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Abstract Background Tracheal cancer is a rare malignancy with limited research but high mortality rates. This study aims to analyse recent data to understand the global burden, trends, and risk factors for tracheal cancer, facilitating improved prevention and treatment strategies. Methods We conducted a study on tracheal cancer using data from the Global Cancer Observatory and the Cancer Incidence in Five Continents databases. We collected information on the incidence of tracheal cancer, risk factors, and the Human Development Index (HDI) at the country level. The univariate linear regression was used to explore the relationship between tracheal cancer and the various risk factors. We utilised joinpoint regression analysis to calculate the Average Annual Percentage Change (AAPC) in tracheal cancer incidence. Results The global age-standardised rate of incidence of tracheal cancer was 2.9 per 10 million (3,472 cases in total) in 2022, with the highest regional incidence observed in Central and Eastern Europe (ASR = 9.0) and the highest national incidence in Hungary (12.5). Higher incidence was found among the males (3.8) than females (2.0); among the older adults aged 50-74 (11.9) than the younger population aged 15-49 (1.2). A higher tracheal cancer incidence ratio was associated with higher levels of smoking, alcohol drinking, diabetes, lipid disorders, and HDI. Despite the overall decreasing trends for all population groups (highest decrease in Thailand; AAPC: -15.06, 95% CI: -21.76 to -7.78, p = 0.002), there was an increase in some female populations (highest increase in Colombia, AAPC: 19.28, 95% CI: 16.48 to 22.15, p

Stephen A LoBue,1,2 Sinan Albear,1,2 Curtis Martin,1 Alan Guagliardo,1 Tom Chang1 1Department of Ophthalmology, Acuity Eye Group, Pasadena, CA, USA; 2Department of Ophthalmology, SUNY Downstate Medical Center, Brooklyn, NY, USACorrespondence: Tom Chang, Acuity Eye Group, Vitreoretinal Surgeon, 100 E California Blvd, Pasadena, CA, 91105, USA, Email tchang@acuityeyegroup.comPurpose: To study the effects of anti–VEGF injections on the prevalence of ocular hypertension (OHT), sustained elevated intraocular pressure (SE-IOP), and primary open-angle glaucoma (POAG) with age-matched controls.Methods: A retrospective case-control study was performed with neovascular age-related macular degeneration (AMD) or diabetic macular edema (DME) against a control group involving atrophic AMD or diabetic retinopathy (DR) without DME. Bevacizumab, ranibizumab, or a combination of both were used in the treatment group. OHT was defined as IOP> 21 mm Hg while SE-IOP was defined as IOP that increased by > 6 mmHg or was > 25 mm Hg on two or more visits, 30 days apart. Patients with a pre-existing history of glaucoma, vein occlusions, IVI steroids, and pars plana vitrectomy were excluded.Results: A total of 1312 eyes of 784 patients were included in the study. Using age-matched controls, the treatment and control group was further refined to 394 eyes of 224 patients compared to 340 eyes from 170 patients respectively. The mean age was 58.4 ± 8.7 for the control versus 58.8 ± 8.8 years for the treatment group. The average IOP was higher in the injection group compared to the control with 25.8 ± 9.3 versus 19.5 ± 5.1 mmHg respectively, P< 0.001. Significant increases in POAG (10.7% vs 2.9%, p< 0.01), OHT (67.0% vs 22.4%, p< 0.001), and SE-IOP (41.1% vs 7.6%, p< 0.001) were seen in the injection group compared to the age-matched control group. The rates of POAG and OHT were positively associated with the number of injections, R2=0.856, P< 0.01 and R2=0.749, P< 0.05, respectively.Conclusion: Compared to age-matched controls, patients treated with anti-VEGF agents demonstrated an increased rate of OHT, SE-IOP, and POAG which correlated with the number of IVIs. However, additional prospective studies are needed to determine if there is a true association between intravitreal anti-VEGF injections and glaucoma.Keywords: intravitreal injection, IVI, sustained-elevated intraocular pressure, SE-IOP, primary open-angle glaucoma, POAG, age-related macular degeneration, AMD

Abstract The cardiac conduction system in large carnivores, such as the African lion (Panthera leo), represents a significant knowledge gap in both veterinary science and in cardiac electrophysiology. Short QT intervals have been reported from zoo‐kept, anaesthetized lions, and our goal was to record the first ECGs from wild, conscious lions roaming freely, and compare them to zoo‐kept lions under the hypothesis that short QT is unique to zoo‐kept lions. Macroscopic and histological examinations were performed on heart tissue removed from nine healthy zoo lions. ECGs were recorded from the nine anaesthetized zoo‐kept lions, and from 15 anaesthetized and conscious wild lions in Africa. Our histological and topographical description of the lion's heart matched what has previously been published. In conscious lions, the ECG recordings revealed a mean heart rate of 70 ± 4 beats/min, with faster heart rates during the night. PQ and QT intervals were heart rate dependent in the conscious lions. Interestingly, QT intervals recorded in wild lions were markedly longer than QT intervals from zoo lions (398 ± 40 vs. 297 ± 9 ms, respectively; P

Abstract Background Therapeutic digital health applications (DiGAs) are expected to significantly enhance access to evidence-based care. Since 2020, German physicians and psychotherapists have been able to prescribe approved DiGAs, which are reimbursed by statutory health insurance. This study investigates the usage, knowledge and perception of DiGAs as well as the growing digitalization among internal medicine physicians in Germany. Methods A web-based survey was distributed at the 2024 annual congress of the German Society for Internal Medicine. Participants could respond by scanning a QR code or directly on a tablet. Results A total of 100 physicians completed the survey, with a mean age of 43.4 years. The majority were internal medicine physicians (85%). Of the respondents, 31% had already prescribed DiGAs, and 29% had tested one. Self-rated knowledge of DiGAs was low (median score 3.17/10). The main barriers identified were lack of knowledge about effective implementation (60%), lack of time for patient onboarding (27%), and concerns about patient adherence (21%). However, 92% believed that DiGAs could improve care, and 88% expressed interest in specific digital health training. The majority (64%) stated that digitalization had a positive impact on medical care and 39% of physicians expected their daily workload to decrease due to digitalization. In addition, 38% believed that the physician-patient relationship would improve as a result of digitalization. Conclusions While physicians widely acknowledged the potential benefits of DiGAs, adoption and understanding remain limited. Specific training in digital health is crucial to accelerate digitalization in internal medicine.

Abstract Variants in mitochondrial genomes (mtDNA) can cause various neurological and mitochondrial diseases such as mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes (MELAS). Given the 16 kb length of mtDNA, continuous sequencing is feasible using long-read sequencing (LRS). Herein, we aimed to show a simple and accessible method for comprehensive mtDNA sequencing with potential diagnostic applications for mitochondrial diseases using the compact and affordable LRS flow cell “Flongle.” Whole mtDNA amplification (WMA) was performed using genomic DNA samples derived from four patients with mitochondrial diseases, followed by LRS using Flongle. We compared these results to those obtained using Cas9 enrichment. Additionally, the accuracy of heteroplasmy rates was assessed by incorporating mtDNA variants at equimolar levels. Finally, mtDNA from 19 patients with Parkinson’s disease (PD) was sequenced using Flongle to identify disease risk-associated variants. mtDNA variants were detected in all four patients with mitochondrial diseases, with results comparable to those obtained from Cas9 enrichment. Heteroplasmy levels were accurately detected (r2 > 0.99) via WMA using Flongle. A reported variant was identified in three patients with PD. In conclusion, Flongle can simplify the traditionally cumbersome and expensive mtDNA sequencing process, offering a streamlined and accessible approach to diagnosing mitochondrial diseases.

Abstract Young healthcare professionals and medical graduates often fall short in the practical experience necessary for handling medical emergencies. This can not only lead to strained feelings of inadequacy and insecurity among future physicians and less experienced healthcare providers in general, but also to detrimental outcomes for patients as emergency medicine demands rapid decision-making with low tolerance for errors. New didactic modalities and approaches may be needed to effectively address this shortcoming. Immersive technologies are powerful novel educational tools with untapped potential in medical training, and may be particularly suitable for simulation trainings in the high-stakes field of emergency medicine. Herein, we systematically explored the educational potential of extended reality (XR) technology, particularly virtual reality (VR), in the management of patients presenting as medical emergencies, combining the use of the STEP-VR application with an untethered hardware setup. Importantly, we aimed at studying multiple, large cohorts of senior medical students involving a total of 529 participants and collecting data over a period of two years. We assessed students’ acceptance of the training through a modified questionnaire measuring device handling, content complexity, degree of immersion, learning success, and seminar design. Our results show high, sustained acceptance and ease of use across different student cohorts and subgroups, with most students finding XR/VR engaging and beneficial for acquiring emergency medicine skills. Importantly, the prevalence of simulation sickness was minimal. Moreover, no major effect of the head-mounted displays (HMDs) price range was noted with regard to the learning experience. The results underscore the potential of XR/VR capabilities in effectively enhancing medical education, particularly in areas of high-stakes clinical scenarios and emergency care, by providing realistic and reproducible immersive training environments. In summary, our findings suggest that XR/VR-based training approaches could significantly contribute to preparing future physicians for the complexities of emergency medical care, encouraging the integration of such technologies into medical curricula. However, careful consideration must be given to its suitability for all students and the practical challenges of its implementation, highlighting the need for further research to harness its full potential for medical education.

