, cell membrane metabolism, and energy metabolism. These results provide potential target genes for the B. velezensis CFS and insights into the antifungal mechanism by which B. velezensis inhibits C. fioriniae.

Climate change and cadmium (Cd) contamination pose severe threats to rice production and food security. Biochar (BC) has emerged as a promising soil amendment for mitigating these challenges. To investigate the BC effects on paddy soil upon GHG emissions, Cd bioavailability, and its accumulation, a meta-analysis of published data from 2000 to 2023 was performed. Data Manager 5.3 and GetData plot Digitizer software were used to obtain and process the data for selected parameters. Our results showed a significant increase of 18% in soil pH with sewage sludge BC application, while 9% increase in soil organic carbon (SOC) using bamboo chips BC. There was a significant reduction in soil bulk density (8%), but no significant effects were observed for soil porosity, except for wheat straw BC which reduced the soil porosity by 6%. Sewage sludge and bamboo chips BC significantly reduced carbon dioxide (CO2) by 7–8% while municipal biowaste reduced methane (CH4) emissions by 2%. In the case of heavy metals, sunflower seedshells-derived materials and rice husk BC significantly reduced the bioavailable Cd in paddy soils by 24% and 12%, respectively. Cd uptake by rice roots was lowered considerably by the addition of kitchen waste (22%), peanut hulls (21%), and corn cob (15%) based BC. Similarly, cotton sticks, kitchen waste, peanut hulls, and rice husk BC restricted Cd translocation from rice roots to shoots by 22%, 27%, 20%, and 19%, respectively, while sawdust and rice husk-based BC were effective for reducing Cd accumulation in rice grains by 25% and 13%. Regarding rice yield, cotton sticks-based BC significantly increased the yield by 37% in Cd-contaminated paddy soil. The meta-analysis demonstrated that BC is an effective and multi-pronged strategy for sustainable and resilient rice cultivation by lowering greenhouse gas emissions and Cd accumulation while improving yields under the increasing threat of climate change.

Introduction/aimsIt is unknown if patients with neuromuscular diseases prefer in-person or virtual telemedicine visits. We studied patient opinions and preference on virtual versus in-person visits, and the factors influencing such preferences.MethodsTelephone surveys, consisting of 11 questions, of patients from 10 neuromuscular centers were completed.ResultsFive hundred and twenty surveys were completed. Twenty-six percent of respondents preferred virtual visits, while 50% preferred in-person visits. Sixty-four percent reported physical interaction as "very important." For receiving a new diagnosis, 55% preferred in-person vs 35% reporting no preference. Forty percent were concerned about a lack of physical examination vs 20% who were concerned about evaluating vital signs. Eighty four percent reported virtual visits were sufficiently private. Sixty eight percent did not consider expenses a factor in their preference. Although 92% were comfortable with virtual communication technology, 55% preferred video communications, and 19% preferred phone calls. Visit preference was not significantly associated with gender, diagnosis, disease severity, or symptom management. Patients who were concerned about a lack of physical exam or assessment of vitals had significantly higher odds of selecting in-person visits than no preference.DiscussionAlthough neither technology, privacy, nor finance burdened patients in our study, more patients preferred in-person visits than virtual visits and 40% were concerned about a lack of physical examination. Interactions that occur with in-person encounters had high importance for patients, reflecting differences in the perception of the patient-physician relationship between virtual and in-person visits.

