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Duloxetine and pregabalin: High-dose monotherapy or their combination?—Study protocol for a randomized trial in patients with postoperative pain after total knee arthroplasty based on the classification of central sensitization inventory scores

Background Residual pain after total knee arthroplasty (TKA) often causes patient dissatisfaction. Patients with preoperative central sensitization (CS) are especially susceptible to chronic pain after TKA. Although duloxetine and pregabalin are known to relieve pain in CS patients, there is limited evidence on the precise effectiveness and safety of increasing the dosage or combining these medications. To address this gap, we designed a randomized, triple-blind clinical trial to assess the efficacy and safety of increasing the maximum dosage or combining these drugs for patients who do not respond to standard doses. Methods Patients scheduled to undergo primary unilateral TKA will be screened for CS using the central sensitization inventory (CSI). CS patients will then be randomly assigned to Groups 1–5, while non-CS patients will be assigned to Group 6. All groups will receive multimodal analgesia. Groups 1 and 6 will receive a placebo. During the initial 6-week period, Groups 2 and 3 will take 60 mg/day of duloxetine, while Groups 4 and 5 will take 300 mg/day of pregabalin. Subsequently, non-responders will enter a 6-week period of high-dose/combination therapy. Group 2 will receive 120 mg/day of duloxetine, Group 3 and 4 will receive a combination of 60 mg/day of duloxetine and 300 mg/day of pregabalin, and Group 5 will receive 600 mg/day of pregabalin. The primary outcome will be to compare residual pain intensity at 6 months between the high-dose monotherapy groups (Groups 2, 5 pooled) and the combination therapy groups (Groups 3, 4 pooled), which will be measured using the brief pain inventory (BPI) 24-hour average pain change. Secondary outcomes will assess pain and functionality. Discussion This study aims to evaluate the efficacy and safety of increasing medication to the highest dose or combining two medications in patients with CS who have not responded well to standard doses of duloxetine or pregabalin after TKA. The goal is to provide clinicians with evidence-based recommendations for choosing an appropriate pain management strategy for these patients. Trial registration Chinese Clinical Trial Registry, ChiCTR2400081990. Registered on 18 March 2024.

ALZET pump implantation in mice for chronic drug delivery to the cochlea

Computational structural studies of SGLT2-related polypharmacy

Introduction Sodium Glucose Cotransporter 2 (SGLT2) is the main active transport protein involved in sodium and glucose reabsorption in the kidney. SGLT2 inhibitors (SGLT2i) are widely recommended for patients with diabetes, heart failure and chronic kidney disease (CKD). Many multimorbid patients are prescribed these compounds, raising questions about polypharmacy. We have performed a computational drug repurposing screen to identify other licensed drugs capable of binding at or near the SGLT2i active site aiming to identify compounds that could either compete with SGLT2i or inhibit sodium and glucose transport. Methods The library of BNF listed compounds was obtained from NCBI PubChem. D-I-TASSER was used to generate monomeric structural models, and MODELLER was used to incorporate MAP-17 and empagliflozin from a reference structure (PDB 7VSI). CHARM-GUI was used to insert the protein into a membrane. The structural model was refined in a 5 nanosecond GROMACS equilibration. Docking studies using PLANTS were performed and compounds interacting with key protein residues were identified. CHARM-GUI was used to prepare membrane- and ligand-bound systems to run in GROMACS using GPUs in Google Colab. 10 nanosecond simulations were undertaken (300 Kelvin and 1 bar) to discriminate between binding and non-binding events. Results The SGLT2-MAP17 structure was obtained in the inward-open conformation, showing good agreement with published structures. Existing SGLT2i (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin) all feature in the top 1% of docked compounds in the repurposing screen. 17 compounds were investigated by MD, with all of them remaining bound to the protein in simulation. Ceftriaxone, tobramycin, clindamycin, fluvastatin, atorvastatin and ticagrelor were among the compounds with potentially significant interactions. Discussion It is not clear whether the stable ligand interactions identified here would result in inhibition of sodium and glucose transport, or if the interactions could provide competitive inhibition for SGLT2i compounds currently used. The compounds identified are not presently recognised as interacting with SGLT2i, nor are they associated with any adverse effects suggesting inhibition of the protein. This study is limited by considering only the protein-ligand interaction and not wider pharmacokinetic or pharmacodynamic factors. Conclusion The indication of interactions with several compounds likely to be prescribed alongside SGLT2 inhibitors, such as antibiotics, statins, and antiplatelet agents, warrants further investigation of the potential for polypharmacological complications.

