Microscopic fungi on the corpse - Promising tool requiring further research.

Forensic microbiology is a relatively new area of forensic sciences. It considers the potential of microorganisms to be used in criminal investigations. As most studies involve the role of bacteria in fields like post-mortem interval estimation, personal identification or geolocation, the data on the role of fungi is comparatively scarce. Forensic mycology involves the application of fungi and their structures in forensic cases. The aim of this review is the evaluation of the current state of knowledge on fungi associated with human cadavers and their possible role in estimating the time since death. In accordance with the available reports, we focused on the relation between microscopic fungi isolated from human corpses and the cadaver condition e.g., the stage of decomposition. We also emphasised the contrast between the reported methodologies and attempted to standardise research methods in forensic mycology from sample collection to its storage, mycological analysis and identification of the obtained fungal cultures. Moreover, the potential usage of microscopic fungi in criminal cases was discussed based on various case reports.

Lower hair cortisol concentration in adolescent and young adult patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Q-Fever Fatigue Syndrome compared to controls.

BACKGROUND: In patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), momentary cortisol concentrations in blood, urine, and saliva are lower compared to healthy controls. Long-term cortisol concentration can be assessed through hair, but it is unclear whether these concentrations are also lower. Additionally, it is unknown if lower cortisol extends to other patients suffering from persistent fatigue and how hair cortisol concentration (HCC) relates to fatigue levels. Therefore, this study examines HCC in fatigued patients with ME/CFS, Q fever Fatigue Syndrome (QFS), Post-COVID-19 condition (PCC), and Juvenile Idiopathic Arthritis (JIA). METHODS: Adolescent and young adult patients with ME/CFS (n=12), QFS (n=20), PCC (n=8), JIA (n=19), and controls (n=57) were included. Patients participated in a randomized cross-over trial (RCT) targeting fatigue through lifestyle and dietary self-management strategies. HCC was measured pre-post RCT in patients and once in controls, quantified using a LC-MS/MS-based method. Fatigue severity was measured with the Checklist Individual Strength-8. HCC was compared between groups with ANOVAs. Relations between HCC, fatigue severity, and other variables were investigated using linear regression analyses. RESULTS: The ME/CFS (p=.009) and QFS (p=.047) groups had lower HCC compared to controls. Overall, HCC was negatively associated with the presence of symptoms related to chronic fatigue syndromes (e.g., sleeping issues, often feeling tired, trouble thinking clearly; ß=-0.018, p=.035), except in the QFS group (ß=.063, p<.001). Baseline HCC did not predict fatigue improvement during the RCT (p=.449), and HCC increased during the trial (Mdif=.076, p=.021) regardless of clinically relevant fatigue improvement (p=.658). CONCLUSION: Lower cortisol concentration can also be observed in the long-term. Lower HCC is not limited to ME/CFS, as it was also observed in QFS. The role of cortisol may differ between these diagnoses and appears to be unrelated to fatigue levels.

Clinicopathological analysis of NEK1 variants in amyotrophic lateral sclerosis.

Many genes have been linked to amyotrophic lateral sclerosis (ALS), including never in mitosis A (NIMA)-related kinase 1 (NEK1), a serine/threonine kinase that plays a key role in several cellular functions, such as DNA damage response and cell cycle regulation. Whole-exome sequencing studies have shown that NEK1 mutations are associated with an increased risk for ALS, where a significant enrichment of NEK1 loss-of-function (LOF) variants were found in individuals with ALS compared to controls. In particular, the p.Arg261His missense variant was associated with significantly increased disease susceptibility. This case series aims to understand the neuropathological phenotypes resulting from NEK1 mutations in ALS. We examined a cohort of three Scottish patients with a mutation in the NEK1 gene and evaluated the distribution and cellular expression of NEK1, as well as the abundance of phosphorylated TDP-43 (pTDP-43) aggregates, in the motor cortex compared to age- and sex-matched control tissue. We show pathological, cytoplasmic TDP-43 aggregates in all three NEK1-ALS cases. NEK1 protein staining revealed no immunoreactivity in two of the NEK1-ALS cases, indicating a LOF and corresponding to a reduction in NEK1 mRNA as detected by in situ hybridisation. However, the p.Arg261His missense mutation resulted in an increase in NEK1 mRNA molecules and abundant NEK1-positive cytoplasmic aggregates, with the same morphologic appearance, and within the same cells as co-occurring TDP-43 aggregates. Here we show the first neuropathological assessment of a series of ALS cases carrying mutations in the NEK1 gene. Specifically, we show that TDP-43 pathology is present in these cases and that potential NEK1 LOF can either be mediated through loss of NEK1 translation or through aggregation of NEK1 protein as in the case with p.Arg261His mutation, a potential novel pathological feature of NEK1-ALS.

