Glioblastoma (GBM) remains a highly aggressive central nervous system malignancy, and its treatment is hindered by poor drug accumulation across the blood-brain barrier (BBB) and autophagy-mediated repair. To address these barriers, rare-earth-doped Nd0.02Fe2.98S4@HA nanozymes (NFSH) are constructed as magneto-NIR-II-programmed cascade nanozymes for trans-BBB delivery, multimodal imaging, and ferroptosis amplification. Hyaluronic acid (HA)-mediated CD44 targeting and oriented magnetic field-enhanced BBB permeability promote tumor enrichment, while Nd[3+] doping endows NFSH with strengthened superparamagnetism, near-infrared second window (NIR-II) photodynamic activity, and NIR-II fluorescence capability. Under alternating magnetic field (AMF) and NIR-II laser stimulation, NFSH activates catalase-, peroxidase-, glutathione oxidase-, and nicotinamide adenine dinucleotide (NADH) oxidase-like cascade catalysis, which amplifies reactive oxygen species (ROS) production, consumes glutathione, and induces ferroptosis. In the acidic tumor microenvironment, AMF further promotes H2S release, disrupts lysosomal autophagic degradation, and aggravates mitophagy inhibition through NADH depletion-mediated ATP deficiency. This cascade mechanism enhances ferroptosis and reshapes the tumor immune microenvironment by relieving hypoxia and promoting M2-to-M1 macrophage polarization. In addition, NFSH enables NIR-II fluorescence and T2-weighted magnetic resonance imaging for real-time visualization of treatment. This strategy provides an integrated trans-BBB theranostic platform for autophagy-suppressed ferroptosis therapy against GBM.

Syncope is a common clinical problem caused by transient cerebral hypoperfusion and encompasses reflex, orthostatic, and cardiac mechanisms. Accurate diagnosis relies on careful history taking and physical examination, as well as targeted testing guided by risk stratification. Management of syncope is determined on the basis of the underlying mechanism and focuses on reducing recurrence and injury risk. In older patients, syncope may manifest as unexplained falls. Early identification of high-risk features is critical to prevent adverse cardiovascular outcomes.

The global prevalence of chronic kidney disease (CKD) is rising and initial studies suggest that diets predominantly based on greater inclusion of plant foods may be associated with lower CKD risk. As population-based studies are lacking, we investigated the association between habitual plant-based diets and CKD in the UK Biobank cohort. The UK Biobank is a large prospective cohort study of participants aged 40-69 years. Habitual diet was assessed using a baseline food frequency questionnaire, and participants were classified into five dietary groups: high meat eaters, low meat eaters, poultry eaters, pescatarians, and vegetarians. To assess the risk of CKD across these groups, we conducted multivariable Cox proportional hazards regression analyses. During follow up of 12.9 years 23,084 out of 416,584 developed CKD. Compared to high meat eaters, the strongest association was observed among vegetarians which had a statistically significant lower risk of CKD [HR = 0.81, 95% CI: 0.71- 0.93]. Our population-based study on plant-based diet types and CKD risk suggests that vegetarian diets are associated with a lower risk of CKD. Future research is needed to assess the feasibility and acceptability of plant-based diets for the prevention of CKD and other chronic diseases.

We explored the epigenomic effects of vegan diet (VD) versus meat-rich diet (MR) and identified mechanisms that help to explain how VD affects epigenetic gene regulation. Genome-wide DNA methylation profiles in 48 healthy individuals were investigated after a 1-month randomized isocaloric dietary intervention comparing effects of a VD versus a MR. Genome-wide DNA methylation analysis revealed changes in differentially methylated positions following dietary intervention, with the VD group showing a higher degree of gene-promoter silencing in cancer-related pathways and cell growth-associated pathways (mTOR and Hippo). Cell type deconvolution indicated an anti-inflammatory shift in the VD group, characterized by decreased neutrophils and increased CD4[+] T-cell proportions, aligning with whole blood count data. Pathway analysis reflected changes in gene promoter methylation consistent with macronutrient changes according to the diets, in that VD silenced lipid metabolism and increased insulin pathway genes. Interestingly, the health-outcome-trained epigenetic clocks PhenoAge and GrimAge indicated a deceleration of biological aging in the VD group, while the chronologically optimized Blood&Skin clock showed an opposing acceleration. Convergent evidence from pathway analysis and health-outcome epigenetic clocks thus suggests that a 1-month VD drives epigenomic changes associated with reduced cancer risk and decelerated biological aging.

Fungal infection is an ongoing public health concern due to its severity and associated complications. Exploring putative targets is needed to overcome this to enhance the therapeutic design. Therefore, a systematic computational-assisted subtractive proteomics approach was implemented to find the putative drug target and its promising inhibitor, examining the 6 Candida species. Considering 6 species, a total of 501,366 sequences were curated from NCBI and UniProt. Furthermore, based on subsequent steps such as non-orthologous, paralogous, and non-homologous, a total of 352 targets were obtained. Of which, 118 were identified as putative based on essential and target screening. Moreover, the target revealed various similar metabolic pathways toward the host organism, of which 5 proteins were found to be unique based on the non-significant similarity. The subcellular localization demonstrated that out of 5 proteins, only histidine kinase was found to be suitable based on its localization in the cytoplasm. Subsequently, the target structures were enhanced and validated, and significant structural proteins were found. The docking analysis following the high-throughput virtual screening was performed which resulted hyaluronic acid (ID: DB08818) and gadopiclenol (ID: DB17084), with docking scores of - 11.975 kcal/mol and - 11.442 kcal/mol as the most promising based on computational hits and high docking score. Moreover, the stability of these complexes was analyzed over 100 ns and found significant stability of the docked complex, based on the analyzed trajectories such as RMSD, RMSF, and PCA, along with the MMPBSA analysis. Based on the implemented strategy, the overall findings suggest that the identified drug target, together with the selected inhibitors, may enable the treatment of candidiasis-causing fungi and their associated infections.

Recurrent reproductive failure impairs women's health, and the efficacy of immunosuppressants for this condition remains uncertain. This study aimed to explore the clinical application of common immunosuppressive agents including cyclosporine A, tacrolimus, etanercept and adalimumab for recurrent reproductive failure, which covers recurrent spontaneous abortion and recurrent implantation failure after IVF/ICSI, and to assess their efficacy and safety so as to provide evidence-based references for clinical practice. We retrieved eligible randomized controlled trials and cohort studies published from January 1, 2005 to February 28, 2025 from PubMed, Web of Science, CNKI and Wanfang databases, and conducted a systematic review and meta-analysis. This study was registered on PROSPERO (ID: CRD420251057130). A total of 13 randomized controlled trials and 7 cohort studies involving 2266 patients were finally included. Meta-analysis revealed that compared with the control group, immunosuppressive therapy significantly elevated live birth rate (RR=1.33, 95%CI:1.20-1.47, P < 0.00001) and clinical pregnancy rate (RR=1.24, 95%CI:1.11-1.39, P = 0.0001), while lowering miscarriage rate (RR=0.45, 95%CI:0.37-0.54, P < 0.00001). No significant differences were found in the incidence of adverse events (RR=0.96, 95%CI:0.69-1.34, P = 0.83) and birth defect rate (RR=0.63, 95%CI:0.19-2.07, P = 0.45) between the two groups. In conclusion, the above immunosuppressive drugs can improve pregnancy outcomes in patients with recurrent reproductive failure and do not obviously increase adverse reactions and birth defects. Considering the limited quality of existing evidence and potential publication bias, the results should be interpreted cautiously, and the use of these drugs is recommended to be limited to clinical trials until verified by more large-scale and high-quality randomized studies.