Factors associated with willingness to use ecological sanitation toilets in Katine sub county Soroti district Uganda: a cross sectional study

Abstract Ecological sanitation (EcoSan) toilets provide a sustainable approach to waste management by converting human excreta into usable agricultural inputs. Despite their environmental and health benefits, uptake remains low in many settings. This study investigated the proportion of community members in Katine sub-county, Soroti district, Eastern Uganda, who had ever used EcoSan toilets, their willingness to use them, and the factors associated with this willingness. A cross-sectional survey was conducted among 395 residents using structured questionnaires. Descriptive statistics estimated the proportions of prior use and willingness to use EcoSan toilets. Multivariable logistic regression was used to identify factors independently associated with willingness. Analyses were conducted in Stata 18, and results are presented in tables and figures. Only 18.5% (73/395) of respondents had used EcoSan toilets, and 13.7% (54/395) expressed willingness to use them. In multivariable analysis, key factors negatively associated with willingness included awareness of Ecosan toilets (adjusted odds ratio [AOR] 0.06, 95% CI 0.02–0.16; p < 0.0001), willingness to use sanitized fecal matter (AOR 0.06, 95% CI 0.02–0.17; p < 0.0001), and perceived ease of use (AOR 0.16, 95% CI 0.05–0.48; p = 0.001). Adoption of EcoSan toilets remains low in this setting, primarily due to limited awareness, cultural reservations, and usability concerns. Community sensitisation, culturally appropriate messaging, and user centered toilet design are essential to improving uptake in similar rural environments.

Depression, anxiety, and stress levels during the COVID-19 pandemic: A longitudinal study among Indonesian psychologists

During the COVID-19 pandemic, while clinical psychologists played a crucial role in supporting mental health, their well-being was overlooked compared to other healthcare professionals. Therefore, this study aimed to examine the trend levels of depressive symptoms, anxiety, and stress among psychologists during the pandemic and explore how these levels are related to demographic characteristics, personality traits, and self-compassion. One hundred and ten psychologists who provided online counseling during the pandemic participated in all three-time points of the study conducted from January to October 2021 in the midst of the pandemic. The validated Indonesian versions of the DASS-21, Big Five Personality, and Self-Compassion Scale were surveyed. The results indicated that despite no significant longitudinal changes in stress, anxiety, and depression levels (p > 0.05) over nine months, the prevalence of moderate-to-severe depressive symptoms, anxiety, and stress was noted in 10.9%−14.5%; 22.7%−30.9%; and 11.8%−14.5%; respectively. In terms of protective and risk factors, being married, older age, higher openness to experience, higher extraversion, and higher conscientiousness emerged as potential protective factors against mental health issues. Additionally, self-compassion was linked to depression, anxiety, and stress at corresponding time points; however, its impact diminished over time. Meanwhile, stress emerged as a significant predictor of both depression and anxiety. These findings demonstrate that the mental health of psychologists during the pandemic was not severely affected over time. Compared with other populations, the levels of depressive symptoms, anxiety, and stress are lower. The results may indicate that Indonesian psychologists are able to cope with very stressful situations, like a global pandemic. Future studies should focus on protective factors.

Author Correction: The study of mechanical properties and fracture evolution of coal-rock masses under hard roof-soft floor conditions

Differential regulation of the eicosanoid biosynthesis pathway in response to Enterocytozoon hepatopenaei infection in Litopenaeus vannamei

The microsporidian Enterocytozoon hepatopenaei (EHP) is a highly contagious pathogen that causes severe growth retardation in penaeid shrimp. EHP infection damages the hepatopancreatic tubules, causes hematopoietic infiltration, and recruits granulocytes and inflammatory cells to the shrimp stomach and intestine. In this study, we investigated whether EHP infection induced the eicosanoid biosynthesis pathway in the gastrointestinal tract of the Pacific white shrimp Litopenaeus vannamei . Shrimp hepatopancreases, stomachs, and intestines were collected on days 0, 7, and 21 of the EHP cohabitation experiment for analysis. On day 7, the levels of cyclooxygenase (COX) and prostaglandin F synthase (PGFS) enzymes, which catalyze the production of prostaglandins, were elevated in the hepatopancreas of EHP-infected shrimp. The stomach of EHP-infected shrimp also contained higher levels of 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-hydroxyeicosapentaenoic acid (12-HEPE) than the control shrimp. Nevertheless, the most significant impact of EHP infection on day 7 was observed in shrimp intestines, in which the levels of prostaglandin F 2α (PGF 2α ), 8-HETE, and four isomers of HEPEs were higher in the EHP-infected shrimp than in the control shrimp. As the EHP infection progressed to day 21, the upregulation of COX and PGFS persisted in the EHP-infected hepatopancreas, leading to increasing levels of PGF 2α and 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ). The upregulation of prostaglandins was in contrast with the decreasing levels of HETEs and HEPEs in the hepatopancreas of EHP-infected shrimp. Meanwhile, the stomach of EHP-infected shrimp contained higher levels of prostaglandin D 2 , PGF 2α , 15d-PGJ 2 , and most of the hydroxy fatty acids than the control shrimp. The levels of eicosanoid precursors, namely arachidonic acid and eicosapentaenoic acid, were upregulated in the shrimp gastrointestinal tract collected on days 7 and 21, suggesting that substrate availability contributes to the increasing levels of eicosanoids after EHP infection. Our study provides the first comprehensive analysis of the eicosanoid biosynthesis pathway in response to EHP infection. Moreover, the results indicate that eicosanoids are part of the host-pathogen interactions in crustaceans.