Susceptibility of pESI positive Salmonella to treatment with biocide chemicals approved for use in poultry meat processing as compared to Salmonella without the pESI plasmid.

Salmonella is a common cause of human foodborne illness which is frequently associated with consumption of contaminated or undercooked poultry meat. Serotype Infantis is among the most common serotypes isolated from poultry meat products globally. Isolates of serotype Infantis carrying the pESI plasmid, the most dominant strain of Infantis, have been shown to exhibit oxidizer tolerance. Therefore, sixteen strains of Salmonella with and without pESI carriage were investigated for susceptibility to biocide chemical processing aids approved for use in U.S. poultry meat processing: peracetic acid (PAA), cetylpyridinium chloride (CPC), calcium hypochlorite, and sodium hypochlorite. Strains were exposed for 15 seconds to simulate spray application and 90 minutes to simulate application in an immersion chiller. All strains tested were susceptible to all concentrations of PAA, CPC, and sodium hypochlorite when applied for 90 minutes. When CPC, calcium hypochlorite, and sodium hypochlorite were applied for 15 seconds to simulate spray time, strains responded similarly to each other. However, strains responded variably to exposure to PAA. The variation was not statistically significant and appears unrelated to pESI carriage. Results highlight the necessity of testing biocide susceptibility in the presence of organic material and in relevant in situ applications.

Evaluating the impact of social media marketing from the perspective of orthodontists.

OBJECTIVE: In developed countries, orthodontists utilize social media platforms as a pivotal component of their marketing strategies. However, there exists a gap in understanding the broader perspective of healthcare professionals on the utilization of social media in healthcare service delivery. Therefore, this study aims to evaluate the perceptions of healthcare professionals in Turkey regarding the integration of social media within healthcare service delivery. MATERIALS & METHODS: This cross-sectional study, conducted between January and February 2023, surveyed 378 members of the Turkish Orthodontic Society. The survey consisted of two parts: a demographic questionnaire with 28 items and a 21-item "Social Media Marketing Activities Scale," developed with input from three experts. Data analysis will include an explanatory factor analysis. This study provides a snapshot of orthodontists' perspectives on social media marketing practices. RESULTS: When participants' views of patient communication through social media were examined, 19.8% said they "thought it was right" and 80.2% said they "thought it was wrong". The treatment and treatment alternatives shared with patients through social media were implemented in 16.5% of cases and not implemented in 83.5% of cases. When examining the social media accounts used by participants to communicate with patients, 56.8% used personal accounts, 43.2% used professional accounts, and when analyzing the social media accounts they used for promotional purposes, 15.8% had personal accounts, 84.2% of them used professional accounts. More than half (59.8%) of orthodontists believed that communicating with patients on social media could cause legal problems. The majority of orthodontists (88.7%) followed their competitors. CONCLUSION: The prevalence of participants' use of social media posts for advertising purposes was low, and it was determined that the main reason for this was the prohibition of advertising in the provision of health services.

Activation of GPER1 by G1 prevents PTSD-like behaviors in mice: Illustrating the mechanisms from BDNF/TrkB to mitochondria and synaptic connection.