Purpose: To compare anterior plate fixation (SP fixation) both alone and in combination with an additional posterior sacroiliac screw (SP+SIS fixation) as a treatment for pelvic ring injuries with widening of the pubic symphysis and disruption to the anterior sacroiliac ligaments. Methods: To find studies with pelvic ring injuries (APC II; B2.3d) and SP or SP+SIS fixation, a systematic literature review was conducted by searching four databases. A protocol was published a priori at Open Science Framework (https://doi.org/10.17605/OSF.IO/3YHAV). Exclusion criteria included perineal injuries, chronic instability of the symphysis, complete sacroiliac separation, and pediatric patients (age

Abstract Development of a vaccine against gonorrhoea is a global priority, driven by the rise in antibiotic resistance. Although Neisseria gonorrhoeae (Ng) infection does not induce substantial protective immunity, highly exposed individuals may develop immunity against re-infection with the same strain. Retrospective epidemiological studies have shown that vaccines containing Neisseria meningitidis (Nm) outer membrane vesicles (OMVs) provide a degree of cross-protection against Ng infection. We conducted a clinical trial (NCT04297436) of 4CMenB (Bexsero, GSK), a licensed Nm vaccine containing OMVs and recombinant antigens, comprising a single arm, open label study of two doses with 50 adults in coastal Kenya who have high exposure to Ng. Data from a Ng antigen microarray established that serum IgG and IgA reactivities against the gonococcal homologs of the recombinant antigens in the vaccine peaked at 10 but had declined by 24 weeks. For most reactive OMV-derived antigens, the reverse was the case. A cohort of similar individuals with laboratory-confirmed gonococcal infection were compared before, during, and after infection: their reactivities were weaker and differed from the vaccinated cohort. We conclude that the cross-protection of the 4CMenB vaccine against gonorrhoea could be explained by cross-reaction against a diverse selection of antigens derived from the OMV component.

Abstract Skeletal muscle contractions are initiated by action potentials, which are sensed by the voltage-gated calcium channel (CaV1.1) and are conformationally coupled to calcium release from intracellular stores. Notably, CaV1.1 contains four separate voltage-sensing domains (VSDs), which activate channel gating and excitation-contraction (EC-) coupling at different voltages and with distinct kinetics. Here we show that a single VSD of CaV1.1 controls skeletal muscle EC-coupling. Whereas mutations in VSDs I, II and IV affect the current properties but not EC-coupling, only mutations in VSD III alter the voltage-dependence of depolarization-induced calcium release. Molecular dynamics simulations reveal comprehensive, non-canonical state transitions of VSD III in response to membrane depolarization. Identifying the voltage sensor that activates EC-coupling and detecting its unique conformational changes opens the door to unraveling the downstream events linking VSD III motion to the opening of the calcium release channel, and thus resolving the signal transduction mechanism of skeletal muscle EC-coupling.

Sustainable energy is central to achieving the global Sustainable Development Goals (SDGs), particularly in electrifying underserved communities. This study examines Sigulu Island, which lacks grid electricity and relies on costly, polluting diesel generators. On-site assessments revealed a daily load demand of 1,455.705 kWh. This study designed and analyzed a Sustainable Techno-economic Hybrid Renewable Energy System (STHRES) combining solar photovoltaics and wind turbines, with battery backup, to meet the island's energy needs. The research adopted both qualitative and quantitative methods, gathering atmospheric weather conditions specific to Sigulu Island. Solar panels and wind turbines were identified as the most viable options, with the system incorporating 677 units of 1 kW solar panels and 27 units of 1 kW wind turbines, generating 839.97 kW and 640.08 kW daily, respectively. Additionally, 527 Li-ion batteries were used to store approximately 1480.05 kW of surplus energy demand to manage fluctuations capable of sustaining the island for 8 hours during a total blackout. The initial installation costs are estimated at $90,393.04 for solar PV, $27,729.82 for wind turbines, $159,169.81 for batteries, and $92,407.00 for the inverter. The STHRES is projected to save $56,917.93 annually, covering 15.4 % of the installation costs compared to diesel operations. Moreover, this system will reduce Uganda's carbon footprint by 436,035.6 kgCO₂ annually, equivalent to a 0.01 % reduction in national emissions. The proposed system decreases the Net Present Cost (NPC) from $426,617.60 to $369,699.67 and the Cost of Energy (COE) from $32.12/kWh to $ 27.79/kWh. With a 9 % Internal Rate of Return (IRR) and a 3 % Return on Investment (ROI), STHRES has a payback period of 8.2 years, demonstrating its financial and environmental benefits for Sigulu Island.

The Isle of Wight situated off the south coast of England is a special place for geological heritage. It is a microcosm of the geology of southern England, with a huge reputation as the home of British dinosaurs. Dinosaur Isle Museum has been the vehicle to take a small local collection to international recognition. This brief account focusing on the museum, explores the role of place in where geological museums are located. The Museum is located close to numerous internationally significant Early Cretaceous geological field localities. Whereas place is important, it is the role of fossils, dinosaurs in particular, in the local economy and culture which has been the sustaining factor for the museum, and therefore its continued role in geoconservation.

Hereditary spastic paraplegias (HSPs) are a diverse set of neurological disorders characterized by progressive spasticity and weakness in the lower limbs caused by damage to the axons of the corticospinal tract. More than 88 genetic mutations have been associated with HSP, yet the mechanisms underlying these disorders are not well understood. We replicated the pathophysiology of one form of HSP known as spastic paraplegia 15 (SPG15) in zebrafish. This disorder is caused in humans by mutations in the ZFYVE26 gene, which codes for a protein called SPASTIZIN. We show that, in zebrafish, the significant reduction of Spastizin caused degeneration of large motor neurons. Motor neuron degeneration is associated with axon demyelination in the spinal cord and impaired locomotion in the spastizin mutants. Our findings reveal that the reduction in Spastizin compromises axonal integrity and affects the myelin sheath, ultimately recapitulating the pathophysiology of HSPs.

Abstract Maintenance of water homeostasis is a fundamental cellular process required by all living organisms. Here, we use the single-celled green alga Chlamydomonas reinhardtii to establish a foundational understanding of osmotic-stress signaling pathways through transcriptomics, phosphoproteomics, and functional genomics approaches. Comparison of pathways identified through these analyses with yeast and Arabidopsis allows us to infer their evolutionary conservation and divergence across these lineages. 76 genes, acting across diverse cellular compartments, were found to be important for osmotic-stress tolerance in Chlamydomonas through their functions in cytoskeletal organization, potassium transport, vesicle trafficking, mitogen-activated protein kinase and chloroplast signaling. We show that homologs for five of these genes have conserved functions in stress tolerance in Arabidopsis and reveal a novel PROFILIN-dependent stage of acclimation affecting the actin cytoskeleton that ensures tissue integrity upon osmotic stress. This study highlights the conservation of the stress response in algae and land plants, and establishes Chlamydomonas as a unicellular plant model system to dissect the osmotic stress signaling pathway.

Abstract Metabolic reprogramming and energetic rewiring are hallmarks of cancer that fuel disease progression and facilitate therapy evasion. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipid metabolism. Through the suppression of BCAA availability, we report significantly reduced lipid content, strongly indicating that BCAAs are important lipogenic fuels in PCa. This work also uncovered a novel compensatory mechanism, whereby fatty acid uptake is increased in response to extracellular valine deprivation. Inhibition of valine degradation via suppression of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) resulted in a selective reduction of malignant prostate cell proliferation, decreased intracellular succinate and impaired cellular respiration. In combination with a comprehensive multi-omic investigation that incorporates next-generation sequencing, metabolomics, and high-content quantitative single-cell imaging, our work highlights a novel therapeutic target for selective inhibition of metabolic reprogramming in PCa.