Reasoning-based LLMs surpass average human performance on medical social skills

Abstract A significant portion of medical licensing examinations assesses key social skills such as communication, ethics, and professionalism, which are vital for quality patient care. Artificial intelligence (AI) has been increasingly integrated into healthcare systems in recent years, raising concerns among regulators, providers, and patients regarding AI’s capacity to handle complex, human-centered scenarios. Previous work has shown that large language models (LLMs) like GPT-3.5 and GPT-4 perform well on social skills questions from the United States Medical Licensing Examination (USMLE). However, newer models like GPT-4o, Gemini 1.5 Pro, and o1 have been introduced, with the latter designed to mimic human thinking through a “chain of thought” reasoning, unlike other LLMs that provide instantaneous answers. The impact of reasoning on LLMs’ ability to navigate scenarios requiring social skills remains unclear. Here, we evaluate five LLMs: GPT-4, GPT-4o, Gemini 1.5 Pro, and o1-preview, and its full version, o1; using forty USMLE-style social skills questions from the UWORLD question bank covering several categories: communication & interpersonal skills, healthcare policy & economics, system-based practice & quality improvement, and medical ethics & jurisprudence. After each LLM answered, it was subjected to an “Are you sure?” follow-up prompt to test consistency. Our results show that o1, the reasoning model, came out on top with 39 out of 40 correct final answers (97.5%). GPT-4o and Gemini 1.5 Pro (87.5%) tied in second place, followed by o1-preview (77.5%) and lastly GPT-4 (75%). All LLMs surpassed the UWORLD question bank’s 64% average. Domain-specific analysis revealed that despite having equal overall scores, GPT-4o and Gemini 1.5 Pro -developed by two different companies- had varying strengths. GPT-4o demonstrated its greatest strengths in communication & interpersonal skills and patient safety, while Gemini 1.5 Pro achieved perfect scores in healthcare policy & economics, system-based practice & quality improvement, and medical ethics & jurisprudence. Although o1-preview demonstrated strong initial performance, its inconsistency under skepticism; changing answers frequently, primarily to incorrect ones, reduced its overall ranking from second to fourth. This phenomenon was not observed in any other model, including the final o1 release, which maintained consistent, high-level performance. These findings, along with prior work, highlight the potential of LLMs to demonstrate effectiveness at answering knowledge-based social skills questions in a medical context, sometimes surpassing average human performance. As LLMs continue to grow in size and sophistication, their performance is expected to improve further. In particular, the strong performance of reasoning-based LLMs suggests that such architectures hold significant promise for advancing AI’s role in socially oriented tasks. These results demonstrate the growing potential for reasoning-based LLMs to complement and enhance clinical training, medical education, and patient care.

Development of nursing quality evaluation indicators for extracorporeal membrane oxygenation based on Donabedian theory: A Delphi study

Extracorporeal membrane oxygenation (ECMO) serves as a vital therapy for refractory severe respiratory and circulatory failure. With its expanding application in China and the heightened demand for high-quality medical services, ensuring top-notch nursing care during ECMO treatment is crucial. However, existing ECMO nursing quality evaluation tools have limitations, such as lacking detailed calculation formulas for some indicators and insufficient scientific grounding due to over-reliance on expert experience. Thus, there is an urgent need to develop a scientific and practical index system for evaluating ECMO nursing quality to provide an objective basis for monitoring and improving care.This Delphi study was conducted to develop and refine quality indicators for ECMO care, adhering to ACCORD guideline. First, a literature review and expert discussions were carried out to design an expert questionnaire. Then, nineteen experts in critical care participated in two rounds of Delphi surveys. After the surveys, the analytic hierarchy process was employed to assign weights to the indicators.This study achieved a 100 questionnaire recovery rate, and there was high agreement among the experts. Through the two-round consultation, the final ECMO care quality indicators were determined, including three primary indicators, nine secondary indicators, and 32 tertiary indicators. A scientific and reliable ECMO care quality evaluation system was successfully created. This system offers a comprehensive basis for future assessments of ECMO care in China, addressing the need for robust quality evaluation tools in this field and contributing significantly to the continuous improvement of clinical nursing.