BACKGROUND: G1 is a specific agonist of G protein-coupled estrogen receptor 1 (GPER1), which binds and activates GPER1 to exert various neurological functions. However, the preventive effect of G1 on post-traumatic stress disorder (PTSD) and its mechanisms are unclear. OBJECTIVE: To evaluate the protective effect of G1 against synaptic and mitochondrial impairments and to investigate the mechanism of G1 to improve PTSD from brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling. METHODS: This study initially detected GPER1 expression in the hippocampus of single prolonged stress (SPS) mice, utilizing both Western blot and immunofluorescence staining. Subsequently, the effects of G1 on PTSD-like behaviors, synaptic, and mitochondrial functions in SPS mice were investigated. Additionally, the involvement of BDNF/TrkB signaling involved in the protection was further confirmed using GPER1 antagonist and TrkB inhibitor, respectively. RESULTS: The expression of GPER1 was reduced in the hippocampus of SPS mice, and G1 treatment given for 14 consecutive days significantly improved PTSD-like behaviors in SPS mice compared with model group. Electrophysiological local field potential (LFP) results showed that G1 administration for 14 consecutive days could reverse the abnormal changes in the gamma oscillation in the CA1 region of SPS mice. Meanwhile, G1 administration for 14 consecutive days could significantly improve the abnormal expression of synaptic proteins, increase the expression of mitochondria-related proteins, increase the number of synapses in the hippocampus, and ameliorate the damage of hippocampal mitochondrial structure in SPS mice. In addition, G15 (GPER1 inhibitor) and ANA-12 (TrkB inhibitor) blocked the ameliorative effects of G1 on PTSD-like behaviors and aberrant expression of hippocampal synaptic and mitochondrial proteins in SPS mice and inhibited the reparative effects of G1 on structural damage to hippocampal mitochondria, respectively. CONCLUSION: G1 improved PTSD-like behaviors in SPS mice, possibly by increasing hippocampal GPER1 expression and promoting BDNF/TrkB signaling to repair synaptic and mitochondrial functional impairments. This study would provide critical mechanism for the prevention and treatment of PTSD.

Management of diabetes in people with advanced chronic kidney disease.

Diabetes is the commonest cause of end stage kidney disease globally, accounting for almost 40% of new cases requiring renal replacement therapy. Management of diabetes in people with advanced kidney disease on renal replacement therapy is challenging due to some unique aspects of assessment and treatment in this group of patients. Standard glycaemic assessment using glycated haemoglobin may not be valid in such patients due to altered red blood cell turnover or iron/erythropoietin deficiency, leading to changed red blood cell longevity. Therefore, use of continuous glucose monitoring may be beneficial to enable more focussed glycaemic assessment and improved adjustment of therapy. People with advanced kidney disease may be at higher risk of hypoglycaemia due to a number of physiological mechanisms, and in addition, therapeutic options are limited in such patients due to lack of experience or license. Insulin therapy is the basis of treatment of people with diabetes with advanced kidney disease due to many other drugs classes being contraindicated. Targets for glycaemic control should be adjusted according to co-morbidity and frailty, and continuous glucose monitoring should be used in people on dialysis to ensure low risk of hypoglycaemia. Post-transplant diabetes is common amongst people undergoing solid organ transplantation and confers a greater risk of mortality and morbidity in kidney transplant recipients. It should be actively screened for and managed in the post-transplant setting.

Mitochondrial sirtuin 3 and role of natural compounds: the effect of post-translational modifications on cellular metabolism.