3D-printed gelatin scaffolds are widely explored for bone regeneration due to their excellent biocompatibility and biodegradability, yet their clinical translation is severely hindered by several inherent defects, including weak mechanical stability, fast in vivo biodegradation, limited osteogenic capability, and the absence of anti-infective functions. Globally, it remains a key challenge in bone tissue engineering to develop integrated scaffold systems that simultaneously satisfy mechanical matching, long-term biological activity, and anti-pathogenic requirements. To address this challenge, a multifunctional CHm/PCA/Cu[2+]/ε-PL@Gel-OCS scaffold with enhanced mechanical properties, outstanding antibacterial, anti-inflammatory, pro-vascularization and osteogenic activities was developed via cryogenic 3D printing of a gelatin (Gel)/oxidized chondroitin sulfate (OCS) composite ink loaded with chitosan microspheres surface-functionalized by protocatechuic aldehyde (PCA), copper ions (Cu[2+]) and ε-polylysine (ε-PL). Scanning electron microscopy and energy-dispersive X-ray analysis confirmed uniform dispersion of the microspheres and sustained release of therapeutic agents as the scaffold degraded. Rheological and mechanical testing demonstrated excellent print fidelity, interconnected porosity (161 ± 37 μm pores), and compressive strengths (100-200 MPa) suitable for cortical bone repair. Such porous structure and mechanical performance are highly compatible with human cortical bone microenvironment, which facilitates cell infiltration, nutrient exchange and mechanical load bearing. In vitro release studies revealed a sequential sustained release profile (OCS > Cu[2+] > ε-PL), ensuring a sustainable osteogenic, angiogenic, anti-inflammatory and antibacterial activity. The scaffold achieved 100% bactericidal efficiency against both Staphylococcus aureus and Escherichia coli, suppressed protein denaturation (anti-inflammation), and promoted neovascularization in a chick chorioallantoic membrane assay. Biocompatibility assays using MC3T3-E1 osteoblasts showed enhanced cell adhesion, proliferation, and live/dead viability over 5 days. Osteogenic potential was significantly elevated on the multifunctional scaffold, as evidenced by time-dependent increases in ALP activity, mineral deposition (Alizarin Red S), and upregulated expression of ALP, RUNX2, OPN, and OCN genes compared with Gel and Gel-OCS controls. Taken together, our cryogenic 3D-printed Gel-OCS scaffold incorporating PCA/Cu[2+]/ε-PL-functionalized chitosan microspheres provides a single-step, customizable platform that combines robust mechanical properties with multi-modal therapeutic functionalities. Different from conventional single-function bone scaffolds reported in most international studies, this multi-component synergistic design successfully realizes the integration of mechanical reinforcement, antibacterial, anti-inflammatory, vascularization and osteogenesis functions in one system. These promising preclinical results highlight a novel therapeutic strategy for bone defect regeneration, it solves the common bottlenecks of traditional gelatin-based bone scaffolds, provides a feasible and universal fabrication strategy for high-performance multifunctional bone repair materials, and offers new insights for the global development and clinical translation of 3D-printed bone tissue engineering scaffolds.

Lack of intrinsic healing potential in cartilage, accompanied by accelerated inflammation and oxidative stress, creates a major clinical challenge for effective treatment of osteoarthritis (OA). This highlights the need for the development of minimally invasive, multifunctional biomaterials capable of tuning the degenerative joint microenvironment. Herein, we designed a compartmentalized dual-drug injectable hydrogel (DD gel) matrix offering rapid inflammation control and sustained chondroprotective function to address the multifaceted challenges of OA. The hydrogel incorporating celecoxib acts as a primary compartment to attain an immediate anti-inflammatory response, whereas the chondroitin sulfate encapsulated GelMA microspheres act as a secondary compartment to facilitate chondroprotection and joint homeostasis. Moreover, the simple and crosslinker-free technique offers rapid gelation at physiological temperature, ensuring good injectability, mechanical strength, and shear-thinning properties. Further, the DD gel significantly improves chondrocyte proliferation, migration, and extracellular matrix (ECM) synthesis while effectively alleviating LPS-induced inflammation, oxidative stress, and ECM degradation. Additionally, in vivo implantation of DD gel stimulates the regeneration of cartilage tissue in a rabbit full-thickness cartilage defect model up to 8 weeks and achieves healing close to the native cartilage tissue. This single injectable system presents a promising approach for the combinatorial therapy for OA.

Patients who have several unsuccessful embryo transfers may be at risk for possible conditions that affect implantation. This document reviews diagnostic criteria for recurrent implantation failure and provides an evidence-based evaluation for these patients.

Herpes Zoster Neuralgia (HZN) is a condition caused by the varicella-zoster virus, characterized primarily by pain. The Transient Receptor Potential Vanilloid 1 (TRPV1), which acts as a pain mediator, plays a significant role in pain signaling and the regulation of neuroinflammation. In this context, this paper summarizes the biological characteristics of TRPV1, its dynamic expression in HZN, and its mechanisms for mediating neuroinflammatory processes and pain signal conduction. It posits that the inhibition of TRPV1 may alleviate HZN. Furthermore, the paper discusses the research and development progress, as well as the challenges associated with TRPV1 antagonists as a new class of analgesics, thereby providing new insights for the treatment of HZN.

Premature ovarian insufficiency (POI) is characterized by an early decline in ovarian function before the age of 40 and is highly associated with infertility and long-term health issues. Increasing evidence suggests that dietary factors and nutritional status may influence ovarian aging and susceptibility to POI. Dietary patterns with high antioxidant and anti-inflammatory potential, such as the Mediterranean and plant-based diets, have been associated with more favorable indicators of ovarian reserve, whereas Western-style dietary patterns may accelerate ovarian functional decline. Nutrients, including vitamin D, omega-3 polyunsaturated fatty acids, and antioxidant compounds, may affect ovarian function through multiple biological processes, including modulation of oxidative stress, inflammation, mitochondrial activity, endocrine and metabolic homeostasis, epigenetic regulation, and the gut microbiota-ovarian axis. However, most available evidence is gained from observational studies and animal models. So far, the causal relationships have not yet been firmly established. Improvement in overall diet quality and appropriate supplementation of key nutrients may represent safe and potentially supportive strategies for the prevention and management of POI. Nevertheless, well-designed longitudinal studies and randomized controlled trials are required to clarify the effects of diet on ovary and to define optimal dietary intervention strategies for preserving ovarian health.

Current osteoporosis treatments fail to balance bone resorption and formation. Here we show that engineered 2-N,6-O-sulfated chitosan (26SCS), a synthetic pentasaccharide, restores 115% bone mass (therapeutic) and prevents 66% bone loss, surpassing bisphosphonates by simultaneously suppressing osteoclastogenesis and promoting vascularized osteogenesis. Mechanistically, 26SCS targets K97 in receptor activator of nuclear factor-κB (RANK) through geometrically matched sulfate pairs, blocking RANK ligand (RANKL) signalling to arrest preosteoclast fusion while enhancing platelet-derived growth factor-BB (PDGF-BB) secretion via preserved preosteoclast viability to drive angiogenesis-coupled mineralization. Structural and functional analyses reveal that carboxyl groups in natural glycosaminoglycans such as heparin competitively bind K97, disrupting therapeutic specificity-a limitation overcome by 26SCS's carboxyl-free design and sequence-controlled sulfation. Unlike monosulfated analogues (2SCS/6SCS) that oversuppress osteoclastogenesis or lack pro-osteogenic effects, 26SCS's dual sulfation balances inhibition with trophic support. Thus, this work redefines glycosaminoglycan therapeutics via sulfation-patterned, topology-engineered biomaterials harmonizing bone metabolism.

Interindividual variability in clinical response to glucagon-like peptide-1 receptor agonists (GLP-1 RAs) represents a significant challenge in the management of obesity and type 2 diabetes (T2D). In recent years, growing interest has focused on the potential role of the gut microbiota as a biological modifier of incretin-based therapy. This narrative review synthesizes current preclinical and human evidence on the bidirectional interactions between GLP-1 RAs and the intestinal microbial ecosystem, with particular attention to microbial composition, metabolite production (including short-chain fatty acids and bile acids), intestinal barrier integrity, and inflammatory signaling. Experimental models consistently demonstrate that GLP-1 RAs can remodel gut microbial communities and influence metabolite profiles. In human studies, GLP-1 RA therapy has been associated with changes in microbial diversity and enrichment of specific taxa; however, most available data remain observational and associative. Small exploratory cohorts suggest that baseline microbiota composition may correlate with differential metabolic response, giving rise to the responder/non-responder framework. Nevertheless, definitions of response are heterogeneous, study populations are limited in size, and mechanistic causality has not been established. Importantly, microbiota changes observed during GLP-1 RA therapy may be influenced by confounding factors such as weight loss magnitude, dietary modifications, and concomitant treatments, particularly metformin. Functional pathway inferences frequently rely on 16S rRNA-based predictions rather than direct metabolomic measurements, warranting cautious interpretation. Overall, current evidence supports the hypothesis that host-microbiome interactions may contribute to therapeutic heterogeneity, but robust longitudinal and interventional human studies are required before microbiome-informed stratification or adjunctive microbiota-targeted interventions can be considered for clinical implementation. Elucidating these interactions may ultimately refine precision approaches to incretin-based therapy in metabolic disease.