Abstract In the current industrial scenario, cadmium (Cd) as a metal is of great importance but poses a major threat to the ecosystem. However, the role of micronutrient − amino chelates such as iron − lysine (Fe − lys) in reducing Cr toxicity in crop plants was recently introduced. In the current experiment, the exogenous applications of Fe − lys i.e., 0 and10 mg L − 1, were examined, using an in vivo approach that involved plant growth and biomass, photosynthetic pigments, oxidative stress indicators and antioxidant response, sugar and osmolytes under the soil contaminated with varying levels of Cd i.e., 0, 50 and 100 µM using two different varieties of canola i.e., Sarbaz and Pea − 09. Results revealed that the increasing levels of Cd in the soil decreased plant growth and growth-related attributes and photosynthetic apparatus and also the soluble protein and soluble sugar. In contrast, the addition of different levels of Cd in the soil significantly increased the contents of malondialdehyde (MDA) and hydrogen peroxide (H2O2), which induced oxidative damage in both varieties of canola i.e., Sarbaz and Pea − 09. However, canola plants increased the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and non-enzymatic compounds such as phenolic, flavonoid, proline, and anthocyanin, which scavenge the over-production of reactive oxygen species (ROS). Cd toxicity can be overcome by the supplementation of Fe − lys, which significantly increased plant growth and biomass, improved photosynthetic machinery and sugar contents, and increased the activities of different antioxidative enzymes, even in the plants grown under different levels of Cd in the soil. Research findings, therefore, suggested that the Fe − lys application can ameliorate Cd toxicity in canola and result in improved plant growth and composition under metal stress.

ObjectiveTo determine whether locally acting ACE-083 is safe, well tolerated, and increases muscle volume, motor function, and quality of life (QoL) in adults with Charcot-Marie-Tooth disease (CMT) type 1.MethodsThis phase 2 study enrolled adults with CMT1 or CMTX (N=63). Part 1 was open-label and evaluated safety and tolerability of different dose levels of ACE-083 for use in Part 2. Part 2 was a randomized, placebo-controlled, 6-month study of 240 mg/muscle ACE-083 injected bilaterally in the tibialis anterior muscle, followed by a 6-month, open-label extension in which all patients received ACE-083. Pharmacodynamic endpoints included total muscle volume (TMV; primary endpoint), contractile muscle volume (CMV), and fat fraction. Additional secondary endpoints included 6-minute walk test, 10-meter walk/run, muscle strength, and QoL. Safety was assessed with treatment-emergent adverse events (TEAEs) and clinical laboratory tests.ResultsIn Part 1 (n=18), ACE-083 was generally safe and well tolerated at all dose levels, with no serious AEs, TEAEs ≥Grade 3, or death reported. In Part 2 (n=45 enrolled, n=44 treated), there was significantly greater change in TMV with ACE-083 compared with placebo (LS mean difference: 13.5%; p = 0.0096). There was significant difference between ACE-083 and placebo for CMV and change in ankle dorsiflexion strength. Fat fraction and all other functional outcomes were not significantly improved by ACE-083. Moderate-to-mild injection-site reactions were the most common TEAEs.ConclusionsDespite significantly increased TMV and CMV, patients with CMT receiving ACE-083 in tibialis anterior muscles did not demonstrate greater functional improvement compared with those receiving placebo.Classification of evidenceThis study provides Class II evidence that intramuscular ACE-083 is safe, well tolerated, and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.

DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription-polymerase chain reaction or high-throughput RNA sequencing methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients.

Background The chickpea pod borer Helicoverpa armigera (Hübner) is a significant insect pest of chickpea crops, causing substantial global losses. Methods Field experiments were conducted in Central Punjab, Pakistan, to investigate the impact of biotic and abiotic factors on pod borer population dynamics and infestation in nine kabuli chickpea genotypes during two cropping seasons (2020–2021 and 2021–2022). The crops were sown in November in both years, with row-to-row and plant-to-plant distances of 30 and 15 cm, respectively, following a randomized complete block design (RCBD). Results Results showed a significant difference among the tested genotypes in trichome density, pod wall thickness, and leaf chlorophyll contents. Significantly lower larval population (0.85 and 1.10 larvae per plant) and percent damage (10.65% and 14.25%) were observed in genotype Noor-2019 during 2020–2021 and 2021–2022, respectively. Pod trichome density, pod wall thickness, and chlorophyll content of leaves also showed significant variation among the tested genotypes. Pod trichome density and pod wall thickness correlated negatively with larval infestation, while chlorophyll content in leaves showed a positive correlation. Additionally, the larval population positively correlated with minimum and maximum temperatures, while relative humidity negatively correlated with the larval population. Study results explore natural enemies as potential biological control agents and reduce reliance on chemical pesticides.