Sirtuins (SIRTs) are a family of proteins with enzymatic activity. In particular, they are a family of class III NAD+-dependent histone deacetylases and ADP-ribosyltransferases. NAD+-dependent deac(et)ylase activities catalyzed by sirtuin include ac(et)ylation, propionylation, butyrylation, crotonylation, manylation, and succinylation. Specifically, human SIRT3 is a 399 amino acid protein with two functional domains: a large Rossmann folding motif and NAD+ binding, and a small complex helix and zinc-binding motif. SIRT3 is widely expressed in mitochondria-rich tissues and is involved in maintaining mitochondrial integrity, homeostasis, and function. Moreover, SIRT3 regulates related diseases, such as aging, hepatic, kidney, neurodegenerative and cardiovascular disease, metabolic diseases, and cancer development. In particular, one of the most significant and damaging post-translational modifications is irreversible protein oxidation, i.e. carbonylation. This process is induced explicitly by increased ROS production due to mitochondrial dysfunction. SIRT3 is carbonylated by 4-hydroxynonenal at the level of Cys280. The carbonylation induces conformational changes in the active site, resulting in allosteric inhibition of SIRT3 activity and loss of the ability to deacetylate and regulate antioxidant enzyme activity. Phytochemicals and, in particular, polyphenols, thanks to their strong antioxidant activity, are natural compounds with a positive regulatory action on SIRT3 in various pathologies. Indeed, the enzymatic SIRT3 activity is modulated, for example, by different natural polyphenol classes, including resveratrol and the bergamot polyphenolic fraction. Thus, this review aims to elucidate the mechanisms by which phytochemicals can interact with SIRT3, resulting in post-translational modifications that regulate cellular metabolism.

Resilience after severe critical illness: a prospective, multicentre, observational study (RESIREA).

BACKGROUND: Critical-illness survivors may experience post-traumatic stress disorder (PTSD) and quality-of-life impairments. Resilience may protect against psychological trauma but has not been adequately studied after critical illness. We assessed resilience and its associations with PTSD and quality of life, and also identified factors associated with greater resilience. METHODS: This prospective, multicentre, study in patients recruited at 41 French ICUs was done in parallel with the NUTRIREA-3 trial in patients given mechanical ventilation and vasoactive amines for shock. Three months to one year after intensive-care-unit admission, survivors completed the Connor-Davidson Resilience Scale (CD-RISC-25), Impact of Event-Revised scale for PTSD symptoms (IES-R), SF-36 quality-of-life scale, Multidimensional Scale of Perceived Social Support (MSPSS), and Brief Illness Perception Questionnaire (B-IPQ). RESULTS: Of the 382 included patients, 203 (53.1%) had normal or high resilience (CD-RISC-25 ≥ 68). Of these resilient patients, 26 (12.8%) had moderate to severe PTSD symptoms (IES-R ≥ 24) vs. 45 (25.4%) patients with low resilience (p = 0.002). Resilient patients had higher SF-36 scores. Factors independently associated with higher CD-RISC-25 scores were higher MSPSS score indicating stronger social support (OR, 1.027; 95%CI 1.008-1.047; p = 0.005) and lower B-IPQ scores indicating a more threatening perception of the illness (OR, 0.973; 95%CI 0.950-0.996; p = 0.02). CONCLUSIONS: Resilient patients had a lower prevalence of PTSD symptoms and higher quality of life scores, compared to patients with low resilience. Higher scores for social support and illness perception were independently associated with greater resilience. Thus, our findings suggest that interventions to strengthen social support and improve illness perception may help to improve resilience. Such interventions should be evaluated in trials with PTSD mitigation and quality-of-life improvement as the target outcomes.

Characterizing the post-traumatic growth trajectory in gastric cancer survivors: a population-based longitudinal study.