Climate-induced heat stress poses a major challenge to small ruminant productivity in arid and semi-arid regions, affecting growth, metabolism, and immune function. This study examined tissue-specific molecular responses to chronic heat stress in lambs by evaluating the expression of key genes associated with inflammation, oxidative stress, proteostasis, and muscle function in the liver and skeletal muscle. Twenty-four lambs were reared at two climatically contrasting field sites (thermoneutral vs. high-THI) for 42 days. In the liver, exposure to the heat-stressed environment was associated with decreased SOD1 expression alongside increased FOXO3 and pro-inflammatory IL-6, while TNF-α and PPARγ were significantly lower. In muscle, a different profile emerged: heat shock proteins (HSP70, HSP90) and the apoptotic marker CASP3 were strongly upregulated, MYOD was suppressed, and ACTB3 remained stable. These results suggest candidate tissue-specific transcriptional signatures associated with impaired muscle regeneration and enhanced proteotoxic stress, although the field-based design confounds thermal load with other site-specific factors and does not permit causal attribution. Composite gene expression ratios-such as SOD1/IL-6 and FOXO3/TNF-α-were elevated under heat stress and negatively correlated with rectal temperature, indicating a potential role as candidate molecular indices associated with thermal response. Principal component analysis further distinguished control and heat-stressed animals based on transcriptional profiles. These findings highlight the coordinated yet divergent molecular strategies employed by liver and muscle tissues under prolonged thermal stress. The study provides preliminary, hypothesis-generating insight into gene-level responses associated with contrasting thermal environments and identifies candidate molecular targets warranting further validation in controlled designs before application to selection or intervention strategies.

Testosterone therapy may benefit postmenopausal women beyond treating low sexual desire and shows cardiovascular safety with potential protective effects. While improvement in sexual desire remains the only guideline-supported indication, expanding research has prompted investigation into testosterone's broader physiologic effects. Evidence supports cardiovascular safety with potential protective vascular effects as well as improvements in sexual function, genitourinary health, lubrication, and tissue integrity. Long-term safety data remain limited, though serious adverse events appear uncommon when testosterone levels are maintained within normal female ranges. These emerging applications should be viewed as hypothesis-generating and do not yet support guideline-level changes to clinical practice.

Linear care cascades (the Rule of Halves and awareness-treatment-control frameworks) quantify attrition among system-recognized cases but cannot represent true disease that remains undiagnosed, system-labeled disease that is absent or non-actionable, or symptomatic individuals whose diagnostic encounters are consumed by competing labels. A structural solution to these simultaneous limitations does not exist within current population health methodology. We conducted a narrative review of prior healthcare uses of the Johari Window, empirical applications and limitations of linear gap frameworks, evidence on the burden and consequences of underdiagnosis and inappropriate labeling, and literature on diagnostic competition and competing-diagnosis bias. We searched PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE) and Google Scholar (2000 to January 2026) using terms spanning Johari Window applications in health, population care cascades, underdiagnosis, overdiagnosis, and competing diagnoses. We adapted the Johari Window by jointly classifying populations along two operational axes, true disease state and health-system labeling state, and applied a priority-ordered classification rule to yield four mutually exclusive, jointly exhaustive quadrants. The adapted framework generates four quadrants: Open (disease present, target-disease label present); Hidden (disease present, no label); Facade (label present without actionable target diagnosis, with two mechanistically distinct subtypes: type I diagnostic misclassification and type II diagnostic competition); and Unknown (disease absent, no label, stratified into at-risk and not at-risk). Four system-level diagnostic performance metrics (system sensitivity, system specificity, positive predictive value (PPV), and negative predictive value (NPV)) are derived directly from quadrant counts, supplemented by the Hidden Burden Index, Facade Burden Index, and Facade-to-Hidden Ratio. The framework is illustrated with global pools of undiagnosed diabetes (~252 million) and hypertension (~580 million), substantial proportions of clinically labeled chronic obstructive pulmonary disease lacking spirometric confirmation (30%-60%), and the diagnostic shadow cast by depression, stroke, and other competing diagnoses. The adapted Johari Window framework provides a structurally complete, operationalizable, and metric-yielding solution to limitations inherent in linear cascade models, enabling simultaneous assessment of underdiagnosis, overdiagnosis, diagnostic competition, and system-level diagnostic performance at the population scale.

Objective:This paper reports a case of a male patient who complained about nasal congestion and loss of smell for 20 years. Physical examination revealed polyp-like masses in bilateral olfactory clefts and middle meatus. The patient was diagnosed with chronic rhinosinusitis with nasal polyps（CRSwNP） and exhibited poor response to an adequate course of topical intranasal corticosteroids, then he enrolled in two clinical trials using anti IL4-Rα and anti-TSLP monoclonal antibodies consequently. The treatment duration for each trial was 16 weeks, respectively. The size of his nasal polyps did not change, which was the main endpoint result for both clinical trials. Then the patient underwent an endoscopic surgery and the pathology was respiratory epithelial adenomatoid hamartoma（REAH）, which was further confirmed by the single cell sequencing results of the operative specimen, which were different from normal nasal polyps. The diagnosis of REAH is dependent on pathology and preoperative examination has limited specificity, and REAH may share similarities with nasal polyps. Therefore, REAH should be considered for the differential diagnosis when patients with polyp-like masses exhibit poor response to sufficient treatment using biologics.

Chronic kidney disease (CKD) represents a significant global health burden, highlighting the need for low-cost, easily accessible biomarkers for early risk detection. The neutrophil-to-lymphocyte ratio (NLR) has demonstrated prognostic value in established CKD; however, its association with incident CKD in the general population without uremia remains poorly understood. We conducted a prospective study of 9,631 adults with preserved renal function from the Shanghai Suburban Adult Cohort. Logistic regression analysis was performed to assess the association between baseline NLR and incident CKD. Dose-response and subgroup analyses were also conducted. During follow-up, 400 participants (4.2%) developed incident CKD. After full adjustment, each 1-unit increase in NLR was associated with a 19% increase in CKD odds (OR = 1.19, 95% CI: 1.06-1.32). A dose-response relationship was observed: compared with the low NLR group (< 1.5), the normal (1.5-3.0) and high (≥ 3.0) NLR groups exhibited 37% (OR = 1.37) and 62% (OR = 1.62) increased odds of developing CKD, respectively. In this community-based population, NLR was positively, independently, and dose-dependently associated with incident CKD risk. These findings suggest that NLR, a low-cost and easily accessible biomarker, is independently associated with incident CKD risk and warrants further validation for early risk stratification in primary care and community health settings.

For more than a century, copper sulfate pentahydrate (CuSO4·5H2O) has been used to combat harmful algal blooms in freshwater systems. Dosing recommendations for copper sulfate are often at 1% of the ambient alkalinity, thus increasing the applied dose with higher alkalinity. This methodology is based on the premise that higher ambient alkalinity makes copper sulfate less toxic to aquatic organisms due to the expected precipitation of copper-carbonate complexes. Using a 21-day, gradient-design, replicated, field experiment in a eutrophic aquaculture pond initially dominated by cyanobacteria, this study showed the opposite effect: copper sulfate became more toxic to phytoplankton as alkalinity increased. To evaluate the effect of sodium bicarbonate-based alkalinity on copper sulfate toxicity in phytoplankton, four target alkalinity concentrations (50, 125, 200, and 275 mg/L CaCO3) across three copper sulfate treatments (an untreated control (0 mg/L CuSO4·5H2O); a low, constant dose (0.324 mg/L) across all alkalinities; and increasingly higher alkalinity-based doses (0.25-1.375 mg/L)) were used. Both the low and high copper sulfate treatments effectively eliminated cyanobacteria (regardless of copper dose or alkalinity), while the low copper treatment allowed beneficial chlorophytes to quickly return to initial concentrations. Notably, the results show that as the ambient alkalinity in the enclosures increased, the effect of the constant low copper sulfate dose on phytoplankton was larger (i.e., less phytoplankton abundance; more negative algal growth rate) contradicting long-standing copper sulfate dosing methodologies. Higher pH at lower alkalinities appears to mediate these effects given that toxic Cu[2+] availability decreases with higher pH. These results suggest that water resource managers should consider pH and alkalinity when making decisions about copper applications to avoid overdosing of copper sulfate that can cause other water quality problems, such as heavy metal accumulation, anoxia, non-target effects on zooplankton, and recurring treatment-resistant algal blooms.