Polydimethylsiloxane based mixed matrix membranes with pretreated fumed silica for efficient CO2 separation

Concordance between self-reported SARS-CoV-2 positivity and laboratory-confirmed positivity

As the use and availability of at-home antigen tests for SARS-CoV-2 infection have increased, the number of individuals with SARS-CoV-2 infections that are reported to state COVID-19 surveillance systems have decreased. Self-reported infection dates are critical to accurately track incidence and outbreaks of COVID-19 and for continued research on illness progression; however, the reliability of self-reported infection dates is unknown to date. To assess accuracy of self-reported test dates, we utilized self-reported SARS-CoV-2 testing data from the Arizona CoVHORT Study (CoVHORT) and laboratory-confirmed testing data collected by the Arizona Department of Health Services (ADHS) and calculated the difference in days between dates to examine their percent agreement. We used logistic regression to assess if any participant characteristics were associated with self-reporting a test date >7 days different than the laboratory confirmed date. A total of 1,900 CoVHORT participants aged 18 years or older were included in our analyses. Most participants (82.5%) reported a test date within 7 days of the laboratory confirmed date of their illness. Increasing age and number of weeks between testing positive and self-reporting the test date were both significantly associated with a difference of 7 days or greater between dates. There was an 84% increase (OR=1.84, 95% CI = 1.11–3.06) in likelihood of inaccurately self-reporting their SARS-CoV-2 test date for participants aged 55 years and older and a 2% increase (OR=1.02, 95% CI = 1.02–1.03) for each elapsed week following their SARS-CoV-2 test. We observed an 82% percent agreement (dates within 7 days of each other) between self-reported and laboratory confirmed test dates, suggesting that self-reported SARS-CoV-2 test dates are sufficient for identifying and tracking Long COVID or Post-COVID Conditions when a laboratory-confirmed test date is not available. However, increasing age and greater time between test date and date of self-report were found to decrease the agreement between self-reported and laboratory confirmed test dates.

Biochemical and structural differences between C3 cotyledons and C4 leaves in species of Salsoloideae (Chenopodiaceae)

Impact of the grassland ecological compensation policy on pastoral production efficiency—evidence from pastoral China

The impact of the Grassland Ecological Compensation Policy (GECP), which protects grassland ecology while promoting the transformation and improvement of grassland animal husbandry, on pastoral production efficiency is among the important indicators for evaluating the sustainable development of animal husbandry, and it directly affects the economic benefits of herders. In this study, based on field questionnaire data from 468 herders in the pastoral areas of the Inner Mongolia Autonomous Region of China, a two-stage semi-parametric DEA model and a mediated effect model were used to measure herders’ pastoral production efficiency and analyze the effect and influence mechanism of the GECP on herders’ pastoral production efficiency, respectively. The results of the study show that (1) the overall pastoral production efficiency of herders in Inner Mongolia is low, with a mean value of 0.43, which is caused mainly by low pure technical efficiency. (2) The factors that have a significant positive effect on the herding efficiency include the number of years of education of the head of the household, whether the head of the household has received technical training, the percentage of herding income from herding, the number of herding machines available, the evaluation of herding socialized services and whether pasture is rented or owned. (3) The realization of appropriate-scale management by herders plays a role in mediating herders’ pastoral production efficiency. The realization of moderate-scale management by herders has a partial intermediary effect on the process through which the GECP affects herders’ pastoral production efficiency, and the direct effect of this policy on the pastoral production efficiency of large-scale herders is significantly greater than that on small-scale herders. Based on the above conclusions, suggestions are proposed for improving support policies that offer ecological bonuses, demonstrating and popularizing breeding technology, and guiding moderate-scale management.