OBJECTIVES: Post-traumatic growth can improve the quality of life of cancer survivors. The objective of this study was to investigate post-traumatic growth heterogeneity trajectory in perioperative gastric cancer survivors, and to identify characteristics that predict membership for each trajectory. METHODS: Gastric cancer survivors (n = 403) were recruited before surgery, their baseline assessment (including post-traumatic growth and related characteristics) was completed, and post-traumatic growth levels were followed up on the day they left the intensive care unit, at discharge, and 1 month after discharge. Latent growth mixture mode was used to identify the heterogeneous trajectory of post-traumatic growth, and the core predictors of trajectory subtypes were explored using a decision tree model. RESULTS: Three post-traumatic growth development trajectories were identified among gastric cancer survivors: stable high of PTG group (20.6%), fluctuation of PTG group (44.4%), persistent low of PTG group (35.0%). The decision tree model showed anxiety, coping style, and psychological resilience-which was the primary predictor-might be used to predict the PTG trajectory subtypes of gastric cancer survivors. CONCLUSIONS: There was considerable variability in the experience of post-traumatic growth among gastric cancer survivors. Recognition of high-risk gastric cancer survivors who fall into the fluctuation or persistent low of PTG group and provision of psychological resilience-centered support might allow medical professionals to improve patients' post-traumatic growth and mitigate the impact of negative outcomes.

Glucose influences endometrial receptivity to embryo implantation through O-GlcNAcylation-mediated regulation of the cytoskeleton.

Phenotypic changes to endometrial epithelial cells underpin receptivity to embryo implantation at the onset of pregnancy but the effect of hyperglycaemia on these processes remains poorly understood. Here we show that physiological levels of glucose (5mM) abolished receptivity in the endometrial epithelial cell line, Ishikawa. However, embryo attachment was supported by 17mM glucose as a result of glucose flux through the hexosamine biosynthetic pathway (HBP) and modulation of cell function via protein O-GlcNAcylation. Pharmacological inhibition of HBP or protein O-GlcNAcylation reduced embryo attachment in co-cultures at 17mM glucose. Mass spectrometry analysis of the O-GlcNAcylated proteome in Ishikawa cells revealed that myosin phosphatase target subunit 1 (MYPT1) is more highly O-GlcNAcylated in 17mM glucose, correlating with loss of its target protein, phospho-myosin light chain 2, from apical cell junctions of polarised epithelium. 2D and 3D morphologic analysis demonstrated that the higher glucose level attenuates epithelial polarity through O-GlcNAcylation. Inhibition of RhoA-associated kinase (ROCK) or myosin II led to reduced polarity and enhanced receptivity in cells cultured in 5mM glucose, consistent with data showing that MYPT1 acts downstream of ROCK signalling. These data implicate regulation of endometrial epithelial polarity through RhoA signaling upstream of actomyosin contractility in the acquisition of endometrial receptivity. Glucose levels impinge on this pathway through O-GlcNAcylation of MYPT1, which may impact endometrial receptivity to an implanting embryo in women with diabetes.

Heparin as a Potential Therapeutic Substance for Post-Traumatic Stress Disorder.

In sexually mature male Wistar rats with modeled post-traumatic stress disorder, personalized characteristics of neurobiological reactions in the population of predator-induced stress-resilient and stress-susceptible heparinized animals were determined. Characteristics of the systemic response of immune mechanisms, hypothalamic-pituitary-adrenal axis, behavioral manifestations, as well as basic properties of the CNS (excitation/inhibition) are presented. The study demonstrated encouraging positive results of the course administration of unfractionated heparin at a dose below the therapeutic and prophylactic doses. The inclusion of heparin drugs into the clinical practice for the treatment of post-traumatic stress disorder will not require large-scale clinical trials, because many effects of heparin as a nonspecific adaptogen are well studied. Moreover, these properties were confirmed at a higher technological level during the COVID-19 pandemic.

Noninvasive transcranial brain stimulation in central post-stroke pain: A systematic review.