Abstract The present study aimed to assess mosquito species diversity, distribution, and ecological preferences in the Covè, Ouinhi, and Zangnanado communes, Southern Benin. Such information is critical to understand mosquito bio-ecology and to focus control efforts in high-risk areas for vector-borne diseases. Mosquito collections occurred quarterly in 60 clusters between June 2020 and April 2021, using human landing catches. In addition to the seasonal mosquito abundance, Shannon's diversity, Simpson, and Pielou's equitability indices were also evaluated to assess mosquito diversity. Ecological niche models were developed with MaxEnt using environmental variables to assess species distribution. Overall, mosquito density was higher in the wet season than in the dry season in all communes. A significantly higher Shannon's diversity index was also observed in the wet season than in the dry seasons in all communes (p

Abstract Background Clinical trials investigating acetabular fractures are heterogeneous in their investigated outcomes and their corresponding measurements. Standardization may facilitate comparability and pooling of research results, which would lead to an increase in knowledge about the optimal treatment of acetabular fractures, resulting in long-term evidence-based treatment decisions and improvements in patient care. The aim of this systematic review is to identify the reported outcomes and their measurements from studies on treatments for acetabular fractures to develop a core outcome set which contains the most relevant outcome measures to be included in future studies. Methods Studies published in English and German including patients aged 16 years and older, with a surgically treated acetabular fracture, will be included. Studies with nonsurgical treatment, pathologic fractures, polytraumatized patients, and patients younger than 16 years of age will be excluded because other outcomes may be of interest in these cases. Any prospective and retrospective study will be included. Systematic reviews will be excluded, but their included studies will be screened for eligibility. The literature will be searched on MEDLINE, CENTRAL, Web of Science, ClinicalTrials.gov, and WHO ICTRP. Risk of selective reporting of outcomes will be assessed using the Outcome Reporting Bias in Trials classification system. Heterogeneously defined outcomes that measure the same outcome will be grouped and subsequently categorized into outcome domains using the taxonomy of the Core Outcome Measures in Effectiveness Trials Initiative. Discussion It is expected that a high number of studies will be included, and many outcomes will be identified using different definitions and measurement instruments. A limitation of this systematic review is that only previously investigated outcomes will be detected, thus disregarding potentially relevant outcomes. Systematic review registration PROSPERO CRD42022357644

Abstract The millions of specimens stored in entomological collections provide a unique opportunity to study historical insect diversity. Current technologies allow to sequence entire genomes of historical specimens and estimate past genetic diversity of present-day endangered species, advancing our understanding of anthropogenic impact on genetic diversity and enabling the implementation of conservation strategies. A limiting challenge is the extraction of historical DNA (hDNA) of adequate quality for sequencing platforms. We tested four hDNA extraction protocols on five body parts of pinned false heath fritillary butterflies, Melitaea diamina, aiming to minimise specimen damage, preserve their scientific value to the collections, and maximise DNA quality and yield for whole-genome re-sequencing. We developed a very effective approach that successfully recovers hDNA appropriate for short-read sequencing from a single leg of pinned specimens using silica-based DNA extraction columns and an extraction buffer that includes SDS, Tris, Proteinase K, EDTA, NaCl, PTB, and DTT. We observed substantial variation in the ratio of nuclear to mitochondrial DNA in extractions from different tissues, indicating that optimal tissue choice depends on project aims and anticipated downstream analyses. We found that sufficient DNA for whole genome re-sequencing can reliably be extracted from a single leg, opening the possibility to monitor changes in genetic diversity maintaining the scientific value of specimens while supporting current and future conservation strategies.

Abstract The present cluster-randomised control trial aims to assess the entomological efficacy of pyrethroid-pyriproxyfen and pyrethroid-chlorfenapyr LLINs compared to the standard pyrethroid-only LLINs, in their third year of community usage. Adult mosquito collections were performed every 3 months, in 4 randomly selected houses in each of the 60 trial clusters, using human landing catches. Adult mosquitoes were morphologically identified and Anopheles vectors were molecularly speciated and screened for the presence of the L1014F kdr mutation using PCR. Plasmodium falciparum sporozoite infection was assessed using ELISA. A subset of An. gambiae s.l. was also dissected to examine parity and fertility rates across study arms. There was no evidence of a significant reduction in indoor vector density and entomological inoculation rate by the pyrethroid-pyriproxyfen [DR 0.94 (95% CI 0.46–1.88), p = 0.8527; and RR 1.10 (95% CI 0.44–2.72), p = 0.8380], and pyrethroid-chlorfenapyr [DR 0.74 (95% CI 0.37–1.48), p = 0.3946; and RR 1.00 (95% CI 0.40–2.50), p = 0.9957] LLINs, respectively. The same trend was observed outdoors. Frequencies of the L1014F kdr mutation, as well as parous and fertility rates, were similar between study arms. In the third year after net distribution, entomological indicators show that the two dual active-ingredients nets performed similarly to the standard pyrethroid-only LLIN. To maintain malaria gains, it is crucial that net distribution cycles fit with their operational lifespan.

Abstract Background Ureteral cancer is a rare cancer. This study aimed to provide an up-to-date and comprehensive analysis on the global trends of ureteral cancer incidence and its association with lifestyle and metabolic risk factors. Methods The incidence of ureteral cancer was estimated from the Cancer Incidence in Five Continents Plus and Global Cancer Observatory databases. We analyzed the (1) global incidence of ureteral cancer by region, country, sex, and age group by age-standardized rates (ASR); (2) associated risk factors on a population level by univariable linear regression with logarithm transformation; and (3) incidence trend of ureteral cancer by sex and age group in different countries by Average Annual Percentage Change (AAPC). Results The global age-standardized rate of ureteral cancer incidence in 2022 was 22.3 per 10,000,000 people. Regions with higher human development index (HDI), such as Europe, Northern America, and East Asia, were found to have a higher incidence of ureteral cancer. Higher HDI and gross domestic product (GDP) and a higher prevalence of smoking, alcohol drinking, physical inactivity, unhealthy dietary, obesity, hypertension, diabetes, and lipid disorder were associated with higher incidence of ureteral cancer. An overall increasing trend of ureteral cancer incidence was observed for the past decade, especially among the female population. Conclusions Although ureteral cancer was relatively rare, the number of cases reported was rising over the world. The rising trends among females were more evident compared with the other subgroups, especially in European countries. Further studies could be conducted to examine the reasons behind these epidemiological changes and confirm the relationship with the risk factors identified.

Abstract With improvements in survival for patients with metastatic cancer, long-term local control of brain metastases has become an increasingly important clinical priority. While consensus guidelines recommend surgery followed by stereotactic radiosurgery (SRS) for lesions >3 cm, smaller lesions (≤3 cm) treated with SRS alone elicit variable responses. To determine factors influencing this variable response to SRS, we analyzed outcomes of brain metastases ≤3 cm diameter in patients with no prior systemic therapy treated with frame-based single-fraction SRS. Following SRS, 259 out of 1733 (15%) treated lesions demonstrated MRI findings concerning for local treatment failure (LTF), of which 202 /1733 (12%) demonstrated LTF and 54/1733 (3%) had an adverse radiation effect. Multivariate analysis demonstrated tumor size (>1.5 cm) and melanoma histology were associated with higher LTF rates. Our results demonstrate that brain metastases ≤3 cm are not uniformly responsive to SRS and suggest that prospective studies to evaluate the effect of SRS alone or in combination with surgery on brain metastases ≤3 cm matched by tumor size and histology are warranted. These studies will help establish multi-disciplinary treatment guidelines that improve local control while minimizing radiation necrosis during treatment of brain metastasis ≤3 cm.

Abstract Digestive Chagas disease (DCD) is an enteric neuropathy caused by Trypanosoma cruzi infection. There is a lack of evidence on the mechanism of pathogenesis and rationales for treatment. We used a female C3H/HeN mouse model that recapitulates key clinical manifestations to study how infection dynamics shape DCD pathology and the impact of treatment with the front-line, anti-parasitic drug benznidazole. Curative treatment 6 weeks post-infection resulted in sustained recovery of gastrointestinal transit function, whereas treatment failure led to infection relapse and gradual return of DCD symptoms. Neuro/immune gene expression patterns shifted from chronic inflammation to a tissue repair profile after cure, accompanied by increased cellular proliferation, glial cell marker expression and recovery of neuronal density in the myenteric plexus. Delaying treatment until 24 weeks post-infection led to partial reversal of DCD, suggesting the accumulation of permanent tissue damage over the course of chronic infection. Our study shows that murine DCD pathogenesis is sustained by chronic T. cruzi infection and is not an inevitable consequence of acute stage denervation. The risk of irreversible enteric neuromuscular tissue damage and dysfunction developing highlights the importance of prompt diagnosis and treatment. These findings support the concept of treating asymptomatic, T. cruzi-infected individuals with benznidazole to prevent DCD development.