IntroductionThe mulberry industry has thrived in China for millennia, offering significant ecological and economic benefits. However, the prevalence of mulberry ring rot disease poses a serious threat to the quality and yield of mulberry leaves.MethodsIn this study, we employed a combination of transcriptomic and metabolomic analyses to elucidate the changes occurring at the transcriptional and metabolic levels in Morus notabilis in response to this disease infestation. Key metabolites identified were further validated through in vitro inhibition experiments.ResultsThe findings revealed significant enrichment in Kyoto Encyclopedia of Genes and Genomes pathways, particularly those related to flavonoid biosynthesis. Notably, naringenin, kaempferol, and quercetin emerged as pivotal players in M. notabilis’ defense mechanism against this disease pathogen. The upregulation of synthase genes, including chalcone synthase, flavanone-3-hydroxylase, and flavonol synthase, suggested their crucial roles as structural genes in this process. In vitro inhibition experiments demonstrated that kaempferol and quercetin exhibited broad inhibitory properties, while salicylic acid and methyl jasmonate demonstrated efficient inhibitory effects.DiscussionThis study underscores the significance of the flavonoid biosynthesis pathway in M. notabilis’ defense response against mulberry ring rot disease, offering a theoretical foundation for disease control measures.

This qualitative research seeks to address the political and Islamic discourses of Shah Abdul Latif Bhittai – an esteemed poet and philosopher of Sindh – on the rise of European colonialism in the Subcontinent. European colonialism was a threat to an established Muslim rule and a separate identity of Muslims in South Asia. The study incorporated thematic analysis to interpret the metaphors, narratives, and symbols fused by Shah Latif in his poetry to comprehend his philosophy of early call for resistance against the upsurge of European companies in the region. Through intensive assessment of Latif’s literary work – particularly his indispensable work ‘Shah Jo Risalo’ – the study identified themes associated with the continuation of culture, national identity, and insolence of foreign intrusion. Integrating the thematic analysis approach, the research enterprise expounds on the ideologies, narratives, strategies, and objectives of Shah Abdul Latif Bhittai to resist European imperialism in the region. The Sur Sarirag and Sur Raamkali have been reviewed and interpreted to address the main theme of this study. The findings of the study reveal that Bhittai’s early call for national resistance against the gradual growth of European imperialism is a beacon for national resistance and consciousness in the history of the South Asian region.

Background The fall armyworm, Spodoptera frugiperda, is an agricultural pest of significant economic concern globally, known for its adaptability, pesticide resistance, and damage to key crops such as maize. Conventional chemical pesticides pose challenges, including the development of resistance and environmental pollution. The study aims to investigate an alternative solution: the application of soluble silicon (Si) sources to enhance plant resistance against the fall armyworm. Methods Silicon dioxide (SiO2) and potassium silicate (K2SiO3) were applied to maize plants via foliar spray. Transcriptomic and biochemical analyses were performed to study the gene expression changes in the fall armyworm feeding on Si-treated maize. Results Results indicated a significant impact on gene expression, with a large number of differentially expressed genes (DEGs) identified in both SiO2 and K2SiO3 treatments. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis identified critical DEGs involved in specific pathways, including amino acid, carbohydrate, lipid, energy, xenobiotics metabolisms, signal transduction, and posttranslational modification, significantly altered at both Si sources. Biochemical analyses further revealed that Si treatments inhibited several enzyme activities (glutamate dehydrogenase, trehalase, glucose-6-phosphate dehydrogenase, chitinase, juvenile hormone esterase, and cyclooxygenase while simultaneously inducing others (total protein, lipopolysaccharide, fatty acid synthase, ATPase, and cytochrome P450), thus suggesting a toxic effect on the fall armyworm. In conclusion, Si applications on maize influence the gene expression and biochemical activities of the fall armyworm, potentially offering a sustainable pest management strategy.