BACKGROUND: The aim of this systematic review is to analyze the efficacy of noninvasive brain stimulation (NBS) in the treatment of central post-stroke pain (CPSP). METHODS: We included randomized controlled trials testing the efficacy of transcranial magnetic stimulation (TMS) or transcranial direct current stimulation versus placebo or other usual therapy in patients with CPSP. Articles in English, Portuguese, Spanish, Italian, and French were included. A bibliographic search was independently conducted on June 1, 2022, by two authors, using the databases MEDLINE (PubMed), Embase (Elsevier), Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science Core Collection. The risk of bias was assessed using the second version of the Cochrane risk of bias (RoB 2) tool and the certainty of the evidence was evaluated through Grading of Recommendations Assessment, Development and Evaluation. RESULTS: A total of 2,674 records were identified after removing duplicates, of which 5 eligible studies were included, involving a total of 119 patients. All five studies evaluated repetitive TMS, four of which stimulated the primary motor cortex (M1) and one stimulated the premotor/dorsolateral prefrontal cortex. Only the former one reported a significant pain reduction in the short term, while the latter one was interrupted due to a consistent lack of analgesic effect. CONCLUSION: NBS in the M1 area seems to be effective in reducing short-term pain; however, more high-quality homogeneous studies, with long-term follow-up, are required to determine the efficacy of this treatment in CSPS.

Retrospective screening of new psychoactive substances (NPS) in post mortem samples from 2014 to 2021.

Systematic retrospective processing of previously analysed biological samples has been proven to be a valuable tool in the search for new drugs (e.g. new psychoactive substances (NPS)) and for quality assessment in clinical and forensic toxicology. In a previous study, we developed a strategy for retrospective data-analysis using a personalized library of synthetic cannabinoids, designer benzodiazepines and synthetic opioids obtained from the crowdsourced database HighResNPS (https://highresnps.com). In this study, the same strategy was employed for the compounds within the groups of NPS that were not previously included such as synthetic cathinones, phenethylamines, aminoindanes, arylalkylamines, piperazine derivates, piperidines, pyrrolidines, indolalkylamines and arylcyclohexylamines. Synthetic opioids and designer benzodiazepines, which were not part of the previous study, were also included. To enhance the effectiveness of the retrospective analysis, a predicted retention time was included for all entries. Data files from the analysis of 2186 forensic post mortem samples with an Agilent Technologies 6540 ultra-high pressure liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) performed in the laboratory from January 2014 to December 2021 were retrospectively processed with the up-to-date library. Tentative findings were classified in two groups: The findings where MS/MS data was acquired for library match (category 1) and the less certain findings where such data lacked (category 2). Five compounds of category 1 (three synthetic cathinones and two indolalkylamines) were identified in 12 samples. Only one of the findings, 4-MEAPP (4-methyl-α-ethylaminopentiophenone), was deemed plausible after reviewing case information. As many as 501 presumably positive category 2 findings were detected. Using the predicted retention time as an additional criterion the number was significantly reduced but still too high for a manual review. This work has demonstrated that the strategy developed in the previous study can be applied to other NPS groups. However, it is important to note the limitations such a method may have in detecting compounds at very low concentrations.

Application of ultrasound-guided thoracic paravertebral block or intercostal nerve block for acute herpes zoster and prevention of post-herpetic neuralgia: A case-control retrospective trial.

OBJECTIVES: Ultrasound (US)-guided intercostal nerve block (ICNB) is an easier approach with a very low incidence of complications for different surgeries; nevertheless, only a few studies estimate the effect of ICNB for acute HZ. To explore the US-guided ICNB for management of herpes zoster (HZ)-related acute pain and possible prophylaxis for post-herpetic neuralgia (PHN) taking the conventional thoracic paraverteral block (TPVB) as control. METHODS: A total of 128 patients with HZ were retrospectively stratified into antiviral treatment (AVT) plus US-guided TPVB (TPVB group), AVT plus US-guided ICNB (ICNB group) or AVT alone (control group) based on the treatment they received. HZ-related illness burden (HZ-BOI) over 30 days after inclusion as the primary endpoint was determined by a severity-by-duration composite pain assessment. Rescue analgesic requirement, health-related quality of life, PHN incidence, and adverse events were also recorded. RESULTS: Significantly lower HZ-BOI scores within post-procedural 30 days using the area under the curve were reported with TPVB and ICNB compared with the control group: mean difference of 57.5 (p < 0.001) and 40.3 (p = 0.003). No difference was reported between TPVB and ICNB (p = 1.01). Significant greater improvements in PHN incidence, EQ-5D-3L scores, and rescue analgesic requirements were observed during follow-up favoring two trial groups, while comparable between two trial groups. No serious adverse events were observed. CONCLUSIONS: US-guided ICNBs were as effective as TPVBs for acute HZ. The ICNB technique was an easier and time-efficient approach as opposed to conventional TPVB, which might be encouraged as a more accessible preemptive mean for preventing PHN.