Background: he surge in the use of Pre-hospital Emergency Medical Systems (EMS) and Emergency Departments (ED) has become a pressing issue worldwide after the COVID-19 pandemic. To address this challenge, we developed an experimental and innovative care pathway supported by telemedicine. The aim of this study is to describe the activity of the Integrated Medical Center (CMI): a new telemedicine-based care model for patients referring to the Emergency Medical System. Methods: A prospective observational study was conducted from January 2022 to December 2022. The CMI was established to manage patients referring to the Emergency Medical System. Results: From January to December 2022, a total of 8680 calls were managed by CMI, with an average of 24 calls per day. 6243 patients (71.9%) were managed without ED access of whom 4884 patients (78.2%) were managed through telemedicine evaluation only, and 1359 (21.8%) with telemedicine evaluation and dispatch of the Home Rapid Response Team (HRRT). The population treated by the HRRT exhibited a higher age. The mean satisfaction score was 9.1/10. Conclusions: Telemedicine evaluation allowed for remote assessments, treatment prescriptions, and teleconsultation for HRRT and was associated with high patient satisfaction. This model could be useful in future pandemics for managing patients with non-urgent illnesses at home, preventing hospital admissions for potentially infectious patients, and thereby reducing in-hospital transmission.

Creatine is consumed by athletes to increase strength and gain muscle. The aim of this study was to evaluate the effects of creatine supplementation on maximal strength and strength endurance. Twelve strength-trained men (25.2 ± 3.4 years) supplemented with 20 g Creatina + 10g maltodextrin or placebo (20g starch + 10g maltodextrin) for five days in randomized order. Maximal strength and strength endurance (4 sets 70% 1RM until concentric failure) were determined in the bench press. In addition, blood lactate, rate of perceived effort, fatigue index, and mood state were evaluated. All measurements were performed before and after the supplementation period. There were no significant changing in maximal strength, blood lactate, RPE, fatigue index, and mood state in either treatment. However, the creatine group performed more repetitions after the supplementation (Cr: Δ = +3.4 reps, p = 0.036, g = 0.53; PLA: Δ = +0.3reps, p = 0.414, g = 0.06), and higher total work (Cr: Δ = +199.5au, p = 0.038, g = 0.52; PLA: Δ = +26.7au, p = 0.402, g = 0.07). Creatine loading for five days allowed the subjects to perform more repetitions, resulting in greater total work, but failed to change the maximum strength.

Introduction With the advancement in technology as well as surgical techniques, laparoscopic ventral hernia repair (LVHR) is more commonly being performed as compared to open repair in various centres throughout the world. Our study aimed to compare the short-term operative outcomes between LVHR and open repair. Materials and methods Sixty patients diagnosed with noncomplicated ventral hernias were included in this prospective study and were randomly divided into the laparoscopic group and the open group. The two groups were compared to evaluate operative time, postoperative pain, length of hospital stay and time taken to return to normal activity. A p-value of less than 0.05 was considered to be statistically significant. Results Mean operative time was longer in LVHR (116 min) as compared to open repair (67 min)(p<0.01). Patients experienced more pain on the first and seventh postoperative days in the open group (p<0.01) and they also had a longer duration of hospital stay as compared to the laparoscopic group (6.23 ± 0.35 vs 2.17 ± 1.12 days, p = 0.02). Patients in the laparoscopic group returned to normal activity faster as compared to the open group (1.47 ± 0.11 vs 2.87 ± 0.34, p<0.01). Conclusion LVHR carries a significant advantage over open hernia repair, especially in terms of reduced postoperative pain, duration of hospital stay, and early resumption of normal activity.

Large studies comparing the surgical outcome of primary versus patch repair in congenital diaphragmatic hernia (CDH) patients are rare. This study aims to evaluate the incidence of surgical complications in both types of CDH repair. PubMed, EMBASE, Cochrane and Web of Science were searched for peer-reviewed articles. Studies on CDH between 1991 and August 2020 were systematically screened and meta-analyses were performed. Primary outcomes of this review were: haemorrhage, chylothorax, recurrences and small bowel obstruction (SBO). A total of 6436 abstracts were screened, after which 25 publications were included (2910 patients). Patch repaired patients have a 2.8 times higher risk on developing a recurrence (20 studies) and a 2.5 times higher risk on developing a chylothorax (five studies). Moreover, they have a two times higher risk on developing a SBO. No studies could be included that evaluated the incidence of surgical haemorrhage between these patients. Although the quality of the studies was relatively low, patch repaired patients have a higher risk on developing a recurrence, chylothorax and small bowel obstruction. Large prospective studies are required to adjust for severity of disease, to reveal the true causative factors in order to minimize the risk on these surgical complications in both types of patients.

Ameloblastomas are epithelial odontogenic tumours that, although benign, are locally invasive and may exhibit aggressive behaviour. In the tumour microenvironment, the concentration of oxygen is reduced, which leads to intratumoral hypoxia. Under hypoxia, the crosstalk between the HIF-1α, MMP-2, VEGF, and VEGFR-2 proteins has been associated with hypoxia-induced angiogenesis, leading to tumour progression and increased invasiveness. This work showcases 24 ameloblastoma cases, 10 calcifying odontogenic cysts, and 9 dental follicles, used to investigate the expression of these proteins by immunohistochemistry. The anti-HIF-1α, anti-MMP-2, anti-VEGF, and anti-VEGFR-2 primary antibodies are used in this work. The results have been expressed by the mean grey value after immunostaining in images acquired with an objective of 40×. The ameloblastoma samples showed higher immunoexpression of HIF-1α, MMP-2, VEGF, and VEGFR-2 when compared to the dental follicles and calcifying odontogenic cysts. Ameloblastomas show a higher degree of expression of proteins associated with intratumoral hypoxia and proangiogenic proteins, which indicates the possible role of these proteins in the biological behaviour of this tumour.

The growing popularity of unpasteurized milk in the United States raises public health concerns. We estimated outbreak-related illnesses and hospitalizations caused by the consumption of cow's milk and cheese contaminated with Shiga toxin-producing Escherichia coli, Salmonella spp., Listeria monocytogenes, and Campylobacter spp. using a model relying on publicly available outbreak data. In the United States, outbreaks associated with dairy consumption cause, on average, 760 illnesses/year and 22 hospitalizations/year, mostly from Salmonella spp. and Campylobacter spp. Unpasteurized milk, consumed by only 3.2% of the population, and cheese, consumed by only 1.6% of the population, caused 96% of illnesses caused by contaminated dairy products. Unpasteurized dairy products thus cause 840 (95% CrI 611-1,158) times more illnesses and 45 (95% CrI 34-59) times more hospitalizations than pasteurized products. As consumption of unpasteurized dairy products grows, illnesses will increase steadily; a doubling in the consumption of unpasteurized milk or cheese could increase outbreak-related illnesses by 96%.

The 5th European Conference on Infections in Leukaemia (ECIL-5) meeting aimed to establish evidence-based recommendations for the prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in non-HIV-infected patients with an underlying haematological condition, including allogeneic HSCT recipients. Recommendations were based on the grading system of the IDSA. Trimethoprim/sulfamethoxazole given 2-3 times weekly is the drug of choice for the primary prophylaxis of PCP in adults (A-II:) and children (A-I:) and should be given during the entire period at risk. Recent data indicate that children may benefit equally from a once-weekly regimen (B-II:). All other drugs, including pentamidine, atovaquone and dapsone, are considered second-line alternatives when trimethoprim/sulfamethoxazole is poorly tolerated or contraindicated. The main indications of PCP prophylaxis are ALL, allogeneic HSCT, treatment with alemtuzumab, fludarabine/cyclophosphamide/rituximab combinations, >4 weeks of treatment with corticosteroids and well-defined primary immune deficiencies in children. Additional indications are proposed depending on the treatment regimen.