Sculpins (coastrange and slimy) and sticklebacks (ninespine and threespine) are widely distributed fishes cohabiting 2 south-central Alaskan lakes (Aleknagik and Iliamna), and all these species are parasitized by cryptic diphyllobothriidean cestodes in the genus Schistocephalus. The goal of this investigation was to test for host-specific parasitic relationships between sculpins and sticklebacks based upon morphological traits (segment counts) and sequence variation across the NADH1 gene. A total of 446 plerocercoids was examined. Large, significant differences in mean segment counts were found between cestodes in sculpin (mean = 112; standard deviation [s.d.] = 15) and stickleback (mean = 86; s.d. = 9) hosts within and between lakes. Nucleotide sequence divergence between parasites from sculpin and stickleback hosts was 20.5%, and Bayesian phylogenetic analysis recovered 2 well-supported clades of cestodes reflecting intermediate host family (i.e. sculpin, Cottidae vs stickleback, Gasterosteidae). Our findings point to the presence of a distinct lineage of cryptic Schistocephalus in sculpins from Aleknagik and Iliamna lakes that warrants further investigation to determine appropriate evolutionary and taxonomic recognition.

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a disease resulting from an overactive type 2 response to Aspergillus. Initial studies suggest that asthma biologics can effectively treat ABPA, but it is unclear which biologic class is superior. Objective: We sought to compare the effectiveness of asthma biologics in the treatment of ABPA. Methods: We performed a retrospective analysis of patients with ABPA treated with asthma biologics, and measured outcomes of respiratory exacerbations, daily oral corticosteroids, and antifungals. We assessed these variables while individuals were treated with 1 of 3 biologic classes: anti-IgE, anti–IL-5/IL-5 receptor alpha (IL-5Ra), anti–IL-4 receptor alpha (IL-4Ra). Results: A total of 21 patients were included in our analysis. Anti–IL-4Ra was associated with a significantly lower number of exacerbations and oral corticosteroid use compared with anti-IgE or anti–IL-5/IL-5Ra therapies. Anti–IL-4Ra also had significantly lower antifungal use than anti-IgE, and there was a trend toward lower antifungal use when compared with anti–IL-5/IL-5Ra. In a subgroup of 10 patients treated with 2 or more biologics sequentially, we found that 8 of them achieved clinical control on anti–IL-4Ra therapy after failing anti-IgE and/or anti–IL-5/IL-5Ra therapies. Conclusions: Dupilumab blocks the IL-4Ra, resulting in the downstream inhibition of both IL-4 and IL-13 effector pathways. Dupilumab may benefit patients with ABPA by inhibiting the generation of airway mucus (IL-13), and by reducing local B-cell differentiation into IgE antibody–secreting cells (IL-4). On the basis of our findings and with the known molecular mechanisms of dupilumab, we believe that anti–IL-4Rα–targeted therapy may be more effective than anti-IgE or anti–IL-5/IL-5Rα therapies to treat ABPA.

Background: Assessing for significant proteinuria in pregnancy (SPIP) stands as a key indicator for diagnosing preeclampsia. However, the initial method typically employed for this assessment, the urine dipstick test, often yields inaccurate results. While a 24-h urine collection is considered the most reliable test, its implementation can lead to delays in diagnosis, potentially affecting both maternal and fetal well-being. The urine protein–creatinine (P/Cr) ratio can be used as an alternative to 24-h urine protein analysis, but its diagnostic accuracy has remained uncertain. There is a need to compare the diagnostic accuracy of urine P/Cr ratio and dipstick urinalysis for SPIP, especially in resource-poor settings. Objectives: To determine and compare the diagnostic accuracy of urine P/Cr ratio and dipstick urinalysis in a spot urine specimen for the diagnosis of SPIP among women evaluated for preeclampsia using 24-h urine protein excretions as a gold standard. Design: This is a comparative cross-sectional study. Methods: The study involved 82 singleton pregnant women evaluated for preeclampsia from 20 weeks of gestation who underwent dipstick and P/Cr ratio tests in the same urine sample. Women at risk of preeclampsia were given a specimen container for the collection of urine samples on an outpatient basis. Participants were trained and told to collect the urine sample 24 h prior to their next antenatal appointment. However, those on admission and evaluated for preeclampsia had their 24-h urine collected in the hospital. The outcome measures included sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio and accuracy for the two tests. Significant proteinuria was defined as a P/Cr ratio >0.27 or ⩾2+ of proteinuria on the dipstick test. Preeclampsia was confirmed in women with both high blood pressure and SPIP. Results: The mean age of participants was 28.65 ± 5.76 years. Comparatively, the diagnostic accuracy (91.46% (95% CI = 83.29–96.59) vs 59.76% (95% CI = 48.34–70.44), p = 0.001), sensitivity (94.74% vs 70.00%, p = 0.021), specificity (84.00% vs 43.75%, p = 0.001), negative predictive value (87.50% vs 48.28%, p = 0.003) and positive predictive value (93.10% vs 66.04%, p = 0.001), respectively, were higher for the spot urine P/Cr ratio than dipstick test. In addition, the positive likelihood ratio and the negative likelihood ratio for spot urine P/Cr ratio versus dipstick test were (1.93 vs 1.24) and (0.07 vs 0.69), respectively. Conclusion: The spot urine P/Cr has superior diagnostic accuracy in the determination of significant proteinuria in pregnant women being evaluated for preeclampsia than the widely used dipstick test. A more robust multicenter study is needed to compare the diagnostic accuracy of spot urine PCR with the standard 24-h urine protein in low-income settings.

Background: This study investigated the impact of socio-economic variables influencing the provision of basic skills for navigating the challenges of the Fourth Industrial Revolution (4IR). Objectives: The study aims to describe the variables underpinning this study, using statistical analysis and quantitative measurement as displayed in Table 1. It also investigates the role of socio-economic variables, using a Chi-Square test and Multinomial Logistic Regression techniques, in the provision of basic skills for handling direct and indirect challenges of the 4IR. Further, it attempts to provide recommendations, based on research findings, on strategies for ensuring that long-distance truck drivers are well-equipped with the necessary skills for meeting the demands of the 4IR. Method: The study utilised a quantitative research method. A multinomial regression model was used to describe long-distance truck driver data collected in South Africa. A total of 314 participants completed the questionnaire. Results: Results revealed that variables such as driver’s education level, frequency of route usage, company type, and driver’s work location are significant predictors in predicting whether a given truck driver possesses basic skills for handling the challenges of the 4IR. This finding holds significant practical implications, as it allows for targeted interventions and tailored strategies aimed at effectively addressing the identified predictors to encourage the desired response of having long-distance truck drivers equipped with essential 4IR skills. Conclusion: This study contributes to the body of knowledge regarding factors affecting long-distance truck drivers in getting basic 4IR skills essential for them to properly implement new technologies arising in the haulage trucking industry. Contribution: It documents the experiences of long-distance truck drivers in the face of newly emerging technologies in the transport industry.

ABSTRACT Lugdunin is a microbiome-derived antibacterial agent with good activity against Gram-positive pathogens in vitro and in animal models of nose colonization and skin infection. We have previously shown that lugdunin depletes bacterial energy resources by dissipating the membrane potential of Staphylococcus aureus. Here, we explored the mechanism of action of lugdunin in more detail and show that lugdunin quickly depolarizes cytoplasmic membranes of different bacterial species and acidifies the cytoplasm of S. aureus within minutes due to protonophore activity. Varying the salt species and concentrations in buffers revealed that not only protons are transported, and we demonstrate the binding of the monovalent cations K+, Na+, and Li+ to lugdunin. By comparing known ionophores with various ion transport mechanisms, we conclude that the ion selectivity of lugdunin largely resembles that of 15-mer linear peptide gramicidin A. Direct interference with the main bacterial metabolic pathways including DNA, RNA, protein, and cell wall biosyntheses can be excluded. The previously observed synergism of lugdunin with dermcidin-derived peptides such as DCD-1 in killing S. aureus is mechanistically based on potentiated membrane depolarization. We also found that lugdunin was active against certain eukaryotic cells, however strongly depending on the cell line and growth conditions. While adherent lung epithelial cell lines were almost unaffected, more sensitive cells showed dissipation of the mitochondrial membrane potential. Lugdunin seems specifically adapted to its natural environment in the respiratory tract. The ionophore mechanism is refractory to resistance development and benefits from synergy with host-derived antimicrobial peptides.IMPORTANCEThe vast majority of antimicrobial peptides produced by members of the microbiome target the bacterial cell envelope by many different mechanisms. These compounds and their producers have evolved side-by-side with their host and were constantly challenged by the host’s immune system. These molecules are optimized to be well tolerated at their physiological site of production, and their modes of action have proven efficient in vivo. Imbalancing the cellular ion homeostasis is a prominent mechanism among antibacterial natural products. For instance, over 120 naturally occurring polyether ionophores are known to date, and antimicrobial peptides with ionophore activity have also been detected in microbiomes. In this study, we elucidated the mechanism underlying the membrane potential-dissipating activity of the thiazolidine‐containing cycloheptapeptide lugdunin, the first member of the fibupeptides discovered in a commensal bacterium from the human nose, which is a promising future probiotic candidate that is not prone to resistance development.