This research venture attempts to revisit the repercussions of Pakistan’s alignment with the U.S. bloc during the reign of the Cold War against the spread of the former communist Soviet Union in the Asian region on its political landscape and Islamic identity. The study also seeks to explore the research gaps associated with Pakistan’s role as a key player in the interplay of the Cold War that changed its political dynamics and shaped religious identity. The findings of the study suggest that Pakistan’s role as a key player in the U.S. war against the spread of communism in the Asian region brought significant geopolitical and strategic changes coupled with shaping unprecedented religious and cultural identities. For instance, the emergence of religious extremism and hatred, sectarianism, terrorism, and militancy resulted from the refugee influx from Afghanistan caused by the Cold War rivalry between the United States and the former Soviet Union on Afghan soil. Finally, the paper fosters an understating of contemporary political and religious challenges to Pakistan by navigating the historical alignment of the country with the United States.

This research enterprise investigates the decolonial movements against the rule of British India and the subsequent spread of Islamism that shaped and influenced the socioeconomic, political, and cultural landscape of Pakistan. To understand this phenomenon, the study employed the analysis of historical events through thematic, discourse, and content analysis of narratives and texts. The data analyzed is based on the qualitative analysis of secondary sources of data. The core objective of the study is to understand the process of decolonization and the development of Islamic philosophy in Pakistan. The findings of the study suggest that the decolonization process has had a significant bearing on the formation and development of religious ideology in Pakistan paying way to the growth of Islamism as a unified cultural and political force in the country. The analysis of historical events also presents a sketch of the contemporary socio-economic, political, and cultural landscape of the country influenced by the ideological grounds.

Background Heavy metal pollution has become a global environmental issue. Heavy metals are contaminating the agro-soils, growing crops, and vegetables through different agricultural practices. In this study, besides the phytoremediation potential of maize, the role of chromium (Cr) and lead (Pb) on crop and soil health has been investigated. Methods Two maize varieties, Pak-Afgoi and Neelem, were grown under varying concentrations of Cr (50–300 ppm) and Pb (30–300 ppm) and different growth parameters i.e., seed germination, leaf size/number, stem girth, plant height, biomass, chlorophyll content, relative growth rate (RGR), and net assimilation rate (NAR) were studied under Cr and Pb stress. Likewise, the effect of metals was also assessed on different soil characteristics including soil texture, pH, EC, soil organic matter, urease activity and nutrients. Results Studied plant attributes were adversely affected by heavy metals toxicity. Affected values of RGR and NAR showed a linear correlation with affected growth and dry matter yield of maize. Heavy metals impacted different soil parameters including soil microbial performance and revealed a declining trend as compared to control soil. Maize varieties showed a significant phytoremediation potential i.e., uptake of Cr and Pb was 33% and 22% in Pak-Afgoi, while Neelem showed 38% and 24% at 300 ppm, respectively. Data regarding metal translocation factor (TF), bioaccumulation factor (ACF), and biomagnification ratio (BMR) significantly revealed the potential of maize varieties in the removal of Cr and Pb metals from affected soils. However, Cr-accumulation was higher in shoots, and Pb accumulated in plant roots showed a differential behavior of metal translocation and affinity with the varieties. These maize varieties may be recommended for general cultivation in the Cr and Pb-contaminated areas.

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

The Ouadi Rimé–Ouadi Achim Reserve (Réserve de l'Ouadi Rimé–Ouadi Achim) in central Chad supports large numbers of livestock and rare antelopes, and is the site of ongoing reintroductions of the scimitar-horned oryx Oryx dammah and addax Addax nasomaculatus. We present results of surveys conducted during 2011–2019 to examine patterns of relative abundance and distribution of dorcas gazelles Gazella dorcas, dama gazelles Nanger dama and livestock in relation to each other and to water sources in a 3,500 km2 area in the centre of the Reserve. Dorcas gazelles numbered 7,700–18,000, moving extensively across the area. Livestock varied between c. 2,000 and 68,000 tropical livestock units across surveys, with density doubling in the wet season. Dorcas gazelle distribution was negatively associated with livestock, and livestock density was positively associated with artificial water sources. Dorcas gazelle densities were positively associated with locations where there had been wild fires in the 6 months prior to a survey. Dama gazelles were encountered only 13 times, insufficient to estimate their population size reliably. Opportunistic observations suggest dama gazelles avoid livestock and burnt ground. Our findings highlight the importance of the Reserve. We recommend the designation of a large, well-managed conservation priority zone in the Reserve's core area in which no further development of water resources is permitted. Management of livestock numbers within this zone at or below current levels is essential to integrate national goals for both biodiversity conservation and pastoralism development.