Clinicians nowadays are confronted with an epidemic of multidrug-resistant (MDR) Acinetobacter infections and are forced to consider every treatment alternative, including older antibiotic agents, not conventionally used. This review aimed to evaluate the published evidence on the antimicrobial activity and clinical effectiveness of trimethoprim/sulfamethoxazole (TMP-SMX) against Acinetobacter spp. Selected in vitro studies included antimicrobial surveillance reports, microbiological studies regarding the activity of TMP-SMX against MDR Acinetobacter isolates, and clinical studies published after the year 2000. Non-susceptibility rates for Acinetobacter spp. in surveillance studies ranged from 4% to 98.2%; in 23 of 28 studies, non-susceptibility to TMP-SMX was >50% and in a subset of 15 studies non-susceptibility was >70%. In studies regarding MDR Acinetobacter spp., non-susceptibility rates ranged from 5.9% to 100%; however, 19 of 21 studies reported >70% non-susceptibility. Extensively drug-resistant Acinetobacter baumannii complex had total (100%) resistance in five of six studies. Carbapenem-resistant Acinetobacter spp. had non-susceptibility rates to TMP-SMX of >80% in 22 of 26 studies. One study on polymyxin-resistant A. baumannii showed a susceptibility rate of 54.2% (13/24). Only seven case reports evaluated TMP-SMX for Acinetobacter spp. infections, mainly in combination with other agents; all cases were deemed therapeutic successes. Although TMP-SMX is not usually active against Acinetobacter spp., it might be considered in cases where there are no other options.

The pharmacokinetics, safety, and tolerability of posaconazole, an investigational triazole antifungal, were evaluated following the administration of rising single and multiple oral doses. A total of 103 healthy adults were enrolled in two phase I trials. Each study had a double-blind, placebo-controlled, parallel-group design with a rising single-dose (RSD) or rising multiple-dose (RMD) scheme. In the RSD study, subjects received single doses of posaconazole oral tablets (50 to 1200 mg) or placebo. In the RMD study, subjects received posaconazole oral tablets (50 to 400 mg) or placebo twice daily for 14 days. By using model-independent methods, the area under the plasma concentration-time curve and the maximum concentration in plasma were determined and used to assess dose proportionality. In the RSD study, the levels of posaconazole in plasma increased proportionally between the 50- and 800-mg dose range, with saturation of absorption occurring above 800 mg. Dose proportionality was also observed in the RMD study. In both studies, the apparent volume of distribution was large (range, 343 to 1341 liters) and the terminal-phase half-life was long (range, 25 to 31 h). Posaconazole was well tolerated at all dose levels, and the adverse events were not dose dependent. No clinically significant changes in clinical laboratory test values or electrocardiograms were observed. Following the administration of single and twice-daily rising doses, the level of posaconazole exposure increased in a dose-proportional manner. The long elimination-phase half-life of posaconazole supports once- or twice-daily dosing in clinical trials; however, additional studies are required to determine if further division of the dose will enhance exposure.

Behavioral and physiological responses differ between primiparous and multiparous female rodents. Specifically, multiparous females respond with the full repertoire of maternal behaviors much more rapidly and with greater intensity than their primiparous counterparts. Since opiates inhibit the expression of maternal behavior in postpartum rats and can be reversed by means of the opiate antagonist naloxone, we investigated whether multiparous females would be resistant to the inhibitory effects of opiates on maternal behavior, relative to primiparous females. In Experiment 1 we evaluated the effects of a range of doses of morphine sulfate (MS; 0.625, 1.25, 2.5, 5.0, and 10.0 mg/kg or saline) on maternal behavior in primiparous females on Days 5-6 of lactation. The 5.0 and 10.0 mg/kg doses effectively disrupted maternal behavior, whereas the lower doses were ineffective or only marginally disruptive. In Experiment 2, age-matched female rats were timed-mated and tested for maternal behavior from Day 5 to 13 of lactation, after daily injections of the 5.0 mg/kg dose of MS. On Day 5 of lactation, this morphine treatment eliminated full maternal behavior in 87% of the primiparous animals, but only 37% of the multiparous animals were affected. By Day 10 of lactation, 100% of the multiparous females displayed full maternal behavior after MS treatment, whereas only 69% of primiparous females were responsive. In Experiment 3, analgesic responses were measured both in rats experiencing their initial or second pregnancy, and in postpartum, lactating rats after MS (5.0 mg/kg) administration. Using a tail-flick apparatus to measure analgesia, we found multigravid females to be significantly less analgesic prepartum than primigravid females, suggesting less sensitivity to endogenous opioids.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of three unmodified hemoglobin solutions on myocardial contractile function was evaluated using isolated perfused rabbit interventricular septa. The hemoglobin solutions tested were: a human hemoglobin solution (SFHS-A), a bovine hemoglobin prepared by a column chromatography (SFHS-B), and a bovine hemoglobin obtained by a ultrafiltration method (SFHS-C). Myocardial effects were assessed by comparing contractile parameters; developed tension (DT), resting tension (RT), and perfusion pressure (PP), measured before (control perfusion with Tyrode buffer) and during hemoglobin perfusion. Further, to examine the effects of hemoglobin solutions on myocardial contractility following a period of impaired flow, septal responses to a 10-minute period of ischemia (stopflow) were also studied. After a 10-minute perfusion with hemoglobin solution, SFHS-C increased DT to 124 +/- 12% (paired t-test, p less than 0.05) without causing a significant increase in RT or PP while SFHS-A and SFHS-B decreased DT to 96 +/- 20% (p greater than 0.05) and to 77 +/- 7% (p less than 0.05), respectively. A significant rise in PP (40-50% above baseline) was also noted with these solutions (p less than 0.05). Similarly, after a 30-minute reperfusion following a 10-minute ischemia, SFHS-C allowed significantly better percentage recovery (95 +/- 3%) than septa perfused with SFHS-A (81 +/- 2%) or SFHS-B (63 +/- 6%) (Student's t-test, p less than 0.05). These results indicate that hemoglobin solution, if properly prepared, does not seem to have acute deleterious effects on contractile function of the isolated heart.

Lyophilized Brucella abortus Strain 19 vaccines were prepared using five recommended mediums. These five vaccines were compared with each other and with liquid vaccine relative to their suitability for (1) maintaning distinguishing cultural characteristics; (2) maintaining viability during lyophilization; (3) quality of restoration; (4) maintaining viability under various storage temperatures and (5) maintaining stable, antigenic and virulence qualities.

500--700 rat oocytes were solubilized in 0.3--0.6 ml of 1% sodium dodecyl sulphate (SDS) --0.06 tris-HCl, pH 6.7. The excess of SDS was removed in the form of unsoluble Ba2 (SDS) and the lysate was placed on the surface of 1% agarose microgel, performed in a glass capillar with the inner diameter 600 and the length of gel 7--8 nm. The microvolume (1.3 mcl) of monospecific antiserum against alpha1-human antitrypsin was placed on the opposite surface of the agarose gel. After 48 hours, the amount of microimmunoprecipitate was determined by staining the gel with Amido Black 10 B, followed by quantitative scanning using a double wave microspectrophotometer. The mean value of alpha1-antitrypsin was about 2.3+/-1.4 pcg per ovum. It is supposed that this antienzyme may terminate the "zone" and "cortical" reactions during the fertilization in mammals.

The authors present their experience with manometric studies, before and after Thal's fundic patch operation, in patients with Chagas' megaesophagus. The preoperative studies showed in the majority of the patients synchronous, waves of normal duration, that had low peak pressure and were repetitive (vigorous achalasia). The postoperative studies showed disappearance of the vigorous achalasia in over half the patients and increase of the contraction peak pressure in one patient.