BackgroundPrehospital telemedicine triage systems combined with machine learning (ML) methods have the potential to improve triage accuracy and safely redirect low-acuity patients from attending the emergency department. However, research in prehospital settings is limited but needed; emergency department overcrowding and adverse patient outcomes are increasingly common. ObjectiveIn this scoping review, we sought to characterize the existing methods for ML-enhanced telemedicine emergency triage. In order to support future research, we aimed to delineate what data sources, predictors, labels, ML models, and performance metrics were used, and in which telemedicine triage systems these methods were applied. MethodsA scoping review was conducted, querying multiple databases (MEDLINE, PubMed, Scopus, and IEEE Xplore) through February 24, 2023, to identify potential ML-enhanced methods, and for those eligible, relevant study characteristics were extracted, including prehospital triage setting, types of predictors, ground truth labeling method, ML models used, and performance metrics. Inclusion criteria were restricted to the triage of emergency telemedicine services using ML methods on an undifferentiated (disease nonspecific) population. Only primary research studies in English were considered. Furthermore, only those studies using data collected remotely (as opposed to derived from physical assessments) were included. In order to limit bias, we exclusively included articles identified through our predefined search criteria and had 3 researchers (DR, JS, and KS) independently screen the resulting studies. We conducted a narrative synthesis of findings to establish a knowledge base in this domain and identify potential gaps to be addressed in forthcoming ML-enhanced methods. ResultsA total of 165 unique records were screened for eligibility and 15 were included in the review. Most studies applied ML methods during emergency medical dispatch (7/15, 47%) or used chatbot applications (5/15, 33%). Patient demographics and health status variables were the most common predictors, with a notable absence of social variables. Frequently used ML models included support vector machines and tree-based methods. ML-enhanced models typically outperformed conventional triage algorithms, and we found a wide range of methods used to establish ground truth labels. ConclusionsThis scoping review observed heterogeneity in dataset size, predictors, clinical setting (triage process), and reported performance metrics. Standard structured predictors, including age, sex, and comorbidities, across articles suggest the importance of these inputs; however, there was a notable absence of other potentially useful data, including medications, social variables, and health system exposure. Ground truth labeling practices should be reported in a standard fashion as the true model performance hinges on these labels. This review calls for future work to form a standardized framework, thereby supporting consistent reporting and performance comparisons across ML-enhanced prehospital triage systems.

In optical experiments, shutters are devices that open or close a path of light. They are often used to limit the duration of light exposure onto a target or onto a detector to reduce possible light-induced damage. Many commercial shutters are available for different applications – some provide very fast opening and closing times, some can handle large optical powers, and others allow for fail-safe operation. Many of these devices are costly and offer limited control options. Here we provide an open-source design for a low-cost, general purpose shutter system based on ubiquitous actuators (servo motors or solenoids) that are connected to an Arduino-based controller. Several shutters can be controlled by one controller, further reducing system cost. The state of the shutters can be controlled via a display built into the controller, by serial commands via USB, or by electrical control lines. The use of a microcontroller makes the shutter controller adaptable – only control options that are used need to be included, and the design accommodates a selection of display and actuator options. We provide designs for all required components, including 3D print files for the actuator holders and cases, the Arduino code, libraries for serial communication (C and python), and example graphical user interfaces for testing.

BackgroundA limited number of single institutions have published retrospective cohort studies on transoral laser microsurgery for supraglottic laryngectomy (TLM-SGL). These studies have shown that the oncologic outcomes of TLM-SGL are comparable to those of open SGL. However, there is limited information available regarding swallowing rehabilitation and quality of life (QoL).Patients and methodsSUPRATOL is a prospective, multicenter trial assessing the functional outcomes of TLM-SGL +/− adjuvant radio-(chemo)-therapy. The primary endpoint was aspiration-free swallowing at 12 months, as established using fibreoptic endoscopic evaluation of swallowing (FEES) and defined as a grade < 6 on the penetration–aspiration scale. Secondary endpoints were swallowing- and voice-related QoL, the prevalence of temporary and permanent tracheostomy and percutaneous gastrostomy, local control, laryngectomy-free survival, overall survival, and disease-free survival, as well as the influence of treatment centers on outcomes.ResultsFrom April 2015 to February 2018, 102 patients were recruited from 26 German Otorhinolaryngology (ORL) hospitals. All patients had TLM-SGL and 96.1% underwent uni- or bilateral, mostly selective neck dissection. To 47.0% of patients, adjuvant radio-(chemo)-therapy (R(C)T) was administered. The median follow-up period was 24.1 months. At 12-month follow-up, completed by 84.3% of patients, 98.2%, 95.5%, and 98.8% were free of aspiration when tested with saliva, liquid, or pulp. Adjuvant R(C)T, pT category, and type of resection had no significant influence on swallowing rehabilitation. A total of 40.2% of patients had been tracheotomized, and in 46.1% of patients, a PEG tube was inserted. At the 24-month follow-up, 5.3% of patients still required a tracheostomy, and 8.0% continued to use a percutaneous endoscopic gastrostomy (PEG) tube. Deterioration of swallowing- and voice-related QoL was observed immediately after treatment, but patients recovered, and baseline values were reached again. The Kaplan–Meier 2-year rates for local control, laryngectomy-free survival, overall survival, and disease-free survival were 88%, 92%, 93%, and 82%, respectively.ConclusionsOur prospective multicenter trial shows that, at 12 months post-TLM-SGL +/− R(C)T, 95.5%–98.8% of patients achieved aspiration-free swallowing. Morbidity was higher than previously reported. The rates of permanent tracheostomy and gastrostomy tube placement correspond to previous cohort studies. The 2-year oncologic outcomes are within the reported range.Clinical trial registrationhttps://drks.de/search/en/trial/DRKS00004641, identifier (DRKS00004641).

Summary: Background: Lung cancer screening recommendations employ annual frequency for eligible individuals, despite evidence that it may not be universally optimal. The impact of imposing a structure on the screening frequency remains unknown. The ENGAGE framework, a validated framework that offers fully dynamic, analytically optimal, personalised lung cancer screening recommendations, could be used to assess the impact of screening structure on the effectiveness and efficiency of lung cancer screening. Methods: In this comparative microsimulation study, we benchmarked alternative clinically relevant structured lung cancer screening programmes employing a fixed (annual or biennial) or adaptive (start with annual/biennial screening and then switch to biennial/annual at ages 60- or 65-years) screening frequency, against the ENGAGE framework. Individuals were eligible for screening according to the 2021 US Preventive Services Task Force recommendation on lung cancer screening. We assessed programmes' efficiency based on the number of screenings per death avoided (LDCT/DA) and the number of screenings per ever-screened individual (LDCT/ESI), and programmes’ effectiveness using quality-adjusted life years (QALY) gained from screening, lung cancer-specific mortality reduction (MR), and number of screen-detected lung cancer cases. We used validated natural history, smoking history generator, and risk prediction models to inform our analysis. Sensitivity analysis of key inputs was conducted. Findings: ENGAGE was the best performing strategy. Among the structured policies, adaptive biennial-to-annual at age 65 was the best strategy requiring 24% less LDCT/DA and 60% less LDCT/ESI compared to TF2021, but yielded 105 more deaths per 100,000 screen-eligible individuals (10.2% vs. 11.8% MR for TF2021, p = 0.28). Fixed annual screening was the most effective strategy but the least efficient and was ranked as the fifth best strategy. All strategies yielded similar QALYs gained. Adherence levels did not affect the rankings. Interpretation: Adaptive lung cancer screening strategies that start with biennial and switch to annual screening at a prespecified age perform well and warrant further consideration, especially in settings with limited availability of CT scanners and radiologists. Funding: National Cancer Institute.

