A document by Ibrahim Nourwali. Click on the document to view its contents.

The use of adeno-associated virus (AAV) vectors in gene therapy has demonstrated great potential in treating genetic disorders. However, infusion-associated reactions (IARs) pose a significant challenge to the safety and efficacy of AAV-based gene therapy. This review provides a comprehensive summary of the current understanding of IARs to AAV therapy, including their underlying mechanisms, clinical presentation, and treatment options. Toll-like receptor activation and subsequent production of pro-inflammatory cytokines are associated with IARs, stimulating neutralizing antibodies and T-cell responses that interfere with gene therapy. Risk factors for IARs include high titers of pre-existing neutralizing antibodies, previous exposure to AAV, and specific comorbidities. Clinical presentation ranges from mild flu-like symptoms to severe anaphylaxis and can occur during or after AAV administration. There are no established guidelines for pre- and post-administration tests for AAV therapies, and routine laboratory requests are not standardized. Treatment options include corticosteroids, plasmapheresis, and supportive medications such as antihistamines and acetaminophen, but there is no consensus on the route of administration, dosage, and duration. This review highlights the inadequacy of current treatment regimens for IARs and the need for further research to improve the safety and efficacy of AAV-based gene therapy.

Background: Studies on post-COVID-19 condition (PCC) in adults have shown deterioration in pulmonary function tests (PFTs), mainly a diffusion limitation. Among pediatric population data are scarce. Aim: To characterize PFTs of children with PCC, including changes over time. Methods: A prospective longitudinal study of children with defined PCC and respiratory complaints referred to a designated multidisciplinary clinic from 11/2020 to 12/2022. Results: 184 children at a mean age of 12.4 years (SD 4.06) were included. A mild obstructive pattern was demonstrated in 19/170 (11%) at presentation, as indicated by spirometry and/or positive exercise challenge test and/or reversibility post bronchodilators- only 3 with a previous diagnosis of asthma. Lung volumes and diffusion were normal in all but one patient (1/134, 0.7%). [Exhaled nitric oxide](https://erj.ersjournals.com/content/21/1/43)  levels were elevated in 32/144 (22%). All 33 children who had repeated PFTs had normal or near-normal PFTs on following testing, including 7 (21.2%) who had mild obstructive PFTs at presentation. Multivariate analysis identified older age [OR 1.36 (95% CI:1.07-1.75)] and specific imaging findings [prominent bronchovascular markings (OR 43.28 (95% CI: 4.50-416.49)[ and hyperinflation ](OR 28.42, 95% CI: 2.18-370.84)] as significant predictors of an obstructive pattern on PFTs. Conclusion: In children with PCC and respiratory symptoms, the most common impairment was mild obstructive pattern; most of them without a history of asthma. Improvement was witnessed in long-term follow-up. As opposed to the adult population, no diffusion limitation was found. Empirical periodic inhaler therapy may be considered in children with factors associated with PFTs abnormalities.

AbstractTumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by renal phosphate wasting, which leads to deranged bone turnover. TIO is usually associated with benign mesenchymal tumors, although it has also been reported in malignant tumors. We report the case of a 56-year-old individual who presented with a long clinical course of hypophosphatemia, weakness, and kyphosis, associated with a tumor in the foot. After several years, this lesion exhibited malignant behavior and was diagnosed as a high-grade sarcoma. To date, this case is among the 10 reported cases in the literature of a mesenchymal tumor associated with TIO undergoing malignant transformation. This report underscores the importance of a comprehensive evaluation of patients with unexplained hypophosphatemia, and highlights the need for diligent follow-up to detect possible malignant transformation of the underlying tumor. Clinicians should consider TIO in the differential diagnosis of hypophosphatemia, and promptly investigate for the presence of an underlying tumor, as early detection may improve the patient’s prognosis.Key words: Oncogenic osteomalacia, Case Reports, Paraneoplastic Syndromes, Rickets, SarcomaIntroductionTumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic syndrome that was first described by McCance in 1947 (1). This condition is characterized by renal phosphate wasting, leading to disrupted bone turnover. Clinically, TIO presents with symptoms such as muscle weakness, bone pain, and fractures. Biochemically, TIO is marked by hypophosphatemia, hyperphosphaturia, normal or low levels of 1,25-dyhydroxi-vitamin D, elevated alkaline phosphatase, normal levels of calcium and parathyroid hormone (PTH), and notably high levels of fibroblast growth factor 23 (FGF23) (2,3). The exact incidence of TIO is not precisely known, but one of the largest studies in Denmark reported it to be below 0.13 per 100,000 person-years for the total population investigated (4). Tumors responsible for TIO are highly heterogeneous, but it is typically induced by mesenchymal tumors originating from soft tissue or bone. Recently, the World Health Organization has recognized phosphaturic mesenchymal tumors (PMT) as morphologically distinctive neoplasms that cause TIO (5). The majority of tumors causing TIO are PMTs, followed by hemangiopericytoma, giant cell tumor, and hemangioma. Only 10% of the tumors in a systematic review were found to be malignant, highlighting the rare occurrence of malignancy in TIO cases (6). Due to the rarity of this condition, the limited knowledge about the disease, and the unpredictable behavior of the underlying tumor, a definitive diagnosis may take years to establish.Case reportA 56-year-old man with hypertension presented with a six-year history of lumbar pain. Several months before his initial assessment, he developed progressive weakness in his lower extremities, leading to total disability. During the physical examination, the patient was bedridden, had a short stature, marked kyphosis, and generalized muscle weakness. His muscular reflexes were diminished, and there was no evidence of neuropathic involvement. Laboratory tests showed a normal complete blood count, preserved renal and hepatic function, negative serologic screening, and negative autoantibodies. A metabolic panel was ordered, revealing an elevation of alkaline phosphatase (543 IU/L), severe hypophosphatemia (phosphorus 1.0 mg/dL), and normal calcium levels (calcium 9.1 mg/dL). PTH levels were slightly above the normal range (57 pg/mL), and vitamin D levels were low (8 pg/mL). A 24-hour phosphorus excretion was 860 mg, and the fractional excretion of phosphorus was 51%, consistent with urinary phosphorus wasting in the context of hypophosphatemia. Urine analysis did not show any features of proximal tubule dysfunction. Hereditary rickets was unlikely given the patient’s age and lack of family history; instead, FGF23-dependent hypophosphatemia as a paraneoplastic syndrome was suspected, and a tumor localization work-up was initiated. Previous chest X-ray and thoraco-abdominal CT, were normal. A whole-body bone scintigraphy with technetium-99m-hydroxy-methylene-diphosphonate (TC99-HMDP) was ordered, revealing heterogeneous involvement of the maxilla, mandible, multiple ribs, right radius, sacrum, iliac, tibia, and bilateral calcaneus. Increased asymmetric uptake was observed in the right foot, so Tc99-Octreotide single photon emission computed tomography (SPECT/CT) and magnetic resonance (SPECT/MR) were performed, revealing a hypodense/hypointense localized lesion in the astragalus with lytic behavior, sclerotic border, and significantly increased metabolism, consistent with a mesenchymal tumor (Figure 1). The patient was referred for a surgical oncology consultation, but unfortunately, he was lost to follow-up.One year later, he returned to our clinic reporting a weight loss of 23 kg over the last three months and an exophytic tumor in the same region where the previous imaging studies had revealed abnormal uptake of Tc99-Octreotide (see Figure 2). A new chest CT scan showed multiple nodular lesions in the lungs, which were compatible with metastases. Histopathological analysis with immunohistochemistry of the foot tumor confirmed a diagnosis of high-grade sarcoma with fusiform, epithelioid, and pleomorphic patterns (Figure 3). The patient began receiving oncologic treatment with a dose-adjusted AIM regimen (doxorubicin, ifosfamide, mesna). Unfortunately, he had an adverse clinical course and died within the next two months.DiscussionTIO is a paraneoplastic syndrome characterized by the excessive expression of FGF-23. As a consequence, FGF-23 mediates the internalization of the sodium-phosphate cotransporter (NaPi) in renal tubular cells, leading to impaired reabsorption of phosphate by the kidneys. Moreover, FGF-23 inhibits the enzymatic hydroxylation of 25-hydroxyvitamin D in the kidneys, resulting in inadequate production of active 1,25-dihydroxyvitamin D, ultimately contributing to the pathogenesis of osteomalacia (7,8). Furthermore, FGF-23 in TIO can impact bone mineralization through indirect mechanisms. It has been shown to suppress the production of PTH. TThis reduction in PTH levels, mediated by FGF-23, hampers the release of calcium from bone, thereby exacerbating the mineralization abnormalities observed in TIO-induced osteomalacia (9). Furthermore, FGF-23 represses the transcription of the alkaline phosphatase gene, subsequently resulting in a diminished function of tissue-nonspecific alkaline phosphatase (TNALP) at the cell membrane. This inhibition results in a reduction in the breakdown of inorganic pyrophosphate, leading to decreased phosphate levels. In addition to this, osteopontin (OPN), a protein vital to the process of bone mineralization, has its production and release stimulated by extracellular phosphate. As such, through the suppression of TNALP gene transcription, FGF-23 indirectly attenuates the secretion of OPN, thus further modulating bone mineralization processes (10,11).Symptoms of TIO often persist for months or even years before a diagnosis is made. The initial symptomatology predominantly comprises musculoskeletal discomfort, including diffuse muscle pain and progressive weakness, often leading to substantial impairment in the patient’s mobility and quality of life. As the disease advances, it progressively impacts the skeletal system, resulting in debilitating bone pain. Furthermore, due to the decreased mineralization and consequent weakening of the bone structure, patients with TIO frequently experience pathological fractures. These fractures occur in bones under normal physiological stresses, highlighting the profound degree of bone fragility associated with this condition (12,13).TIO indeed represents a rare and unique disease entity. Although it predominantly manifests in middle-aged adults, it bears the potential to present across all age groups without displaying a particular gender predilection (14,15). As stated previously, it is associated with benign mesenchymal tumors in the vast majority of cases, approximately 90% (3). Yet, it is well-documented that malignant tumors, most notably sarcomas, also have the capacity to induce this condition (15–18)In cases lacking an initial biopsy, as in the patient under discussion, it becomes challenging to conclusively determine the tumor’s original nature. It remains uncertain whether the initial tumor was benign and subsequently underwent malignant transformation, or if the neoplasm was inherently sarcomatous. Given the patient’s extended history of hypophosphatemic symptoms spanning six years, the radiologic findings on the 99mTc-Octreotide Scintigraphy with SPECT/CT, and the abrupt onset and rapid progression of signs indicative of malignancy, including metastatic disease and substantial weight loss over a three-month period, the likelihood of malignant transformation is substantially high.The presentation of our patient, characterized by the manifestation of a localized mesenchymal tumor in the foot subsequently diagnosed as a high-grade sarcoma one year post TIO identification, brings to the fore the criticality of considering TIO in the differential diagnosis of unexplained hypophosphatemia. This case underscores the potential for malignant transformation within the clinical course of TIO, thereby emphasizing the imperative nature of vigilant longitudinal follow-up. Such conscientious monitoring is paramount in early detection of malignant transformation, thereby facilitating timely and appropriate therapeutic interventions, significantly impacting patient prognosis and the management of this complex disease.Disclosure and funding statementsWe declare that we have no conflict of interest and did not receive funding for the elaboration of the manuscript.References1. McCANCE RA. Osteomalacia with Looser’s nodes (Milkman’s syndrome) due to a raised resistance to vitamin D acquired about the age of 15 years. Q J Med. enero de 1947;16(1):33–46.2. Florenzano P, Hartley IR, Jimenez M, Roszko K, Gafni RI, Collins MT. Tumor-Induced Osteomalacia. Calcif Tissue Int. enero de 2021;108(1):128–42.3. Hautmann AH, Hautmann MG, Kölbl O, Herr W, Fleck M. Tumor-Induced Osteomalacia: an Up-to-Date Review. Curr Rheumatol Rep. junio de 2015;17(6):512.4. Abrahamsen B, Smith CD, Minisola S. Epidemiology of Tumor-Induced Osteomalacia in Denmark. Calcif Tissue Int. agosto de 2021;109(2):147–56.5. Choi JH, Ro JY. The 2020 WHO Classification of Tumors of Soft Tissue: Selected Changes and New Entities. Adv Anat Pathol. 2021;28(1):44-58. doi:10.1097/PAP.00000000000002846. Bosman A, Palermo A, Vanderhulst J, De Beur SMJ, Fukumoto S, Minisola S, et al. Tumor-Induced Osteomalacia: A Systematic Clinical Review of 895 Cases. Calcif Tissue Int. octubre de 2022;111(4):367–79.7. Chong WH, Molinolo AA, Chen CC, Collins MT. Tumor-induced osteomalacia. Endocr Relat Cancer. junio de 2011;18(3):R53-77.8. Jacquillet G, Unwin RJ. Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi). Pflugers Arch. enero de 2019;471(1):83–98.9. Berndt T, Kumar R. Phosphatonins and the regulation of phosphate homeostasis. Annu Rev Physiol. 2007;69:341–59.10. Nizet A, Cavalier E, Stenvinkel P, Haarhaus M, Magnusson P. Bone alkaline phosphatase: An important biomarker in chronic kidney disease - mineral and bone disorder. Clin Chim Acta Int J Clin Chem. febrero de 2020;501:198–206.11. Murali SK, Roschger P, Zeitz U, Klaushofer K, Andrukhova O, Erben RG. FGF23 Regulates Bone Mineralization in a 1,25(OH)2 D3 and Klotho-Independent Manner. J Bone Miner Res Off J Am Soc Bone Miner Res. enero de 2016;31(1):129–42.12. Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY, et al. Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol. enero de 2004;28(1):1–30.13. Boland JM, Tebben PJ, Folpe AL. Phosphaturic mesenchymal tumors: what an endocrinologist should know. J Endocrinol Invest. octubre de 2018;41(10):1173–84.14. Agaimy A, Michal M, Chiosea S, Petersson F, Hadravsky L, Kristiansen G, et al. Phosphaturic Mesenchymal Tumors: Clinicopathologic, Immunohistochemical and Molecular Analysis of 22 Cases Expanding their Morphologic and Immunophenotypic Spectrum. Am J Surg Pathol. octubre de 2017;41(10):1371–80.15. Weidner N, Bar RS, Weiss D, Strottmann MP. Neoplastic pathology of oncogenic osteomalacia/rickets. Cancer. el 15 de abril de 1985;55(8):1691–705.16. Rodriguez-Velver KV, Zapata-Rivera MA, Montes-Villarreal J, Lavalle-Gonzâlez FJ, González-González JG, Villarreal-Pérez JZ, et al. Tumour-induced Osteomalacia Secondary to a Sarcoma. Eur Endocrinol. agosto de 2016;12(2):104–6.17. Pallavi R, Ravella PM, Gupta P, Popescu A. A case of phosphaturic mesenchymal tumor. Am J Ther. 2015;22(2):e57-61.18. Olivas-Mazón R, Martín-Cazaña M, Pérez-Mohand P, Garzón-Lorenzo L, Espino-Hernández M, Baro-Fernández M, et al. Tumor-induced osteomalacia in an adolescent with an undifferentiated embryonal sarcoma of the liver. Pediatr Blood Cancer. julio de 2020;67(7):e28386.Figures:Figure 1. SPECT/MR showing a localized lesion in the right astragalus with significantly increased metabolism.Figure 2. Exophytic tumor in the right foot.Figure 3. H&E. Malignant mesenchymal neoplasm with spindle cells and epithelioid patterns.