The evaluation of EEG-findings during the acute phase of stroke-patients is somewhat difficult particularly in regard to the voltage-production, less in regard to the temporary retardation of frequency. Within comparable neurophysiological and biochemical examinations of the experimental brain-infarct under standardized conditions of silicon-rubber-embolus was introduced intracarotideally and an occlusion of the media-trunk evoked. One day prior to the embolisation and on the first, third and fifth day thereafter EEG-derivation took place which were stored on analogous-tape, digitalized and were then confronted with the FFT-Algorithm. From the statistical point of view four animal groups were the result: HO-group (control group), H1-, H3- and H5-group (each time N = 6). Visual evaluation of the curves, descriptive and inferential statistics of the spectral EEG estimators showed a significant loss of power within five days after the infarction; it always was more distinct across the focal side than across the not immediately involved hemisphere. On the fifth day the original level of voltage was almost reached again. From the clinical standpoint the neurological deficits had practically been disappeared. The biochemical finishing of the dog-brains -- the results of which are planned to be confronted with the electrophysiological results in another paper -- in accordance with the papers of other authors brings close the assumption that the decrease of tension i.e. the loss of power of the electric potential during the first days after infarction is combined with a temporary decrease of the energetic potential of the metabolically active corticocerebral cells which is tied to the phosphagene-system of the highly energetical phosphates and metabolites of the energy-metabolism in the brain.

In a strictly selected material of 80 patients, who were all outpatients of a special nephrological clinic, with chronic renal insufficiency with retention values of 1.4-14.5 mg% serum creatinine, an EEG was done besides thorough neurological and internal examinations. In 21 cases (26.2%) a pathological EEG in the form of background slowing and general dysrhythmia. There was a tendency to increase in pathological EEG findings in correlation with increase of the retention values. The patients with pathological EEG had on the average a creatinine value of 5.89 mg%, those without EEG findings had an average creatinine value of 3.98 mg%. The difference is statistically significant (alpha less than or equal to 0.015). It is notable that there is a statistical correlation (alpha less than or equal to 0.005) between the presence of pathological EEG and the motor conduction velocity of the peroneal nerve: only 12% of the patients with a conduction velocity of less than 43 m/sec had a pathological EEG while 60% of the patients with a conduction velocity of more than 43 m/sec had EEG findings. No statistical correlation were found between the EEG changes and other neurological and internal signs and symptoms, including cardiovascular findings like the blood pressure.

Two patients from families with hereditary spastic paraplegia (recessive and dominant type) were examined electromyographically. It was found that the peripheral motor neuron is involved. It is assumed that in cases of infantile recessive familial spastic paraplegia the peripheral motor neuron is rather more involved than in those of the dominant type of spastic paraplegia.

The H reflex in the triceps surae muscle was elicited by just supraliminal stimulation of the tibial nerve. It was conditioned by paired impulses to the brachial plexus or the forelimb nerves and in some cases to other sites of the body. With a conditioning test interval of 32-47 msec a facilitation occurred which reached its maximum at about 80 msec and lasted for about 400 msec. The facilitation evoked by ipsilateral conditioning had a shorter latency than that from contralateral (ipsilateral: 32-42 msec, contralateral; 37-47 msec). The facilitation at the optimum interval (about 80 msec) ranged between 1;5 and 11.3 times of the control values. Ipsilateral conditioning was slightly more effective than the contralateral one (Fig. 1, 2). Stimulation of different forelimb nerves at an interval of 80 msec showed only insignificant differences in the amount of facilitation but was more effective than skin stimulation in the most cases (Fig. 3). Varying the intensity of the conditioning stimulus showed that facilitation occurred with just perceptable stimuli but it became more pronounced as soon as pain threshold (2-3 time of perception threshold) was exceeded (Fig. 3). This suggests that facilitation was mainly due to activation of nociceptor afferents. From the onset of facilitation and the conduction velocities of the respective forelimb and hindlimb afferents (cf. 6) a central reflex lantency of about 43 msec was calculated. To get further insight into the central connections of the reflex loop the H reflex was conditioned by paravertebral stimulation at C5 and L1 level. Both stimuli caused a distinct facilitation. However, the latency of the onset was 10-15 msec shorter with lumbar stimulation than with cervical stimulation. This and the similar time course of facilitation seen in animal experiments (12) suggest that an early part of facilitation is mediated via a descending propriospinal pathway. The major part, however, is supposed to be mediated via supraspinal pathways and seems to be related to a startle response.

Several esophageal cytologic tecniques (sponge biopsy, sponge smear, and espohageal washings) were assessed and compared with endoscopy and biopsy of esophageal tumors. Esophageal cytology rendered better results than esophagoscopy or biopsy, with a 97% positivity in cases of esophageal carcinoma, when using sponge biopsy and sponge smear techniques, and of 91.4% for esophageal and gastric carcinoma of the fundus invading gastroesophageal junction, when considered together. The combination of sponge techniques was better for diagnosisng esophageal carcinoma than the application of esophageal washings, a more difficult, time consuming, and sometimes unfeasible method. However, the utilization of three mehtods enhanced the overall diagnostic possibilities in all cases of esophageal tumors when considered together.

Renal fibrosis is a critical pathological hallmark of chronic kidney disease. Although nonalcoholic fatty liver disease (NAFLD) has been implicated in kidney disease progression, its specific role and underlying mechanisms in renal fibrosis remain poorly understood. This study aims to investigate these mechanisms by establishing a mouse model of renal fibrosis through unilateral ureteral obstruction (UUO) combined with a high-fat diet-induced NAFLD. Single-cell RNA sequencing, untargeted metabolomics, flow cytometry, and immunofluorescence are performed, along with in vitro experiments involving primary renal macrophages and coculture models. It is demonstrated that NAFLD exacerbates renal fibrosis, as HFD-induced hepatocytes release significant levels of ANGPTL8, which activates renal CCR2[+]PIRB[+] macrophages. These specialized macrophages disrupt linoleic acid metabolism and increase the production of inflammatory cytokines, aggravating renal fibrosis. In addition, CCR2[+]PIRB[+] macrophages promote the activation and proliferation of Th17 cells, which can further contribute to the worsening of renal fibrosis. Thus, the ANGPTL8/PIRB/ALOX5AP axis is a crucial signaling pathway between the liver and kidneys, and CCR2[+]PIRB[+] macrophages play a pivotal role in the progression of NAFLD-induced renal fibrosis. These findings suggest potential therapeutic targets to treat NAFLD-related renal fibrosis.

Autoimmune diseases (AIDs) are multifaceted, chronic illnesses characterized by immune dysregulation and systemic inflammation. Newer evidence has pointed a finger at the human gut microbiota, a trillion-fold population of microorganisms that inhabits the human GI tract, as a major influential modulator of immune reactivity and a significant contributor to autoimmune pathogenesis. This systematic review will seek to address how the literature correlates with systematic changes in the gut microbiota in AIDs as well as explore mechanistic associations with biological processes like intestinal permeability and modulation of the immune system, coupled with determining the effectiveness of microbiota-directed interventions. An extensive literature search was conducted in PubMed, Embase, Cochrane Central, and Web of Science, involving the availability of studies until May 2025. The eligible studies included observational studies, randomized controlled trials, and relevant mechanistic research regarding autoimmune diseases and alterations of the gut microbiome or administered interventions. Data extraction and risk of bias (ROB) assessments were performed by two independent reviewers, and a narrative synthesis with an illustrative meta-analysis was applied. Inclusion criteria were met by 10 studies, encompassing various autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), autoimmune thyroid diseases (AITDs), and psoriasis. Familiar patterns of microbiome dysbiosis were identified, such as a reduction in microbial diversity, increased intestinal permeability, and the expansion of pro-inflammatory species like Ruminococcus gnavus. Dietary interventions, fecal microbiota transplantation, and probiotics demonstrated positive effects on clinical outcomes and immune measures across multiple studies. The meta-analysis revealed that microbiota-directed interventions significantly improved disease activity and immune response markers in AIDs, indicating a robust link between gut microbiota composition and autoimmune pathology. In autoimmune disorders, gut microbiota is a key factor in immunopathology. Gut biology as an adjunct interventional strategy provides potential in managing these diseases. Additional studies are required to help standardize methods and identify microbial targets specific to diseases that can then be addressed through therapeutic interventions.