We systematically searched the literature for studies with a randomized design that compared different inter-set rest interval durations for estimates of pre-/post-study changes in lean/muscle mass in healthy adults while controlling all other training variables. Bayesian meta-analyses on non-controlled effect sizes using hierarchical models of all 19 measurements (thigh: 10; arm: 6; whole body: 3) from 9 studies meeting inclusion criteria analyses showed substantial overlap of standardized mean differences across the different inter-set rest periods [binary: short: 0.48 (95%CrI: 0.19–0.81), longer: 0.56 (95%CrI: 0.24–0.86); Four categories: short: 0.47 (95%CrI: 0.19–0.80), intermediate: 0.65 (95%CrI: 0.18–1.1), long: 0.55 (95%CrI: 0.15–0.90), very long: 0.50 (95%CrI: 0.14–0.89)], with substantial heterogeneity in results. Univariate and multivariate pairwise meta-analyses of controlled binary (short vs. longer) effect sizes showed similar results for the arm and thigh with central estimates tending to favor longer rest periods [arm: 0.13 (95%CrI: −0.27 to 0.51); thigh: 0.17 (95%CrI: −0.13 to 0.43)]. In contrast, central estimates closer to zero but marginally favoring shorter rest periods were estimated for the whole body [whole body: −0.08 (95%CrI: −0.45 to 0.29)]. Subanalysis of set end-point data indicated that training to failure or stopping short of failure did not meaningfully influence the interaction between rest interval duration and muscle hypertrophy. In conclusion, results suggest a small hypertrophic benefit to employing inter-set rest interval durations >60 s, perhaps mediated by reductions in volume load. However, our analysis did not detect appreciable differences in hypertrophy when resting >90 s between sets, consistent with evidence that detrimental effects on volume load tend to plateau beyond this time-frame. Systematic Review Registration: OSF, https://doi.org/10.17605/OSF.IO/YWEVC.

Abstract Microsatellite instability-high (MSI-H) is a tumor-agnostic biomarker for immune checkpoint inhibitor therapy. However, MSI status is not routinely tested in prostate cancer, in part due to low prevalence and assay cost. As such, prediction of MSI status from hematoxylin and eosin (H&E) stained whole-slide images (WSIs) could identify prostate cancer patients most likely to benefit from confirmatory testing to evaluate their eligibility for immunotherapy and need for Lynch syndrome testing. Prostate biopsies and surgical resections from prostate cancer patients referred to our institution were analyzed. MSI status was determined by next-generation sequencing. Patients sequenced before a cutoff date formed an algorithm development set (n = 4015, MSI-H 1.8%) and a paired validation set (n = 173, MSI-H 19.7%) that consisted of two serial sections from each sample, one stained and scanned internally and the other at an external site. Patients sequenced after the cutoff date formed a temporally independent validation set (n = 1350, MSI-H 2.3%). Attention-based multiple instance learning models were trained to predict MSI-H from H&E WSIs. The predictor achieved area under the receiver operating characteristic curve values of 0.78 (95% CI [0.69–0.86]), 0.72 (95% CI [0.63–0.81]), and 0.72 (95% CI [0.62–0.82]) on the internally prepared, externally prepared, and temporal validation sets, respectively, showing effective predictability and generalization to both external staining/scanning processes and temporally independent samples. While MSI-H status is significantly correlated with Gleason score, the model remained predictive within each Gleason score subgroup.

Abstract Background Lung volume optimization maneuvers (LVOM) are necessary to make physiologic use of high-frequency oscillatory ventilation (HFOV), but lung behavior during such maneuvers has not been studied to determine lung volume changes after initiation of HFOV, to quantify recruitment versus derecruitment during the LVOM and to calculate the time to stabilization after a pressure change. Methods We performed a secondary analysis of prospectively collected data in subjects

Abstract Background The residual activity of a clothianidin + deltamethrin mixture and clothianidin alone in IRS covered more than the period of malaria transmission in northern Benin. The aim of this study was to show whether the prolonged residual efficacy of clothianidin-based products resulted in a greater reduction in vector populations and subsequent malaria transmission compared with the shorter residual efficacy of pirimiphos-methyl. Methods Human bait mosquito collections by local volunteers and pyrethrum spray collections were used in 6 communes under IRS monitoring and evaluation from 2019 to 2021. ELISA/CSP and species PCR tests were performed on Anopheles gambiae sensu lato (s.l.) to determine the infectivity rate and subspecies by commune and year. The decrease in biting rate, entomological inoculation rate, incidence, inhibition of blood feeding, resting density of An. gambiae s.l. were studied and compared between insecticides per commune. Results The An. gambiae complex was the major vector throughout the study area, acounting for 98.71% (19,660/19,917) of all Anopheles mosquitoes collected. Anopheles gambiae s.l. collected was lower inside treated houses (45.19%: 4,630/10,245) than outside (54.73%: 5,607/10,245) after IRS (p

Abstract There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and applied this model for targeted rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug response to patients’ clinical response to chemotherapy, and investigated treatment-induced adaptive stress responses. PD tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked clinical response to cisplatin and temozolomide ex vivo. When we investigated treatment-induced adaptive stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5 A and interferon-beta, which act synergistically in combination with cisplatin. Since ex vivo drug response in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our rapid and functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN.

Abstract Background Indoor residual spraying (IRS) was first implemented in the Atacora department, Benin from 2011 to 2012 using bendiocarb (carbamate) followed by annual spraying with pirimiphos-methyl (organophosphate) from 2013 to 2018. Before and after IRS implementation in Atacora, standard pyrethroid insecticide-treated bed nets were the main method of vector control in the area. This study investigated the knockdown resistance (kdr) gene (L1014F) and the acetylcholinesterase (ace-1) gene (G119S), before and during IRS implementation, and 4-years after IRS withdrawal from Atacora. This was done to assess how changes in insecticide pressure from indoor residual spraying may have altered the genotypic resistance profile of Anopheles gambiae s.l. Method Identification of sibling species of An. gambiae s.l. and detection of the L1014F mutation in the kdr gene and G119S mutation in ace-1 genes was done using molecular analysis. Allelic and genotypic frequencies were calculated and compared with each other before and during IRS implementation and 4 years after IRS withdrawal. The Hardy–Weinberg equilibrium and genetic differentiation within and between populations were assessed. Results Prevalence of the L1014F mutation in all geographic An. gambiae s.l. (An. gambiae s.s., Anopheles. coluzzii, Anopheles. arabiensis, and hybrids of “An. gambiae s.s. and An. coluzzii”) populations increased from 69% before IRS to 87% and 90% during and after IRS. The G119S allele frequency during IRS (20%) was significantly higher than before IRS implementation (2%). Four years after IRS withdrawal, allele frequencies returned to similar levels as before IRS (3%). Four years after IRS withdrawal, the populations showed excess heterozygosity at the ace-1 gene and deficit heterozygosity at the kdr gene, whereas both genes had excess heterozygosity before and during IRS (F IS

Abstract Background To assess the long-term association between organised colorectal cancer (CRC) screening strategies and CRC-relate mortality. Methods We systematically reviewed studies on organised CRC screening through PubMed, Ovid Medline, Embase and Cochrane from the inception. We retrieved characteristics of organised CRC screening from included literature and matched mortality (over 50 years) of those areas from the International Agency for Research on Cancer in May 2023. The variations of mortality were reported via the age-standardised mortality ratio. A random-effects model was used to synthesis results. Results We summarised 58 organised CRC screening programmes and recorded > 2.7 million CRC-related deaths from 22 countries where rollout screening programmes were performed. The CRC screening strategy with faecal tests (guaiac faecal occult blood test (gFOBT) or faecal immunochemical tests (FIT)) or colonoscopy as the primary screening offer was associated with a 41.8% reduction in mortality, which was higher than those offered gFOBT (4.4%), FIT (16.7%), gFOBT or FIT (16.2%), and faecal tests (gFOBT or FIT) or flexible sigmoidoscopy (16.7%) as primary screening test. The longer duration of screening was associated with a higher reduction in the pooled age-standardised mortality ratio. In particular, the pooled age-standardised mortality ratio became non-significant when the screening of FIT was implemented for less than 5 years. Conclusions A CRC screening programme running for > 5 years was associated with a reduction of CRC-related mortality. Countries with a heavy burden of CRC should implement sustainable, organised screening providing a choice between faecal tests and colonoscopy as a preferred primary test.