Purpose：Transcatheter aortic valve replacement (TAVR) is a suitable option for elderly patients who are unable to undergo traditional thoracotomy. In this case, the patient was frail and had multiple underlying diseases, in addition to suffering from atrial septal defect and moderate to severe aortic stenosis and regurgitation, resulting in abnormalities in cardiac function and morphology. To address these issues, a combination of imaging methods such as three-dimensional ultrasound was used to guide the patient to undergo a one-stop transcatheter aortic valve replacement and interventional closure of atrial septal defect during the operation. This one-stop surgery required a highly professional team of doctors and advanced medical equipment. Methods：Prior to the surgery, a thorough assessment of the patient’s cardiac function was conducted using transthoracic echocardiography and transesophageal echocardiography. The degree of stenosis above and below the valve was also measured. During the procedure, real-time monitoring of the release of the self-expanding flap was done using TEE to guide the surgeon in adjusting the surgical strategy as needed. Postoperatively, transthoracic echocardiography is utilized to monitor the patient’s prognosis with accuracy. Results：Ultrasound assessment is a crucial tool in the perioperative period, serving as an essential screening method for surgical patients. Furthermore, it is instrumental in quantifying the degree of aortic valve stenosis, selecting valve size, and determining the optimal location for the surgical approach. By utilizing ultrasound-guided one-stop transcatheter aortic valve replacement and interventional closure of atrial septal defect, we were able to effectively address the patient’s heart condition and enhance their overall quality of life. Conclusion：This surgical technique involves replacing traditional surgery with a minimally invasive approach, which eliminates the need for a second open heart surgery and reduces trauma to the body. Furthermore, it considerably reduces the operation and postoperative recovery time. By utilizing minimally invasive techniques, patients can achieve significant surgical results in a shorter period and with a faster recovery time.