A wearable electrochemical biosensor for real-time monitoring of neurotransmitters in sweat during physical exercise is presented. The biosensor utilizes a CuMOF@InMOF architecture, enhanced with gold nanoparticles (AuNPs), to improve electron transfer, surface area, and overall stability. Thiolate nucleic acid aptamers, highly specific to dopamine, serotonin, and epinephrine, are immobilized on the biosensor surface, enabling precise and simultaneous detection of these key neurotransmitters. The flexible, multi-electrode platform is integrated into a microfluidic patch that adheres to the skin, facilitating seamless sweat collection and continuous neurochemical analysis. Structural validation confirmed the successful synthesis of the CuMOF@InMOF architecture with enhanced surface area, stability, and electron transfer properties, contributing to the biosensor's high sensitivity and selectivity. Impressively, the biosensor achieved detection limits of 0.18 nM for dopamine, 0.33 nM for serotonin, and 0.27 nM for epinephrine, with a broad dynamic range from 1 nM to 10 µM. Performance was validated through square wave voltammetry and amperometry, demonstrating exceptional sensitivity, selectivity, and stability. This innovative biosensor offers a powerful tool for non-invasive, real-time neurochemical monitoring, with significant potential in personalized healthcare.

The prevalence of morbid obesity in today's population around the world is alarming. Morbid obesity involves substantial changes in body composition and function, which can affect the pharmacodynamics and pharmacokinetics of many drugs. This paper aims to discuss the application of muscle relaxants and their reversing agents in patients with morbid obesity. This work is based both on the available literature and the author's personal experience. Dosage recommendations for muscle relaxants in morbidly obese patients are as follows: non-depolarizing relaxants like rocuronium, vecuronium, atracurium, and cisatracurium should be based on ideal body weight. Succinylcholine dosage should be adjusted to total body weight with a 200 mg maximum, while mivacurium should also be based on total body weight. Pancuronium is not used due to its long duration. Neostigmine dosing remains uncertain, but some suggest using total body weight. When it comes to Sugammadex opinions of the authors are divided, some indicate that it should be dosed based on ideal body weight, but more recent studies show that it should be based on 40% of corrected body weight.

Kidney disease is a critical and potentially life-threatening degenerative condition that poses a significant global public health challenge due to its elevated rates of morbidity and mortality. It manifests primarily in two distinct clinical forms: acute kidney injury (AKI) and chronic kidney disease (CKD). The development of these conditions hinges on a multitude of factors, including the etiological agents and the presence of coexisting medical conditions. Despite disparities in their underlying pathogenic mechanisms, both AKI and CKD can progress to end-stage kidney disease (ESKD). This advanced stage is characterized by organ failure and its associated complications, greatly increasing the risk of mortality. There is an urgent need to delve into the pathogenic mechanisms underlying these diseases and to identify novel biomarkers that can facilitate earlier diagnosis. Such early detection is crucial for enhancing the efficacy of therapy and impeding disease progression. In this context, proteomic approaches have emerged as invaluable tools for uncovering potential new markers of different pathological conditions, including kidney diseases. In this chapter, we overview the recent discoveries achieved through diverse proteomic techniques aimed at identifying novel molecules that may play a pivotal role in kidney diseases such as diabetic kidney disease (DKD), IgA nephropathy (IgAN), CKD of unknown origin (CKDu), autosomal dominant polycystic kidney disease (ADPKD), lupus nephritis (LN), hypertensive nephropathy (HN), and COVID-19-associated acute kidney injury (COVID-AKI).

‘Nothing to be done’ (Beckett 2012: 11). Samuel Beckett’s play Waiting for Godot is not about healthcare, but its first line seems to hover between prognosis and diagnosis, suggesting that some kind of existential ‘doctoring’ is afoot, even as it is clear that no prescriptions are going to be dispensed. For the play’s two central characters, Vladimir and Estragon, ‘nothing to be done’ empties out the urgency of curative political action from Vladimir Lenin’s famous question: ‘What is to be done?’ Every possibility of change on the horizon of the play is derailed by the inertia of the fixing refrain: ‘we’re waiting for Godot’. Waiting is the nothing that famously happened twice (Mercier 1956: 6), and came to be figured, in many early critical receptions of Beckett, as a representation of the existential human condition (Graver and Federman 1979). In the early 1950s, when the play was first performed, perhaps abstractions were more available for critical absorption than the possibility that postwar Europe was still in a present denuded of an inhabitable future (Kenner 1973: 133; Gibson 2010: 108) – an endless time of living on without any real hope of change in the wake of an unspecified disaster. Beckett’s play materializes a waiting that becomes a form of endurance through the promise of what might come to change the present for there is always some orientation towards the future in such practices. But the clear unavailability of Godot decouples the for (Schweizer 2008: 11), the most obvious preposition or relation, from the action of waiting. Neither weak enough to cease and desist nor strong enough to leave, Vladimir and Estragon endure and persist, not, in the end, waiting for Godot but waiting with and sometimes even on one another. Although in this chapter we will pay close attention to existential claims about the place of waiting in human experience, we will suggest that waiting is significantly shaped by the promises and narratives of particular historical moments and lifeworlds, and their distinct ways of understanding time. Indeed, if tarrying in Godot’s waiting room seems to speak to the existential human condition, we would argue that it is because the audiences the play found and continues to find persist in a time when the promises of the future feel increasingly unavailable. Godot’s characters, alongside their audiences, wait with their diagnosis, which is also their prognosis: ‘nothing to be done’. Perhaps one reason the slow modernism of Godot found and made its mark so sharply was its insistence on attending to the disavowed underside of the dominant timescapes of modernity. In 1931, Aldous Huxley was able to state that ‘[s]peed […] provides the one genuinely modern pleasure’ (Huxley 2001: 263), and it has been a critical commonplace to read aesthetic modernism as a reflection of the shock of the new and a pacing, racing present. Planes, trains, and automobiles; ragtime and jazz; epiphanies and revolutions; telegraphs and telephones; production lines and new mass media: humanities scholarship has thoroughly mined how the modernity of the early and mid-twentieth century produced, for better and worse, accelerated lives and shaped technologies capable of both registering and increasing sensations of speed (Duffy 2009). Engaged with a more contemporary moment and less concerned with aesthetic practices, Paul Virilio (2006) has described how a logic of acceleration that has compressed, foreshortened, and fractured time still sits at the heart of modernity and its drives towards destruction; while Jonathan Crary (2013) has critiqued a culture of 24/7 availability fuelled by unsleeping technologies that has turned even the slowing of rest into an act of embodied resistance. But there were always other times folded into the modern, as Elisabeth Kirtsoglou and Bob Simpson’s idea of ‘chronocracy’ suggests (this volume). For example, the managed and mechanized time of the working classes in a newly industrialized Europe was consistently used to service a version of a progressive future that was not shaped in their interests (Thompson 1967). Craig Jeffery has also identified ‘chronic, fruitless waiting’ (Jeffery 2010: 3) as a particular temporal experience of those colonized populations who provided much of the material resources for acceleration of Empire and modernity, noting it as a prominent feature of the experience of subaltern peoples globally since the 1960s. Bendixsen and Eriksen indeed point out that for certain groups waiting can be an expression of power and domination, generating vulnerability and humiliation (2018: 92). And while a ‘new chronic’ temporal imaginary has become more generally palpable in the late liberalism of the contemporary global north (Cazdyn 2012), many of the most acute experiences of ‘chronic, fruitless waiting’ remain ‘zoned’ in specifically gendered, raced, and classed ways. As Lisa Baraitser has argued in Enduring Time (2017), despite an ever-increasing sense of acceleration, because the spooling of time towards a possible future seems to have come unravelled in the contemporary moment, experiences of interruption, suspension, delay, and slowness strongly insist in affective life in highly differential ways. Here, however, we track this sense of time enduring rather than passing back to an earlier moment in the twentieth century, noting the ways in which waiting uncoupled from a future into which one might step came to be understood as a key feature of the affective condition termed ‘melancholia’, or, in its more contemporary configuration, ‘depression’. This is not to claim that either condition is simply a response to modern times or, more strongly still, a social construction; nor is it to seek to medicalize distress that may be the result of other social relations of inequality or injustice (Thomas et al. 2018). Rather, we are interested in exploring how understandings of melancholia in twentieth-century Europe came to be focalized through particular ideas and sensations of stuck, suspended, impeded, or ungraspable time that shaped and continue to mould the contours of the temporal landscapes and psychological imaginaries of (late) modernity. Furthermore, we argue that care in the context of depression, which we understand as imbricated with psychosocial relations and experiences and therefore ‘more than biomedical’ or psychological in constitution (Hinchliffe et al. 2018), may turn out to hinge around the offer and use of extended periods of time and the capacity to stay with those whose experience is that of a temporality that no longer flows. Although the disciplinary perspective here is not anthropological, our concern with examining melancholia and depression through experiences and practices of waiting brings our chapter into contact with an important body of anthropological literature. In his interdisciplinary volume, Ghassen Hage describes waiting as an experience that is always both existential and historically articulated or situational (Hage 2009: 4, 6). Manpreet Janeja and Andreas Bandak similarly suggest that analysing waiting requires a capacity to shuttle between existential and more clearly social or institutional perspectives, as they demonstrate how focussed ethnographic work can illuminate both waiting’s poetics and its politics (Janeja and Bandak 2018: 3). But this chapter uses a more dispersed, eclectic, and textual archive of experience to open up a theoretical account of melancholia/depression as a condition fundamentally entangled with existential, cultural, and socio-historical experiences and theorisations of European (late) modernity. Remaining broadly within the climate of these anthropological approaches to waiting, however, we propose that the remarkable tradition of phenomenological psychiatry from the late nineteenth and early twentieth century provides a significant opportunity to trace the relationship between accounts of lived experience of mental distress that emerged explicitly alongside existential philosophies, and more broadly socio-historical accounts of time. As time became a topic of intense debate across the sciences and arts and humanities in early twentieth century Europe and North America, multiple disciplines explored the tension between accounts of intuitive/subjective time and understandings of mathematical/objective time (Fryxell 2019: 5–6). Phenomenological psychiatry established its distinctive approach in this context by refusing the dominant third-person approach to psychopathology exemplified by Emil Kraepelin (Broome et al. 2012: 90) in favour of paying careful attention to the first person, subjective experience of disruptions of well-being. The discipline was profoundly influenced by the new philosophies of temporality of Henri Bergson and Martin Heidegger in the first three decades of the twentieth century and one of its key insights was that chronic mental distress can be understood as a disturbance of a sense of lived time. However, phenomenological psychiatry paid scant explicit attention to the temporal demands of treatment (Fryxell 2019: 23) – the time bound up in the intersubjectivity of the clinical encounter or simply the time that treatment takes. But psychoanalysis, which emerged alongside phenomenological psychiatry in historical terms, insisted on reflecting, with particular self-consciousness, on the complex, often seemingly interminable temporality of treatment (Freud 1937). Both phenomenological psychiatry and psychoanalysis developed in explicit dialogue with the conditions of modernity and alongside the devastating experiences of industrialized warfare, but while phenomenology negatively articulated a temporal attitude of normalcy that recedes in experiences of mental illness, psychoanalysis used the rhythms of psychopathology and the inevitability of falling ill as a way of illuminating the structures of all mental life and of a psychic life of time that can never be simply linear, teleological, or smoothly flowing. Instead of suggesting that sensations of waiting without a for break apart what is proper to lived time, psychoanalysis comes to understand such experiences to be part of the inevitable conditions of psychic life. Psychoanalysis thus offers up a specifically chronic cure – the offer of time and care, and of remembering, repeating and working through (Freud 2014) – to contain, understand, and ameliorate the chronic condition of mental distress. By highlighting this link between the chronicity of the mind and the broader psychosocial contexts in which endurance plays out, this paper aims to open up a historically nuanced sense of the value of psychoanalytic temporal practices of waiting not for but with. We also suggest that by attending specifically to the relationships between depression, temporality, and historical and psychosocial experience, the urgent debates about uses of time in contemporary mental healthcare delivered by the UK’s National Health Service might tentatively be reframed.

