Indirect Evidence Research Articles

Local inconsistency detection using the Kullback–Leibler divergence measure

BackgroundThe standard approach to local inconsistency assessment typically relies on testing the conflict between the direct and indirect evidence in selected treatment comparisons. However, statistical tests for inconsistency have low power and are subject to misinterpreting a p-value above the significance threshold as evidence of consistency.MethodsWe propose a simple framework to interpret local inconsistency based on the average Kullback–Leibler divergence (KLD) from approximating the direct with the corresponding indirect estimate and vice versa. Our framework uses directly the mean and standard error (or posterior mean and standard deviation) of the direct and indirect estimates obtained from a local inconsistency method to calculate the average KLD measure for selected comparisons. The average KLD values are compared with a semi-objective threshold to judge the inconsistency as acceptably low or material. We exemplify our novel interpretation approach using three networks with multiple treatments and multi-arm studies.ResultsAlmost all selected comparisons in the networks were not associated with statistically significant inconsistency at a significance level of 5%. The proposed interpretation framework indicated 14%, 66%, and 75% of the selected comparisons with an acceptably low inconsistency in the corresponding networks. Overall, information loss was more notable when approximating the posterior density of the indirect estimates with that of the direct estimates, attributed to indirect estimates being more imprecise.ConclusionsUsing the concept of information loss between two distributions alongside a semi-objectively defined threshold helped distinguish target comparisons with acceptably low inconsistency from those with material inconsistency when statistical tests for inconsistency were inconclusive.

Do high-profile investigations of corruption deter corruption in non-targeted firms: indirect evidence from reductions in real earnings management

Do high-profile investigations of corruption deter corruption in non-targeted firms: indirect evidence from reductions in real earnings management

Does Concomitant Use of Methotrexate with JAK Inhibition Confer Benefit for Cardiovascular Outcomes? A Commentary.

This commentary explores the potential cardiovascular (CV) benefits of combining methotrexate (MTX) and Janus kinase inhibitors (JAKis) in the treatment of rheumatoid arthritis (RA). While European guidelines recommend MTX as first-line treatment, concerns about the CV risks associated with JAKis have emerged. This article reviews the existing literature to assess the role of concomitant MTX in reducing CV risk when used with JAKis. Clinical trials confirm the efficacy of JAKis in combination with MTX in terms of treatment outcomes in RA. However, the number of major adverse cardiovascular events (MACEs) reported is too low to draw conclusions on adverse CV outcomes. Indirect evidence does, however, suggest potential protective effects of MTX on CV outcomes, as several mechanisms may contribute to MTX's cardioprotective effects, including reduced inflammation, adenosine monophosphate-activated protein kinase (AMPK) activation, increased cholesterol efflux, and adenosine accumulation. These mechanisms and the available data may support the case for CV benefits of concomitant MTX when JAKis are used in the treatment of patients with RA, although further research is needed. In particular, the lipid paradox associated with RA highlights the complex relationship between RA treatments (MTX, JAKis, tumor necrosis factor (TNF) inhibitors, and interleukin (IL)-6 receptor inhibitors), inflammation, different lipid profiles, and CV risk. In the absence of contraindications and when MTX is tolerated, this commentary suggests the concomitant use of MTX and JAKis as a preferred option for optimizing CV protection in patients with RA.

Effect of touch on proprioception: non-invasive trigeminal nerve stimulation suggests general arousal rather than tactile-proprioceptive integration.

Proprioceptive error of estimated fingertip position in two-dimensional space is reduced with the addition of tactile stimulation applied at the fingertip. Tactile input does not disrupt the participants' estimation strategy, as the individual error vector maps maintain their overall structure. This relationship suggests integration of proprioception and tactile information improves proprioceptive estimation, which can also be improved with trained mental focus and attention. Task attention and arousal are physiologically regulated by the reticular activating system (RAS), a brainstem circuit including the locus coeruleus (LC). There is direct and indirect evidence that these structures can be modulated by non-invasive trigeminal nerve stimulation (nTNS), providing an opportunity to examine nTNS effect on the integrative relationship of proprioceptive and tactile information. Fifteen right-handed participants performed a simple right-handed proprioceptive estimation task with tactile feedback (touch) and no tactile (hover) feedback. Participants repeated the task after nTNS administration. Stimulation was delivered for 10 min, and stimulation parameters were 3,000 Hz, 50 μs pulse width, with a mean of 7 mA. Error maps across the workspace are generated using polynomial models of the participants' target responses. Error maps did not demonstrate significant vector direction changes between conditions for any participant, indicating that nTNS does not disrupt spatial proprioception estimation strategies. A linear mixed model regression with nTNS epoch, tactile condition, and the interaction as factors demonstrated that nTNS reduced proprioceptive error under the hover condition only. We argue that nTNS does not disrupt spatial proprioceptive error maps but can improve proprioceptive estimation in the absence of tactile feedback. However, we observe no evidence that nTNS enhances tactile-proprioceptive integration as the touch condition does not exhibit significantly reduced error after nTNS.