A document by Nishan Shrestha. Click on the document to view its contents.

Aim: Elamipretide is a mitochondrial-targeting agent being developed for the treatment of mitochondrial dysfunction-associated diseases. While prior studies have shown that subcutaneous elamipretide is generally safe/well tolerated, injection site reactions (ISRs) were reported in most subjects. We evaluated the efficacy of interventions to mitigate ISRs, identify underlying ISR mechanisms, and evaluate the pharmacokinetic and safety profile of subcutaneous elamipretide. Methods: Subcutaneous elamipretide 60 mg was administered to healthy subjects (N=10) on six separate occasions with/without potential ISR interventions (mometasone furoate, ice application, tacrolimus ointment, doxepin cream, and oral diphenhydramine). ISR clinical/self-assessments, blood samples, and safety data were collected at predetermined intervals. Preclinical studies investigated mast cell-specific receptor MRGPRX2 mediation of ISRs. Results: Mometasone significantly reduced the incidence of induration/swelling and pruritus. Diphenhydramine significantly decreased the incidence of induration; 50% reported somnolence. Ice application significantly reduced the incidence of pain, although it reduced elamipretide’s maximum plasma concentration and area-under-the-curve from time 0-6hrs versus elamipretide alone. Preclinical data suggest that SQ-elamipretide induced ISRs by activating MRGPRX2 in humans and its ortholog Mrgprb2 in mice. Conclusion: Elamipretide activated MRGPRX2 and Mrgprb2 receptors, resulting in activation of mast cells and inflammation in mouse models, suggesting that targeting mast-cell activation may ameliorate elamipretide ISRs. Topical mometasone prior to subcutaneous elamipretide demonstrated significant reductions in ISR signs and symptoms and did not cause significant changes in elamipretide plasma exposure or additional adverse events. Therefore, mometasone prior to subcutaneous injection of elamipretide warrants further investigation in clinical studies for alleviating ISRs.

Off-grid solar systems provide clean and affordable energy.Adoption of off-grid solar energy is becoming increasingly popular in Kenya as a source of renewable energy,with an estimated 6 million people now using off-grid solar power systems.However, the rising off-grid solar systems technology uptake comes with a growing amount of solar e-waste, which can have harmful environmental and health effects if not managed properly.Current data on the exact amount of solar e-waste being generated in Kenya is unavailable and this amount will continue to rise with the expiry of many of these off-grid solar systems lifespans.This study through stakeholder's workshop engagement and document analysis approaches,established that the country has robust general waste policy,legal and institutional framework but there is no specific policies and regulations on off grid-solar electronic waste management,just like it is the case in many developing countries. In addition, there is a lack of awareness on hazardous nature of off-grid solar systems e-waste to both consumers and institutions of governance.Furthermore,there is little enforcement of the general regulations in addition to inadequate management infrastructures.This calls for development of effective off-grid solar e-waste management policies and regulations within the backdrop of the rising uptake of off-grid solar energy systems in Kenya.