Abstract The study objective was to assess the frequency of the kdr-L995F and ace-1 G280S genetic mutations in Anopheles gambiae s.l. mosquitoes and examine their ability to transmit Plasmodium falciparum in areas where indoor residual spraying (IRS) was implemented with Clothianidin 50 WG. The study was conducted in six communes in the Alibori and Donga departments of which four were IRS-treated and two were untreated and served as control. Post-IRS monthly samples of adult mosquitoes were collected in study communes using human landing catches (HLC). An. gambiae s.l. specimens were processed to detect kdr-L995F and ace-1 G280S mutations via PCR as well as Plasmodium falciparum infectivity through CSP ELISA. Our data revealed a high and similar allelic frequency for the kdr-L995F mutation in both treated and control communes (79% vs. 77%, p = 0.14) whilst allelic frequency of the ace-1 G280S mutation was lower across the study area (2–3%, p = 0.58). The sporozoite rate was 2.6% and 2.4% respectively in treated and untreated communes (p = 0.751). No association was found between Plasmodium falciparum infection in Anopheles gambiae s.l. vectors and carriage of kdr-L995F and ace-1 G280S mutations regardless of genotypes. The study findings underline the need for an integrated approach to malaria control, combining different control methods to effectively target transmission. Regular monitoring of insecticide resistance and genetic mutations is essential to guide control strategies.

Abstract Background Lung cancer is one of the most commonly diagnosed cancers and the leading cause of cancer-related death worldwide. Although smoking is the primary cause of the cancer, lung cancer is also commonly diagnosed in people who have never smoked. Currently, the proportion of people who have never smoked diagnosed with lung cancer is increasing. Despite this alarming trend, this population is ineligible for lung screening. With the increasing proportion of people who have never smoked among lung cancer cases, there is a pressing need to develop prediction models to identify high-risk people who have never smoked and include them in lung cancer screening programs. Thus, our systematic review is intended to provide a comprehensive summary of the evidence on existing risk prediction models for lung cancer in people who have never smoked. Methods Electronic searches will be conducted in MEDLINE (Ovid), Embase (Ovid), Web of Science Core Collection (Clarivate Analytics), Scopus, and Europe PMC and Open-Access Theses and Dissertations databases. Two reviewers will independently perform title and abstract screening, full-text review, and data extraction using the Covidence review platform. Data extraction will be performed based on the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS). The risk of bias will be evaluated independently by two reviewers using the Prediction model Risk-of-Bias Assessment Tool (PROBAST) tool. If a sufficient number of studies are identified to have externally validated the same prediction model, we will combine model performance measures to evaluate the model’s average predictive accuracy (e.g., calibration, discrimination) across diverse settings and populations and explore sources of heterogeneity. Discussion The results of the review will identify risk prediction models for lung cancer in people who have never smoked. These will be useful for researchers planning to develop novel prediction models, and for clinical practitioners and policy makers seeking guidance for clinical decision-making and the formulation of future lung cancer screening strategies for people who have never smoked. Systematic review registration This protocol has been registered in PROSPERO under the registration number CRD42023483824.

Rapeseed (Brassica napus L.), as one of the most important oil crops around the world, has been affected by drought considerably, particularly at flowering when crops are most sensitive to water stress. It has been shown that film antitranspirant (AT) can effectively reduce the yield loss of droughted crops if applied at the critical stage. However, the mechanism remains unclear by which AT mitigates drought damage to plants under different rates of water depletion. Two experiments in randomised complete block designs were conducted on spring rapeseed with two levels of irrigation, well-watered (WW) and water-stressed (WS), where slow and fast soil water depletion were imposed during the flowering stage in mesocosms (Expt 1_SD) and pots (Expt 2_FD), respectively, and different concentrations of AT, 0, 0.25%, 0.5%, and 1% and 0, 0.5%, and 1%, were applied. Leaf physiological traits, seed yield, and yield components were determined. The results showed that compared to WW, water stress reduced leaf relative water content (RWC) by 2% and 6% in Expt 1_SD and Expt 2_FD, respectively, and had detrimental effects on stomatal conductance, CO2 assimilation rate, and intrinsic water use efficiency. Following AT application, a positive linear relationship was observed in leaf RWC against AT concentrations, albeit with large variations. In Expt 1_SD, seed dry weight and aboveground biomass increased significantly with increasing AT concentrations, while no yield responses were observed in Expt 2_FD, indicating that soil water status may play an important role in rapeseed responses to AT application regardless of concentrations. Therefore, the timing of AT application needs to consider soil water conditions in addition to the growth development of rapeseed plants.

Introduction: To accelerate cutaneous wound healing and prevent scarring, regenerative approaches such as injecting a mechanically derived tissue stromal vascular fraction (tSVF) are currently under clinical and laboratory investigations. The aim of our study was to investigate a platform to assess the interaction between skin-derived extracellular matrix (ECM) hydrogels and tSVF and their effects on their microenvironment in the first ten days of culture. Material and Methods: A tSVF mixed with ECM hydrogel was cultured for ten days. After 0, 3, 5, and 10 days of culture viability, histology, immunohistochemistry, gene expression, and collagen alignment and organization were assessed. Results: The viability analysis showed that tSVF remained viable during 10 days of culture and seemed to remain within their constitutive ECM. The fiber analysis demonstrated that collagen alignment and organization were not altered. No outgrowth of capillaries was observed in (immuno)histochemical staining. The gene expression analysis revealed that paracrine factors TGFB1 and VEGFA did not change and yet were constitutively expressed. Pro-inflammatory factors IL1B and IL6 were downregulated. Matrix remodeling gene MMP1 was upregulated from day three on, while MMP14 was upregulated at day three and ten. Interestingly, MMP14 was downregulated at day five compared to day three while MMP2 was downregulated after day zero. Conclusions: Skin-derived ECM hydrogels appear to be a versatile platform for investigating the function of a mechanically isolated adipose tissue stromal vascular fraction. In vitro tSVF remained viable for 10 days and sustained the expression of pro-regenerative factors, but is in need of additional triggers to induce vascularization or show signs of remodeling of the surrounding ECM. In the future, ECM-encapsulated tSVF may show promise for clinical administration to improve wound healing.

Deep learning has become the preferred method for automated object detection, but the accurate detection of small objects remains a challenge due to the lack of distinctive appearance features. Most deep learning-based detectors do not exploit the temporal information that is available in video, even though this context is often essential when the signal-to-noise ratio is low. In addition, model development choices, such as the loss function, are typically designed around medium-sized objects. Moreover, most datasets that are acquired for the development of small object detectors are task-specific and lack diversity, and the smallest objects are often not well annotated. In this study, we address the aforementioned challenges and create a deep learning-based pipeline for versatile small object detection. With an in-house dataset consisting of civilian and military objects, we achieve a substantial improvement in YOLOv8 (baseline mAP = 0.465) by leveraging the temporal context in video and data augmentations specifically tailored to small objects (mAP = 0.839). We also show the benefit of having a carefully curated dataset in comparison with public datasets and find that a model trained on a diverse dataset outperforms environment-specific models. Our findings indicate that small objects can be detected accurately in a wide range of environments while leveraging the speed of the YOLO architecture.

Large dam removal is being used to restore river systems, but questions remain regarding their outcomes. We examine how the removal of two large dams in the Elwha River, coupled with hatchery production and fishing closures, affected population attributes of Chinook salmon (Oncorhynchus tshawytscha) and steelhead (O. mykiss). Initial responses by returning adult Chinook salmon and steelhead was an increase in the number and spatial extent of natural and hatchery origin fish. Although few naturally produced juvenile Chinook salmon and steelhead outmigrants were observed prior to and during dam removal, abundances increased three years after adult fish passage was restored, suggesting that impacts due to downstream sedimentation after dam removal were reduced. The Chinook salmon population demographics remain dominated by hatchery production, while increases in winter steelhead abundance included both hatchery and natural-origin spawners. The spatial expansion of winter steelhead upstream of former dam sites was predominantly by natural-origin spawners. We also observed a natural “reawakening” of summer steelhead that were in part derived from an up-river resident population that returned to the Upper Elwha. Our results showed that a combination of habitat, hatchery, and harvest actions can result in positive responses for salmonid populations.