Disturbances of Interoception in Schizophrenia – Focus on Neuroimaging

Abstract: The current paper presents the most recent theoretical understanding of interoception (INTC) in light of the predictive processing framework and the Embodied Predictive Interoceptive Coding model and reviews recent experimental data on different interoceptive disturbances in schizophrenia (SCZ) such as lower interoceptive accuracy, nociceptive dysfunction reflected by reduced pain sensitivity, disturbed thermoregulation, impaired gastrointestinal regulation, cardiovascular and respiratory dysfunction, and immune disturbances. The immense clinical implications of these disturbances are discussed in the context of the high rates of morbidity and mortality in SCZ related to suicide and cardiac death. Next, the potential of INTC-related treatments is reviewed, and conclusions are made on the evidence for the use of vagus nerve stimulation, mindfulness-based interventions, and exercise therapy. The neuroimaging perspective is given in a brief account of the INTC-related findings in healthy individuals suggesting the right anterior insula and anterior cingulate cortex as key brain areas for interoceptive awareness, accuracy, and sensibility, by supporting higher-order representation and integration of visceral, and somatosensory interoception with exteroceptive information. In SCZ, on the other hand, neuroimaging research on specific interoceptive abilities is lacking but indirect evidence points to disrupted activation of major INTC network hubs. There is converging evidence of changes in these hubs in terms of both structure and function (volume reductions, aberrant activation, and connectivity). This narrative review identifies several gaps in contemporary INTC-related research in SCZ that need to be addressed in future experimental and clinical studies to elucidate the exact nature of the disturbances of interoceptive abilities in modalities other than cardioception; the interactions between different interoceptive modalities; the association between interoceptive abilities and other mental functions (such as emotion recognition and regulation, decision making, learning, memory, etc.); the efficacy of nonpharmacological and pharmacological INTC-based interventions; and the relation of disturbed interoceptive abilities with brain structure and function.

Role of ACSBG1 in Brain Lipid Metabolism and X-Linked Adrenoleukodystrophy Pathogenesis: Insights from a Knockout Mouse Model.

"Bubblegum" acyl-CoA synthetase (ACSBG1) is a pivotal player in lipid metabolism during mouse brain development, facilitating the activation of long-chain fatty acids (LCFA) and their incorporation into lipid species that are crucial for brain function. ACSBG1 converts LCFA into acyl-CoA derivatives, supporting vital metabolic processes. Fruit fly mutants lacking ACSBG1 exhibited neurodegeneration and had elevated levels of very long-chain fatty acids (VLCFA), characteristics of human X-linked adrenoleukodystrophy (XALD). To explore ACSBG1's function and potential as a therapeutic target in XALD, we created an ACSBG1 knockout (Acsbg1-/-) mouse and examined the effects on brain FA metabolism during development. Phenotypically, Acsbg1-/- mice resembled wild type (w.t.) mice. ACSBG1 expression was found mainly in tissue affected pathologically in XALD, namely the brain, adrenal gland and testis. ACSBG1 depletion did not significantly reduce the total ACS enzyme activity in these tissue types. In adult mouse brain, ACSBG1 expression was highest in the cerebellum; the low levels detected during the first week of life dramatically increased thereafter. Unexpectedly, lower, rather than higher, saturated VLCFA levels were found in cerebella from Acsbg1-/- vs. w.t. mice, especially after one week of age. Developmental changes in monounsaturated ω9 FA and polyunsaturated ω3 FA levels also differed between w.t. and Acsbg1-/- mice. ACSBG1 deficiency impacted the developmental expression of several cerebellar FA metabolism enzymes, including those required for the synthesis of ω3 polyunsaturated FA, precursors of bioactive signaling molecules like eicosanoids and docosanoids. These changes in membrane lipid FA composition likely affect membrane fluidity and may thus influence the body's response to inflammation. We conclude that, despite compelling circumstantial evidence, it is unlikely that ACSBG1 directly contributes to the pathology of XALD, decreasing its potential as a therapeutic target. Instead, the effects of ACSBG1 knockout on processes regulated by eicosanoids and/or docosanoids should be further investigated.

Death by Frostbite: From Theory to Reality: A Case Report

Background: When the body temperature falls below 35 °C, a condition known as hypothermia occurs. This renders it impossible to regulate the body temperature and produce heat. In these cases, death is due to a cessation of vital functions and is triggered by a body temperature below 25 °C. A multidisciplinary approach is typically required when hypothermia is suspected to combine circumstantial evidence, external examination, autopsy, microscopic and biochemical findings, and other data useful to assess the diagnosis of fatal hypothermia. Post-mortem diagnosis of death by hypothermia frequently presents a medico-legal dilemma. Methods and Results: The authors present a case of hypothermia in which site inspection, autopsy, and histological examination simultaneously revealed the forensic and anatomopathological characteristic findings of hypothermia with some peculiar evidence: paradoxical undressing, thanatochronological phenomena, frost erythema, polyvisceral congestion and Wischnewski spots, and subnuclear vacuolization of renal tubular epithelial cells.