Synthetic pesticides are excessively consumed to control crop pests but abundant use of chemicals may implicate the whole ecosystem badly in the end. Despite the growing concern, few natural products are commercialized for pest control whilst onfarm use of existing botanically-based pesticides remains a small, but growing, component of crop protection practice. The experiment was conducted to assess the potential trade-offs of using botanical extracts (Neem leaf extract, NLE, and Moringa leaf extract, MLE) along with synthetic insecticide, Confidor 200 SL, against Aphis gossypii Glover. Meanwhile, impact of these insecticides on natural enemies were also determined in the field experiment. Data were recorded 12h before, as well as 1, 3, and 7 days after the application (DPA) of insecticides. Results revealed that chemical insecticide after 1DPA were showed higher mortality (%) of aphid’s population at leaf (33%) and boll stage (41%), whereas, the botanical treated plots showed lower mortality used alone as well combined application but lower numbers were observed on the negative controls. The same trend of insecticidal activity was observed from all treatments after 3DPA, but interestingly, after 7DPA, the resurgence of beneficial insects were only recorded in botanical extract-treated plots. The Confidor presented an adverse effect on natural enemies whereas no or few natural enemies were observed compared to herbal extracts. Overall, for long-term control, the combined use of botanical insecticides is proved to be more efficient in the management of the aphids than Confidor and caused no or little adverse impact on the beneficial insects.

Human health is the main concern related to use of crop products irrigated with contaminated irrigation sources. Present research has been conducted to explore heavy metal status of sewage and industrial wastewater being used up for irrigation purpose in the peri-urban areas of the district Dera Ghazi Khan which has not been explored widely before. The analysis also followed heavy metal detection in the subsequent irrigated soil and vegetables/crop plants in relation to assessment of health risk to the consumer to plan the future monitoring in this area. An unremitting boost of heavy metals into the environment from wastewater irrigation has become a global issue. These heavy metals enter the food chain and pose health assumptions to consumers upon utilization. In the present study, an investigation has been conducted to determine metal concentrations in the wastewater, soil, and different plant species. For wastewater samples, pH, total dissolved solids (TDS), electrical conductivity (EC), and selected heavy metals such as Al, As, Cr, Cu, Fe, Mn, Pb, Zn, and Ni were determined. The mean values of heavy metals in the soil samples were within the WHO/FAO safe limit, while Cr and Pb were the most frequent (100%) among the metals. However, differentiating the sites, the concentration of Cr and Cu, Ni, and Fe were elevated. The metal transfer was highly effective from soil to the growing plants i.e. brinjal, red corn, wheat, tomato, and spinach than other plant species. Among the metals, Cr, Ni, Mn, and Pb in plant samples were exceeding the WHO/FAO safe limit. Health risk index (HRI) have revealed the possible potential risk of heavy metal contaminated plant species in the order of spinach (6.4) > wheat (6.4) > brinjal (5.9) > tomato (4.7) > red corn (4.5) > apple gourd (4.3) > white corn (3.8) > cabbage (3.1) > luffa (2.9). Likewise, HRI of different metals was calculated as Cu (19.6) > Zn (17.9) > Cr (2.95) > Ni (0.85) > Mn (0.48) > Fe (0.15) > Cd (0.11) > Pb (0.05) > As (0.00001). The level of HRI through the use of dietary plants revealed an elevated risk level than the acceptable limit (HRI > 1) for Cu > Zn > Cr in adults. Our findings suggest that there would be a serious health risk to the consumers due to the consumption of these plant species being irrigated with the wastewater. Therefore, a strict regulatory mechanism is proposed for the safety of food plants in the study area including monitoring and recycling of crop plants, and building water treatment plants to remove pollutants and clean wastewater.