The neural circuits of reward processing and interval timing (including perception and production) are functionally intertwined, suggesting that it might be possible for momentary reward processing to influence subsequent timing behavior. Previous animal and human studies have mainly focused on the effect of reward on interval perception, whereas its impact on interval production is less clear. In this study, we examined whether feedback, as an example of performance-contingent reward, biases interval production. We recorded EEG from 20 participants while they engaged in a continuous drumming task with different realistic tempos (1728 trials per participant). Participants received color-coded feedback after each beat about whether they were correct (on time) or incorrect (early or late). Regression-based EEG analysis was used to unmix the rapid occurrence of a feedback response called the reward positivity (RewP), which is traditionally observed in more slow-paced tasks. Using linear mixed modelling, we found that RewP amplitude predicted timing behavior for the upcoming beat. This performance-biasing effect of the RewP was interpreted as reflecting the impact of fluctuations in dopaminergic activities on timing, and the necessity of continuous paradigms to make such observations was highlighted.

As the prevalence of electromagnetic interference (EMI) continues to rise, there is a growing demand for shielding materials, which play a crucial role in electronic devices, communication systems, and health protection etc. However, conventional EMI shielding materials encounter difficulties in effectively addressing the escalating intricacies of electromagnetic environments and diverse shielding scenarios, wherein foldability, flexibility and lightweight are desired. In this work, we develop a novel EMI shielding material, silver-hollow-fiber (AgHF), by combining blow-spinning, UV radiation and temperature-controlled annealing technologies. During fabrication process, UV radiation was used to selectively reduce silver ions on the outer surface of precursor fiber, and temperature-controlled annealing was further employed to remove the inside polymer, forming a hollow fiber structure. The AgHF exhibits superior flexibility, lightweight, remarkable mechanical stability, and excellent EMI shielding efficiency (SE). Particular, the AgHF with a thickness of 163 μm demonstrates an EMI SE of 101.65 dB, and with minimal degradation of less than 10% even after undergoing 2,000 bending cycles. The remarkable EMI shielding performance, combined with the lightweight, flexibility, and mechanical stability of AgHF, positions it as a highly promising material for a wide range of EMI shielding applications in the future.

Abstract: Background: The European Academy of Allergy and Clinical Immunology’s (EAACI) is updating the Guidelines on Food Allergy Diagnosis. We aimed to undertake a systematic review of the literature with meta-analyses to assess the accuracy of diagnostic tests for IgE-mediated food allergy. Methods: We searched three databases (Cochrane CENTRAL (Trials), MEDLINE (OVID) and Embase (OVID)) for diagnostic test accuracy studies published between 1 st October 2012 and 30 th June 2021 according to a previously published protocol (CRD42021259186). We independently screened abstracts, extracted data from full-texts, and assessed risk of bias with QUADRAS 2 tool in duplicate. Meta analyses were undertaken for food-test combination where 3 or more studies were available. Results: 149 studies comprising 24,489 patients met the inclusion criteria and were generally heterogeneous. 60.4% of studies were in children ≤12 years of age, 54.3% undertaken in Europe, ≥95% conducted in a specialized pediatric or allergy clinical setting and all included oral food challenge in at least a percentage of enrolled patients, in 21.5% DBPCFC. Skin prick test (SPT) with fresh cow’s milk and raw egg had high sensitivity (90% and 94%) for milk and cooked egg allergies. Specific IgE to individual components had high specificity: Ara h 2 had 92%, Cor a 14 95%, Ana o 3 94%, casein 93%, ovomucoid 92/91% for the diagnosis of peanut, hazelnut, cashew, cow’s milk and raw/cooked egg allergies, respectively. BAT was highly specific for the diagnosis of peanut (90%) and sesame (93%) allergies. Conclusions: SPT and specific IgE to extracts had high sensitivity whereas specific IgE to components and BAT had high specificity to support the diagnosis of individual food allergies. PROSPERO registration: CRD42021259186 Funding: European Academy of Allergy (EAACI).

While flocculation has demonstrated its efficacy in enhancing yeast robustness and ethanol production, its potential application for lactic acid fermentation remains largely unexplored. Our study examined the differences between flocculating and nonflocculating Saccharomyces cerevisiae strains in terms of their metabolic dynamics when incorporating an exogenous lactic acid pathway, across varying cell densities and in the presence of lignocellulose-derived byproducts. Comparative gene expression profiles revealed that cultivating a nonflocculant strain at higher cell density yielded a substantial upregulation of genes associated with glycolysis, energy metabolism, and other key pathways, resulting in elevated levels of fermentation products. Meanwhile, the flocculating strain displayed an inherent ability to sustain high glycolytic activity regardless of the cell density. Moreover, our investigation revealed a significant reduction in glycolytic activity under chemical stress, potentially attributable to diminished ATP supply during the energy investment phase. Conversely, the formation of flocs in the flocculating strain conferred protection against toxic chemicals present in the medium, fostering more stable lactic acid production levels. Additionally, the distinct flocculation traits observed between the two examined strains may be attributed to variations in the nucleotide sequences of the flocculin genes and their regulators. This study uncovers the potential of flocculation for enhanced lactic acid production in yeast, offering insights into metabolic mechanisms and potential gene targets for strain improvement.