Functional capacity is an important component of risk assessment for major surgery. Doctors' clinical subjective assessment of patients' functional capacity has uncertain accuracy. We did a study to compare preoperative subjective assessment with alternative markers of fitness (cardiopulmonary exercise testing [CPET], scores on the Duke Activity Status Index [DASI] questionnaire, and serum N-terminal pro-B-type natriuretic peptide [NT pro-BNP] concentrations) for predicting death or complications after major elective non-cardiac surgery.

The effect of cisapride on plasma concentrations of paracetamol was investigated with respect to hepatic metabolism. Paracetamol (1 g) together with cisapride (7.5 mg) or placebo was orally administered to five healthy male volunteers. Venous blood samples were taken before and after administration. Plasma paracetamol and its glucuronide and sulfate conjugates were measured by HPLC. The pharmacokinetic variables were calculated from the plasma concentration-time curves of each volunteer. The area under the plasma paracetamol concentration-time curve from 0 to 180 min (mean +/- s.d.) increased from 1875.0 +/- 112.8 micrg min mL(-1) (placebo coadministration) to 2238.8 +/- 125.8 microg min mL(-1) (cisapride coadministration) (P < 0.01). The mean maximum plasma paracetamol concentration(18.2 microg mL(-1))with placebo was reached 30 min after administration, whereas mean maximum plasma paracetamol concentration (21.2 microg mL(-1)) with cisapride occurred 45 min after administration. The plasma paracetamol concentrations with cisapride were significantly greater at 45 to 120 min after administration compared with placebo. Plasma paracetamol glucuronide conjugate concentrations with cisapride were decreased at 15 to 60 min compared with placebo (P< 0.05), whereas plasma paracetamol sulfate conjugate concentrations did not change significantly. Hence the coadministration of paracetamol with cisapride reduced plasma paracetamol glucuronide concentrations and increased plasma paracetamol concentrations, presumably due to inhibition of paracetamol metabolism via paracetamol glucuronyltransferase. Thus, care is necessary when paracetamol and cisapride are coadministered.

Meningococcal conjunctivitis is typically described as an acute purulent infection. An atypical case of mild catarrhal conjunctivitis occurred in a 19-year-old college student. The meningococci were identified as Neisseria meningitidis, group A, and were isolated from the throats of the patient and her roommate. The conjunctivitis responded rapidly to treatment with sodium sulfacetamide, and it was not treated systemically. A short review of the literature of meningococcal conjunctivitis is presented, and the current recommendation for prophylaxis is discussed.

Artificial air pouches in the connective tissue of mice were evaluated as a means of studying Neisseria gonorrhoeae infections. Animals inoculated with type-1 N. gonorrhoeae cells developed an infection characterised by infiltration of polymorphonuclear leucocytes. Viable cocci could be recovered from the air pouches for up to 10 days after infection and intracellular cocci were evident in electronmicrographs within connective-tissue fibroblasts for at least 35 days, indicating that a persistent infection had been established. The mouse air pouch should be of value in the study of gonococcal and other infections.

We describe nine patients with methyl alcohol poisoning who were treated with hemodialysis. The time from ingestion to dialysis varied from 4 to 100 hours. Predialysis blood methanol levels ranged from 3 to 570 mg/dl. All patients were acidotic and had an increased anion gap. Two patients died, seven recovered, but three had permanent visual impairment. There was little correlation between the blood methanol level or anion gap and visual outcome. The interval from ingestion to treatment appears to be more important than the initial biochemical status. We recommend prompt hemodialysis if the blood methanol level is above 50 mg/dl, when an amount of methanol exceeding the minimal lethal dose (30 ml) is known to have been ingested, when there is evidence of acidosis or when an abnormality has developed in vision, funduscopic examination or mental state. Concurrent therapy with alkali and ethanol is vital.

The authors describe the fibro-granulomatous lesions with scar formation on a splenectomy specimen removed for familial spherocytosis, eight weeks after the onset of cat scratch disease. This original observation, apparently unique in the literature, is in favour of the blood spread of the agent responsible for benign inoculation lymphoreticulosis, and suggests a pathogenic theory for the unusual visceral manifestations.

Each year, >9 million foodborne illnesses are estimated to be caused by major pathogens acquired in the United States. Preventing these illnesses is challenging because resources are limited and linking individual illnesses to a particular food is rarely possible except during an outbreak. We developed a method of attributing illnesses to food commodities that uses data from outbreaks associated with both simple and complex foods. Using data from outbreak-associated illnesses for 1998-2008, we estimated annual US foodborne illnesses, hospitalizations, and deaths attributable to each of 17 food commodities. We attributed 46% of illnesses to produce and found that more deaths were attributed to poultry than to any other commodity. To the extent that these estimates reflect the commodities causing all foodborne illness, they indicate that efforts are particularly needed to prevent contamination of produce and poultry. Methods to incorporate data from other sources are needed to improve attribution estimates for some commodities and agents.