Deciphering the intricate dynamics of inflammasome regulation in visceral and post-kala-azar dermal leishmaniasis: A meta-analysis of consistencies.

Post Kala-azar dermal leishmaniasis (PKDL) arises as a significant dermal sequel following Visceral leishmaniasis (VL) caused by protozoan parasite Leishmania donovani (LD). PKDL acts as a significant constrain for VL elimination serving as a crucial reservoir for LD. PKDL patients exhibit depigmented macular and papular lesions on their skin, which results in social discrimination due to loss of natural skin color. Inflammatory reactions, prevalent in both VL and PKDL, potentially lead to tissue damage in areas harboring the parasite. Disruption of the immune-inflammasomal network not only facilitates LD persistence but also leads to the skin hypopigmentation seen in PKDL, impacting social well-being. Activation of inflammasomal markers like STAT1, NLRP1, NLRP3, AIM2, CASP11, and NLRP12 have been identified as a common host-defense mechanism across various Leishmania infections. Conversely, Leishmania modulates inflammasome activation to sustain its presence within the host. Nevertheless, in specific instances of Leishmania infection, inflammasome activation can worsen disease pathology by promoting parasite proliferation and persistence. This study encompasses recent transcriptomic analyses conducted between 2016 and 2023 on human and murine subjects afflicted with VL/PKDL, elucidating significant alterations in inflammasomal markers in both conditions. It offers a comprehensive understanding how these markers contribute in disease progression, drawing upon available literature for logical analysis. Furthermore, our analysis identifies validated miRNA network that could potentially disrupt this crucial immune-inflammasomal network, thereby offering a plausible explanation on how secreted LD-factors could enable membrane-bound LD, isolated from the host cytoplasm, to modulate cytoplasmic inflammasomal markers. Insights from this study could guide the development of host-directed therapeutics to impede transmission and address hypopigmentation, thereby mitigating the social stigma associated with PKDL.

HMGB1-Mediated Cell Death-A Crucial Element in Post-Hepatectomy Liver Failure.

Liver resection (LR) is the primary treatment for hepatic tumors, yet posthepatectomy liver failure (PHLF) remains a significant concern. While the precise etiology of PHLF remains elusive, dysregulated inflammatory processes are pivotal. Therefore, we explored the theragnostic potential of extracellular high-mobility-group-box protein 1 (HMGB1), a key damage-associated molecular pattern (DAMP) released by hepatocytes, in liver recovery post LR in patients and animal models. Plasma from 96 LR patients and liver tissues from a subset of 24 LR patients were analyzed for HMGB1 levels, and associations with PHLF and liver injury markers were assessed. In a murine LR model, the HMGB1 inhibitor glycyrrhizin, was administered to assess its impact on liver regeneration. Furthermore, plasma levels of keratin-18 (K18) and cleaved cytokeratin-18 (ccK18) were quantified to assess suitability as predictive biomarkers for PHLF. Patients experiencing PHLF exhibited elevated levels of intrahepatic and circulating HMGB1, correlating with markers of liver injury. In a murine LR model, inhibition of HMGB1 improved liver function, reduced steatosis, enhanced regeneration and decreased hepatic cell death. Elevated levels of hepatic cell death markers K18 and ccK18 were detected in patients with PHLF and correlations with levels of circulating HMGB1 was observed. Our study underscores the therapeutic and predictive potential of HMGB1 in PHLF mitigation. Elevated HMGB1, K18, and ccK18 levels correlate with patient outcomes, highlighting their predictive significance. Targeting HMGB1 enhances liver regeneration in murine LR models, emphasizing its role in potential intervention and prediction strategies for liver surgery.