Traditional deep neural network model training process will deepen the network to a certain number of layers will produce network degradation phenomenon, and then affect the training effect and prediction accuracy. To address this problem, a PV power prediction model based on deep residual network (DRN) and gated recurrent unit (GRU) neural network is proposed. Firstly, the Pearson correlation coefficient method is used to filter out the meteorological variables with high correlation with PV power from historical data and reduce the data dimensionality. Secondly, the DRN-GRU prediction model is proposed to be trained using the adaptive learning rate Adam optimization algorithm to obtain the optimal parameters. Finally, a DRN-GRU rolling prediction model is built based on the historical data series to derive the PV power prediction results. The results of the algorithm show that the model can still maintain good training effect in the network training of deep numbers, effectively solve the network degradation problem, and have higher prediction accuracy compared with models such as artificial neural networks and traditional convolutional neural networks.

This paper is based on the problems of difficulty in determining the location of practice teaching points on electronic maps, difficulties in multimedia knowledge distribution and complex and changeable field environment in previous physical geography and geology practice. The design implements a service system for physical Geography and Geology practice of Geodesy and Geomaticse, which is based on the WeChat Mini Program and combines the spatial database engine technology to solve the difficulties and problems in the above geological field practice process. This system can provide a platform for information inquiry and exchange for teachers and students in geological field practice, provide safety and decision-making assistance for interns. It has been applied in the 2022 physical Geography and Geology practice of China University of Geosciences, and provide reference and reference for relevant practical teaching and research.

AbstractIdentifying the areas and drivers of high-risk interfaces for human-wildlife interaction is crucial for managing and reversing human zoonotic disease risk. We suggest that continent-wide improvement to African housing is inadvertently creating roosting habitat for synanthropic free-tailed bats (family Molossidae), and opportunity for human exposure to bat-associated pathogens. We mapped building use by free-tailed bats from 1,109 buildings along a residential gradient in rural south-eastern Kenya where viruses of concern have been detected. We show that bats frequently roost in human-occupied buildings; almost one-in-ten buildings showed evidence of bat occupation (9.2%), and one-in-13 were active roosts (7.6%). We identified modern-build style and triangular roofing as building-level predictors of bat occupation, and the proportion of modern buildings as a landscape-level predictor of bat occupancy. Given the international focus on building improvement in Africa, and the increasing access to improved housing already reported in the literature, we suggest that this is a rapidly accelerating exposure interface that needs urgent attention and investment. Ethical pre-emptive exclusion of bats (by sealing bat entrance points) and restoration of natural roosting habitats should be prioritized as One Health land-use planning strategies in rural Africa.  Introduction The emergence and re-emergence of zoonotic disease is driven by ecosystem changes at the landscape level 1. Ecosystem disturbances through anthropogenic land use changes have been key drivers of emerging infectious diseases over the last century 2. Changes to ecosystem features – such as wildlife abundance, community composition, demography, behaviour, movement, contact patterns, and pathogen susceptibility – directly and indirectly alter the risk of pathogen transmission from wildlife to humans, through modifying disease dynamics within wildlife hosts and contact between wildlife and humans1. Because spatial overlap between wildlife reservoirs and humans is a key requirement for cross-species transmission (spillover), studies that investigate how human activities increase exposure to wildlife are critical for mitigating the transmission and emergence of zoonoses 3.Urbanisation commonly results in destruction and fragmentation of wildlife habitat, with ensuing encroachment creating human-wildlife interfaces at the edges of anthropogenic areas. For synanthropic wildlife, urbanisation can additionally create habitat and increase key resources, creating mosaics of human-wildlife interfaces within anthropogenic areas. Human pathogen exposure from synanthropic wildlife has been observed for various zoonoses, including tick-borne bacterial pathogens and viral infections (e.g., McFarlane et al. 2012; Bermúdez et al. 2016; Bermúdez et al. 2017). Identifying the specific drivers of these high-risk interfaces is especially important in global hotspots for emerging infectious diseases 7,8, countries with limited resources for disease surveillance, prevention and control7, and for taxonomic groups identified to harbour zoonotic pathogens 9. However, information on wildlife-human exposure remains limited for many under-resourced disease hotspots, particularly in sub-Saharan Africa and parts of Asia, as well as for many host taxa, including bats. These deficiencies are exacerbated by limited understanding of basic bat ecology in remote parts of Africa and Asia 10.African molossid bats, or free-tailed bats, are some of the most widely distributed and abundant bats on the African continent11. Several Molossid species host zoonoses-associated viral families, including corona-, filo-, paramyxo-, rota-, astro-, flavi-, and lyssaviruses12–17. Two Molossid species (Mops condylurusand Mops pumilus ) are also putative ebolavirus hosts, both showing evidence of infection in the wild, and the ability to replicate ebolaviruses without morbidity following experimental inoculation18–20.Synanthropic free-tailed bat species are increasingly using human-built structures as roosts, instead of natural roosts in tree hollows and rock crevasses 21. Continent-wide changes to African housing have seen human dwellings change from traditional buildings with natural materials (e.g., mud walls and thatch roofs), to modern-style buildings with finished materials and modern design elements, including structural beams and ceilings22. Spaces in ceilings, and between beams and walls, create roosting habitat for free-tailed bats, and appear to sustain larger colonies than natural roosts and traditional buildings (up to thousands in modern housing) 23. Changing patterns of bat-bat and bat-human contact through the use of these anthropogenic structures creates an exposure interface that may increase pathogen transmission, both among bat species and from bats to humans.Given the limited information available on basic bat ecology and wildlife-human exposure in remote parts of Africa, particularly at landscape scales, this study aimed to: 1) map high-risk interfaces of bat-human exposure along a residential gradient in rural south-eastern Kenya, and 2) to identify building- and landscape-level attributes of bat-human exposure risk. This study provides empirical information on the roosting of anthropogenic free-tailed bats in south-eastern Kenya, and describes the conditions in which housing improvement (without proper consideration of local bat ecology) could facilitate the emergence of zoonotic disease in remote parts of Africa. This information is critical to better understand bat-virus exposure interfaces that drive disease risk, and to inform strategies for One Health land-use planning in changing landscapes.