Cognitive, neuroimaging, and genetic insights on the interthalamic adhesion from a large cohort study of 591 subjects

Personal and perceived stigma towards mental disorders among attendants of patients with mental illness in selected health facilities of Bangladesh

The objective of this study was to explore the stigma among attendants (close relatives or other caregivers) who brought patients with mental illness to the selected mental health facilities in Bangladesh. This mixed-method study was part of a nationwide survey where respondents were conveniently selected. Cross-sectional data were collected from 176 attendants of patients with mental illness, and qualitative data were collected from 40 respondents. Quantitative data were collected in hand-held tablets using the Day’s Mental Illness Stigma Scale questionnaire. Qualitative data was collected in recorders, using a semi-structured guideline. The attendants had more stigma around the patients’ ability to maintain relationships, hygiene and discretion regarding their illness, with the highest level of stigma towards hygiene issues (score: 5.4). There was more positive attitude towards the treatability, curability, and recovery of the patients due to faith in the professional expertise of the service providers at mental health facilities, with the least level of stigma towards professional expertise (score: 6.4). Older people, females, and educated attendants were generally less stigmatized towards patients with mental illness than their counterparts. This study found that more stigma was present around the domains’ relationships, hygiene, anxiety, and visibility, while less stigma was present around the domains’ treatability, curability, and recovery of the patients. Further studies can be conducted to understand the effect of various factors on stigma, to aid in the development of interventions and counselling frameworks.

Feasibility of intelligent logistics management for operational efficiency in smart hospitals: a case study

Effects of a loaded change of direction training program on physical performance in U-19 elite soccer players

Changes of direction are one of the most repeated actions during football matches, which is why the inclusion of these actions in the training of the football player must be a fundamental aspect. The aim of this study was to assess the effects of 6-week a loaded change of direction (COD) movements training on speed, jump, COD speed, and repeated sprint ability (RSA) in soccer players. Twenty-eight male soccer players (age: 19.12 ± 0.75 years; height: 1.75 ± 0.06 m; body mass: 72.78 ± 4.87 kg; systematic practice: 8.62 ± 1.33 years) were randomly assigned to an experimental group (EG, n = 14) or a control group (CG, n = 14). The research was conducted during a training camp. During the intervention period, the EG performed two weekly sessions of loaded change of direction training, while the CG performed FIFA 11 prevention program. EG significantly improved the performance of 5-m, CMJ, SJ, Illinois and the percentage of decrement (%Dec and %Dec-COD). However, CG only showed significant improvements in CMJ and SJ. Between-groups analysis revealed differences in favor of the EG in 5-m, CMJ, SJ. The main results show that the effect of loaded COD movements training using a weighted vest on the physical performance of soccer players is significantly greater compared to the FIFA 11 prevention program. This study shows that including an additional load in COD exercises is a good method to increase performance on key variables for soccer players.

Green synthesis of magnetite (Fe3O4) and hematite (Fe2O3) nanoparticles using Moringa oleifera and Psidium guajava leaf extracts for sustainable applications

Utility of cochlear perilymph biomarkers for hearing loss - A systematic review

The live cochlea is a critical and delicate sensory organ with tissue sampling posing a risk to balance and hearing functions. Consequently, a researchers’ ability to investigate the pathogenesis of sensorineural hearing loss (SNHL) has been limited, commonly involving in vitro models, translational animal models and post-mortem analysis. Previous human studies investigating SNHL have primarily been restricted to using peripheral blood or cerebrospinal fluid samples that indirectly measure inner ear pathologies. More recently, the establishment of a novel, safe, and feasible technique for intraoperative perilymph sampling has enabled the collection of a ‘liquid biopsy’ of the cochlea whilst still preserving inner ear function. This crucial development has opened avenues for characterising the cochlea microenvironment and subsequently investigating the mechanisms of SNHL. Perilymph sampling may also provide insights into why postoperative outcomes vary between cochlear implant users with otherwise similar preoperative clinical characteristics. The present systematic review aimed to elucidate the gap in the literature regarding the utility of perilymph biomarkers in SNHL diagnosis, treatment, and prognosis. Medline, Embase, Web of Science, and Scopus were searched for two groups of keywords related to ‘biomarker’ and ‘SNHL’. Of the 7471 studies initially identified, 15 met the inclusion criteria. Based on the findings of these studies, biomarkers were grouped into six main categories based on their underlying pathological processes: heat shock proteins (HSP), immune-related, microRNA, neurotrophic, metabolome, and structural. For each category, this review identifies potential biomarkers that should be carefully validated in future studies. In particular, HSP70 and HSP90, complement components, mi1299, mi1270, and brain-derived neurotrophic factor regulated proteins may help direct future studies focused on characterising the biomarker profile in patients with SNHL. Future studies should ideally also utilise larger cohorts of patients with specified hearing loss aetiologies. Such studies may help to pave the way towards a more accurate diagnosis of SNHL, improved prediction of cochlear implantation prognosis, and targeted therapeutic management.

Overexpression of LINC01354 predicts well prognosis and suppresses esophageal cancer progression