Adaptive management, a process of planning, implementing, and evaluating management strategies, is often recommended for monitoring ecological systems. However, few examples of successful implementation and retrospective case studies exist. We provide a case study of adaptively managing hatchery-assisted protection and recovery for Chinook salmon (Oncorhynchus tshawytscha) and winter steelhead trout (O. mykiss) during and after the removal of two large mainstem dams in the Elwha River, WA. We summarize key aspects of the monitoring and adaptive management plan over the last decade and highlight successes, challenges, and complications during the plan’s implementation. The Elwha Monitoring and Adaptive Management Guidelines included a trigger-based system for moving through four phases of recovery that included preservation, recolonization, local adaptation, and viable natural population, each with differing levels of hatchery production as the management actions. The monitoring component of the plan has been very successful, providing critical data to guide management actions that otherwise may not have occurred and, opportunistically, provided data for other native species in the Elwha River. Implementing adaptive management provided mixed results and was at times hindered by divergent management goals among project partners, the inflexibility of the Endangered Species Act regulatory requirements as implemented for this project, and conflicting information among guidance documents. We learned that some metrics and triggers in the plan were ill-defined or too difficult to measure in the field. In some cases, the performance indicators and/or triggers were successfully modified to incorporate what was learned; however, in other cases, we were unable to revise the values due to differing opinions among partners. The ability to reach consensus on revised triggers appeared to be influenced by the recovery trajectory of the species involved. The implemented adaptive management strategy resulted in substantial collaboration and learning, which resulted in revised management strategies, but was imperfect. Sufficient long-term funding is necessary to implement a well-designed monitoring program and could benefit from including a defined leadership position to shepherd and facilitate a multi-stakeholder adaptive management program. Additionally, incorporating adaptive management into legally binding conditions under the Endangered Species Act is feasible, but requires substantial pre-planning in close coordination with regulatory agencies.

Abstract Background and Aim Obesity has been a global public health issue due to the increasing mortality rate and prevalence among children. However, there are scarce studies on obesity prevalence in Hong Kong children. The study aims to identify the risk factors of obesity among primary and secondary school students by assessing the relationship between sociodemographic factors, health‐related behaviors, and social relationships. Methods Self‐administrated surveys were collected from 30 primary schools and 25 secondary schools participating in the “Quality Education Fund Thematic Network on Health Schools” project. Descriptive analysis was conducted to examine the proportions of different characteristics and to compare the disparity between primary and secondary school students with obesity. Results A total of 4884 responses were collected. A larger proportion of primary school students with obesity were male (adjusted odds ratio [aOR]: 2.55, 95% confidence interval [CI]: 1.77–3.67, p

PurposeThe ideal treatment of peri-implant femur fractures (PIFFs) remains unclear due to the thin clinical and biomechanical evidence concerning the most suitable form of osteosynthesis. The purpose of the present study was thus to determine the biomechanical stability that results from combining a cephalomedullary nail and a plate for proximal PIFFs, especially when the nail–plate docking technique is applied.MethodsTwenty four PIFFs were simulated in both 12 foam and 12 composite specimens and were stabilized via a combination of a cephalomedullary nail and a plate. The control group (n = 6) had a nail and a plate without a connection, while the intervention group (n = 6) had a screw that connected the plate with the interlocking screw hole of the nail, thereby creating a nail–plate docking system. The specimens were evaluated under axial and torsional loading using a material-testing machine and a 3D metrology system.ResultsThe data regarding stiffness, failure load, and failure displacement showed significantly higher stability for specimens without nail–plate docking. For docked specimens, a non-significant trend toward a higher resistance to torque was observed. Both techniques displayed no significant difference in fracture gap displacement or total displacement.ConclusionThe present study suggests that nail–plate docking of a cephalomedullary nail, and a plate significantly decreases the stiffness and stability of osteosynthesis under axial loading. However, there seems to be a tendency toward higher resistance to torque. Therefore, surgeons should consider this technique if higher torsional stability is necessary, and they should decide against it, if axial stability is preferred.

Study area: Tana River Basin in Kenya. Study Focus: Flood-related impacts and losses have been rising. Therefore, understanding flood characteristics, drivers, and predictability is critical for informed decisions in the ongoing flood early warning (FldEWS) projects. This study presents an in-depth analysis of hydro-meteorological, Sentinel Mission (SM), and ensemble hydrological model datasets. We examine flood characteristics using observed hydro-meteorological and SM datasets, followed by statistical analysis of climate drivers of flood events at inter-annual and sub-seasonal (S2S) time scales. Finally, reforecasts from Global Flood Awareness System (GloFAS) are assessed against observed river flows. New hydrological insights for the study region: There is a high inter-annual variability of flood events with flood peaks occurring in May and December. SM satellites have the ability to map flooded areas in near-real time. At inter-annual timescales, positive Indian Ocean Dipole (IOD) and warm El Niño Southern Oscillation (ENSO) drives short rains (October to December). At Sub-Seasonal (S2S) timescales, Madden Julian Oscillation (MJO; phases 2-4) is a notable driver of flood related extreme rainfall. GloFAS offers reliable forecasts depending on the flood magnitude, trigger probability, and 'anticipation window' and it meets the tolerable skill requirements for flood preparedness actions (FAR < 50% and POD > 50%) with up to a 20-day lead time for 1 and 2-year return periods. We subsequently discuss how our research findings can inform the development of FldEWS in Kenya, with an emphasis on improved co-production of flood forecast information with relevant stakeholders.

ABSTRACT Recombination of short DNA fragments via horizontal gene transfer (HGT) can introduce beneficial alleles, create genomic disharmony through negative epistasis, and create adaptive gene combinations through positive epistasis. For non-core (accessory) genes, the negative epistatic cost is likely to be minimal because the incoming genes have not co-evolved with the recipient genome and are frequently observed as tightly linked cassettes with major effects. By contrast, interspecific recombination in the core genome is expected to be rare because disruptive allelic replacement is likely to introduce negative epistasis. Why then is homologous recombination common in the core of bacterial genomes? To understand this enigma, we take advantage of an exceptional model system, the common enteric pathogens Campylobacter jejuni and C. coli that are known for very high magnitude interspecies gene flow in the core genome. As expected, HGT does indeed disrupt co-adapted allele pairings, indirect evidence of negative epistasis. However, multiple HGT events enable recovery of the genome’s co-adaption between introgressing alleles, even in core metabolism genes (e.g., formate dehydrogenase). These findings demonstrate that, even for complex traits, genetic coalitions can be decoupled, transferred, and independently reinstated in a new genetic background—facilitating transition between fitness peaks. In this example, the two-step recombinational process is associated with C. coli that are adapted to the agricultural niche.IMPORTANCEGenetic exchange among bacteria shapes the microbial world. From the acquisition of antimicrobial resistance genes to fundamental questions about the nature of bacterial species, this powerful evolutionary force has preoccupied scientists for decades. However, the mixing of genes between species rests on a paradox: 0n one hand, promoting adaptation by conferring novel functionality; on the other, potentially introducing disharmonious gene combinations (negative epistasis) that will be selected against. Taking an interdisciplinary approach to analyze natural populations of the enteric bacteria Campylobacter, an ideal example of long-range admixture, we demonstrate that genes can independently transfer across species boundaries and rejoin in functional networks in a recipient genome. The positive impact of two-gene interactions appears to be adaptive by expanding metabolic capacity and facilitating niche shifts through interspecific hybridization. This challenges conventional ideas and highlights the possibility of multiple-step evolution of multi-gene traits by interspecific introgression.

BackgroundThe incidence of early-onset colorectal cancer (EOCRC) is increasing globally. This study aims to describe the temporal trends of incidence and explore related risk exposures in early-life at the country level based on the GBD 2019.MethodsData on the incidence and attributable risk factors of EOCRC were obtained from the GBD 2019. Temporal trends of age-standardized incidence were evaluated by average annual percentage change (AAPC). Early-life exposures were indicated as summary exposure values (SEV) of selected factors, SDI and GDP per capita in previous decades and at ages 0–4, 5–9, 10–14 and 15–19 years. Weighted linear or non-linear regressions were applied to evaluate the ecological aggregate associations of the exposures with incidences of EOCRC.ResultsThe global age-standardized incidence of EOCRC increased from 3.05 (3.03, 3.07) to 3.85 (3.83, 3.86) per 100,000 during 1990 and 2019. The incidence was higher in countries with high socioeconomic levels, and increased drastically in countries in East Asia and Caribbean, particularly Jamaica, Saudi Arabia and Vietnam. The GDP per capita, SDI, and SEVs of iron deficiency, alcohol use, high body-mass index, and child growth failure in earlier years were more closely related with the incidences of EOCRC in 2019. Exposures at ages 0–4, 5–9, 10–14 and 15–19 years were also associated with the incidences, particularly for the exposures at ages 15–19 years.ConclusionThe global incidence of EOCRC increased during past three decades. The large variations at regional and national level may be related with the distribution of risk exposures in early life.