The present study sought to evaluate the reproducibility of prominent findings stated by Fehr et al. (2008) in their developmental resource allocation experiment. The experiment involved children making decisions about distributing sweets between themselves and either an in-group or an out-group recipient. Fehr et al. found that (1) inequity aversion develops with age; (2) 3- to 4-year-old children are inclined toward self-advantageous allocations, whereas 7- to 8-year-olds distribute sweets more evenly in divisions, and (3) the influence of group status increases as children age. In our attempts to reproduce Fehr et al.’s original analyses and reanalyse the raw data set, we found that one of the key variables was miscoded. After rectifying the miscoded variable, the reproduction results revealed only one ambiguously irreproducible result regarding a group status main effect in the sharing mini-game—with three other tests exhibiting either strong reproducibility or ambiguous reproducibility following the classifications suggested by Artner et al. (2021). Reanalysis results indicated that Fehr et al.’s conclusions are robust when tested with alternative analytical tests.

The alkenylzincation of internal alkynes is an effective method for the synthesis of multi-substituted conjugated dienes; however, the current catalytic systems for this reaction are limited in terms of substrate scope and selectivity control, which restricts its practical applications. Herein, we report the first iron-catalyzed alkenylzincation of internal alkynes, which features mild conditions, simple oper-ation, broad substrate scope (including aryl/alkyl, diaryl, and dialkyl acetylenes), excellent functional group tolerance (tolerating highly active functional groups such as ester, methylthio, amide, sulfonyl, cyano, etc), and high activity (with a turnover number of up to 11500, the highest record for carbometallation reactions). Notably, the catalytic system described in this article also realized the highly selective vinylzincation of unfunctionalized internal alkynes as well as the alkenylzincation of unsymmetrical diarylacetylenes and dial-kyl acetylenes, which have not been achieved with other catalytic systems reported in the literatures. The current study provides a highly selective access to synthetically important multi-substituted conjugated dienes.

Objectives: The aim of our study was to determine the efficacy of prophylactic desmopressin administered via intranasal or intravenous routes in reducing intraoperative bleeding during nasal surgery. We conducted a meta-analysis of relevant literature to investigate the role of preoperative desmopressin in minimizing bleeding complications associated with nasal surgery. Data Sources: Pubmed, SCOPUS, Google scholar, Embase, and the Cochrane Register of Controlled Trials Design& Setting: We screened the relevant literature published before February 2023. Nine articles that compared the perioperative use of desmopressin (treatment group) with a placebo or no treatment (control group) were included for this analysis of outcomes, which included intraoperative bleeding and postoperative morbidity in nasal surgery. Results: The treatment group showed significant improvement in intraoperative bleeding, surgical field, and surgeon satisfaction compared to the control group. However, prophylactic use of desmopressin was associated with elevated blood pressure and decreased serum sodium levels. Despite this, no significant adverse effects were reported in the included studies. Subgroup analyses comparing the route of administration (IV vs intranasal) and type of surgery (rhinoplasty vs ESS) showed that desmopressin had a beneficial effect on intraoperative bleeding and surgical field, regardless of the route of administration or type of surgery. Conclusion: The prophylactic use of desmopressin for nasal surgery effectively reduced intraoperative bleeding, improved the surgical field, and increased surgeon satisfaction with no significant adverse effects reported. However, caution should be exercised when administering desmopressin as it may cause an elevation in postoperative blood pressure in patients with cardiopulmonary problems. Level of Evidence: Ia

There still is inadequate literature regarding the surgical indications and postoperative outcomes of cochlear implantation (CI) in patients with Branchio-oto-renal syndrome; therefore, the aim of this study was to investigate whether CI surgery improved the hearing and speech performance of children with BOR syndrome-related severe hearing loss. Clinical manifestations, genetic results,audiological features, intraoperative findings and post-CI outcomes of four children were ascertained and analysed. All patients had bilateral profound HI before CI). The surgery of one patient with aural atresia and complex ear deformity was rather challenging, but the outcome after CI was satisfactory. However,auditory and speech performance of other three patients wasn’t good enough, which was probably related to cochlear nerve deficiency.