Exosomes Derived from Hypertrophic Scar Fibroblasts Suppress Melanogenesis in Normal Human Epidermal Melanocytes.

Post-burn hypertrophic scars often exhibit abnormal pigmentation. Exosomes play important roles in maintaining normal physiological homeostasis and in the pathological development of diseases. This study investigated the effects of the exosomes derived from hypertrophic scar fibroblasts (HTSFs) on melanocytes, which are pigment-producing cells. Normal fibroblasts (NFs) and HTSFs were isolated and cultured from normal skin and hypertrophic scar (HTS) tissue. Both the NF- and HTSF-exosomes were isolated from a cell culture medium and purified using a column-based technique. The normal human epidermal melanocytes were treated with both exosomes at a concentration of 100 µg/mL at different times. The cell proliferation, melanin content in the medium, apoptotic factors, transcription factors, melanin synthesis enzymes, signaling, signal transduction pathways, and activators of transcription factors (STAT) 1, 3, 5, and 6 were investigated. Compared with the Dulbecco's phosphate-buffered saline (DPBS)-treated controls and NF-exosomes, the HTSF-exosomes decreased the melanocyte proliferation and melanin secretion. The molecular patterns of apoptosis, proliferation, melanin synthesis, Smad and non-Smad signaling, and STATs were altered by the treatment with the HTSF-exosomes. No significant differences were observed between the DPBS-treated control and NF-exosome-treated cells. HTSF-derived exosomes may play a role in the pathological epidermal hypopigmentation observed in patients with HTS.

Early clinical and quality impacts of the Age-Friendly Health System in a Veterans Affairs skilled nursing facility.

BACKGROUND: Skilled nursing facilities (SNFs) are an ideal setting to implement the Age-Friendly Health System (AFHS) approach, an initiative by the Institute for Healthcare Improvement (IHI) centered on the 4Ms: what matters, mobility, mentation, and medication. AFHS implementation has not been well studied in SNFs. METHODS: A 112-bed VA SNF implemented a facility-wide AFHS initiative including the following: (1) participating in a national IHI Age-Friendly Action Community; (2) establishing an AFHS workgroup centered on the 4Ms; (3) identifying meaningful clinical tools and frameworks for capturing each M; and (4) developing sustainment methods. Clinical (life-sustaining treatment, falls, disruptive behaviors, and medication deprescribing) and quality outcomes (rehospitalization, emergency department utilization, and discharge to the community) in addition to patient satisfaction were compared pre- and post-AFHS implementation (bed days of care [BDOC] 17413) to post-implementation (BDOC 20880). RESULTS: Clinical outcomes demonstrated improvements in the 4Ms, including: (1) what matters: 14% increase in life-sustaining treatment documentation (82%-96%; p < 0.01); (2) mobility: reduction in fall rate by 34% (8.15 falls/1000 BDOC to 5.41; p < 0.01); (3) mentation: decrease in disruptive behavior reporting system (DBRS) by 62% (5.11 DBRS/1000 BDOC to 1.96; p = 0.04); (4) medications: 53% increase in average potentially inappropriate medications (PIMs) deprescribing (0.38-0.80 interventions/patient; p < 0.01). Quality outcomes improved including rehospitalization (25.6%-17.9%) and emergency department utilization (5.3%-2.8%) within 30 days of admission. Patient satisfaction scores improved from a mean of 77.2 (n = 31, scale 1-100) to 81.3 (n = 42). CONCLUSIONS: Implementation of the AFHS initiative in a SNF was associated with improved clinical and quality outcomes and patient satisfaction. We describe here a sustainable, interprofessional approach to implementing the AFHS in a SNF.