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/ CFS) is a disabling, chronic, multi-system and complex disease. Currently, there are no specific laboratory tests to directly [diagnose ME/CFS](https://www.cdc.gov/me-cfs/symptoms-diagnosis/diagnosis.html). In this work we study the use of impedance spectroscopy as a potential technique for the diagnosis of this disease. A specific device for the electrical characterization of peripheral blood mononuclear cells was designed and implemented. Impedance spectroscopy measurements in the range from 1 Hz to 500 MHz were made after osmotic stress of the samples with sodium chloride solution 1M. The evolution in time after the osmotic stress at two specific frequencies (1.36 kHz and 154 kHz) was analysed. The device showed its sensitivity to the presence of cells and the evolution of the osmotic process. Higher values of impedance were measured for 1.36 kHz in ME/CFS patients compared to control samples. Results help to further understand the relation of bioimpedance measurements with ME/CFS samples physical properties and osmotic processes.

Recognition of the role that biofilms play in the persistence of chronic wounds and lack of response to therapy in horses is increasing. Prevention of biofilm development in early stages of wound care involves three primary strategies: wound debridement and cleansing to reduce bacterial counts in the wound bed, appropriate use of advanced wound dressings, and implementation of topical antimicrobial agents. Once formed, eradication of biofilms requires elimination to improve the wound environment for contraction and epithelialization while not further harming the native cells integral to the healing process, which is achieved predominantly through repeated lavage and debridement combined with topical antimicrobial therapy. This review will establish why and how biofilms form, how to recognize clinical indications that biofilms have formed in equine wounds, and to review current diagnostic options and biofilm-based wound care (BBWC) strategies to eradicate biofilms. Clinical scenarios for cases in which biofilms developed and were successfully treated will be presented. This review will advance practitioners’ understanding of the presence and role of biofilms in chronic wounds and provide an updated summary of recommended treatment strategies.

The screening and identification of porcine epidemic diarrhea virus (PEDV) host restriction factors are of great significance for the prevention, control and treatment of porcine epidemic diarrhea (PED), but due to the lack of a suitable research platform, this field has been progressing slowly. In this study, label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantitatively identify the differentially expressed proteins (DEPs) between porcine kidney cell lines LLC-PK1 and PK15, whose susceptibility to PEDV was distinct. We identified 118 and 69 specific expressed proteins (fold changes >20 and with p < 0.05) in LLC-PK1 and PK15 cells, respectively. In addition, another 1138 DEPs, including 652 upregulated and 486 downregulated proteins, were identified in LLC-PK1 cells. Alterations in the expression of selected proteins were verified by western blot. Bioinformatics analyses, including GO, KEGG, and STRING, further demonstrated that the DEPs are involved in numerous crucial biological processes and signaling pathways, such as organelle organization, nucleotide binding, phagosome, lysosome, focal adhesion pathways and metabolic pathways. Altogether, this is the first proteomic study of porcine cell lines with high homology but different infectivity to PEDV, which shall provide valuable clues for further investigation of PEDV pathogenesis.

A document by Maria Perez Rubi. Click on the document to view its contents.

E.coli from broiler is a reservoir for ESBL (extended spectrum beta-lactamase) and presence of ESBL is a growing concern for antibiotic resistance. The aim of the study was to investigate and characterize ESBL and AmpC beta-lactamases in E. coli with traditional and new-generation methods. As well as biochemical analyses, the identification of isolates was performed with the MALDI-TOF MS. Within the scope of phyloproteomic analysis, all components of MALDI-TOF MS-based Principal Component Analysis (PCA) (dendrogram, scatter plotting, composit corelation index (CCI) and variance,) were applied. In the present study which is the first report for Duzce (Türkiye), 28.6% of 122 CFEC (chicken feces E. coli) isolates were identified as CFEC -ESBL. blaCTX-M, blaCTX-M-1, blaCTX-M-15, blaSHV, blaTEM, blaOXA-10, AmpC, blaCIT, blaMOX, blaSHV, blaCIT, and blaMOX genes were explored with PCR and blaCTX-M-1 gene was detected with the highest rate (68.5%). At least one of the resistance genes was detected in the phenotype screening tests, except one of the isolates (CFEC-ESBL-90). On the other hand CFEC-ESBL-38 contained only bla CTX-M-15 and the fact that this isolate was the only atypical ESBL strain with indole (-) and lac (-) characteristics among all isolates explains the highest variance (41%) and the most different from other PCA components. Also, this isolate had a high degree of similarity (87%; CCI) with the other isolate (CFEC-ESBL-90), which had low similarity to CFEC-ESBLs. As a result, phyloproteomic analyses with MALDI-TOF MS are considered to be beneficial in the characterization of phenotypic bacterial behavior.