Torsion-Induced Traumatic Optic Neuropathy (TITON): A Physiologically Relevant Animal Model of Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) is a common cause of irreversible blindness following head injury. TON is characterized by axon damage in the optic nerve followed by retinal ganglion cell death in the days and weeks following injury. At present, no therapeutic or surgical approach has been found to offer any benefit beyond observation alone. This is due in part to the lack of translational animal models suitable for understanding mechanisms and evaluating candidate treatments. In this study, we developed a rat model of TON in which the eye is rapidly rotated, inflicting mechanical stress on the optic nerve and leading to significant visual deficits. These functional deficits were thoroughly characterized up to one week after injury using electrophysiology and immunohistochemistry. The photopic negative response (PhNR) of the light adapted full field electroretinogram (LA ffERG) was significantly altered following injury. This correlated with increased biomarkers of retinal stress, axon disruption, and ganglion cell death. Together, this evidence suggests the utility of our model for mimicking clinically relevant TON and that the PhNR may be an early diagnostic for TON. We also found indirect evidence that ketamine, which was used for anesthesia, may ameliorate TON. Future studies will utilize this animal model for evaluation of candidate treatments.

Serum metabolomics analysis reveals potential biomarkers of penicillins-induced fatal anaphylactic shock in rats

Immunoglobulin E (IgE)-mediated immediate hypersensitivity reactions are the most concerning adverse events after penicillin antibiotics (PENs) administration because of their rapid progression and potential for fatal outcome. However, the diagnosis of allergic death is a forensic challenge because it mainly depends on nonspecific characteristic morphological changes, as well as exclusion and circumstantial evidence. In this study, an untargeted metabolomics approach based on liquid chromatography-mass spectrometry (LC-MS) was used to screen potential forensic biomarkers of fatal anaphylactic shock induced by four PENs (benzylpenicillin (BP), amoxicillin (AMX), oxacillin (OXA), and mezlocillin (MEZ)), and analyzed the metabolites, metabolic pathway and the mechanism which were closely related to the allergic reactions. The metabolomics results discovered that a total of 24 different metabolites in all four anaphylactic death (AD) groups, seven of which were common metabolites. A biomarker model consisting of six common metabolites (linoleic acid, prostaglandin D2, lysophosphatidylcholine (18:0), N-acetylhistamine, citric acid and indolelactic acid) AUC value of Receiver Operating Characteristic (ROC) curve was 0.978. Metabolism pathway analysis revealed that the pathogenesis of PENs-induced AD is closely related to linoleic acid metabolism. Our results revealed that the metabolomic profiling has potential in PENs-induced AD post-mortem diagnosis and metabolic mechanism investigations.

Abrolophus from Australasia, and the mysterious Mypongia (Trombidiformes: Parasitengona: Erythraeidae)

An undetermined species of Abrolophus Berlese was intercepted in quarantine by Australian biosecurity on kiwifruit imported from New Zealand. Here, we show that these are the Australian species Abrolophus ripicola (Womersley, 1934), a species known from the post-larval stages only. We present evidence that the larva of A. ripicola is probably the taxon Mypongia brevipes Southcott, 1961, which belongs to a monotypic genus with unique morphology that is placed in a different subfamily to Abrolophus. The larval and post-larval stages we examined share a similar morphology, most notably a reduction of the prodorsal shield and much reduced leg setation. Three M. brevipes larvae were intercepted on kiwifruit imported from New Zealand, and with an additional larval specimen from South Australia, these four specimens represent the first collections of this taxon since its description. Further circumstantial evidence supporting the conspecificity of the two taxa includes a female specimen of A. ripicola collected from Myponga, the type locality of M. brevipes, and larval stages of an undescribed Mypongia collected together with the post-larval stages of an undescribed Abrolophus, from the same locality in South Africa. Keys are provided for the post-larval stages of Abrolophus species in Australia (6 spp.), Papua New Guinea (Abrolophus novaeguinensis (Gunther, 1941)) and New Zealand (Abrolophus zelandicus Luxton, 1989).

Frequent Use of Premenopausal Progestin in Prior Pre-Eclamptic Women.

Women with a history of pre-eclamptic pregnancy are predisposed to later occlusive vascular diseases. We compared the use of cyclic progestins or levonorgestrel-releasing intrauterine device (LNG-IUD) for treatment of menstrual cycle abnormalities between premenopausal women with and without a prior pre-eclamptic pregnancy. Register-based cohort study during 1994-2019 of oral progestin or levonorgestrel-releasing intrauterine device (LNG-IUD) in Finnish women with (n=31 688) and without (n=91 726) prior pre-eclampsia in 1969-1993. Cyclic progestin or LNG-IUD use and its association with future use of menopausal hormone therapy (MHT). Prior pre-eclamptic women had used cyclic progestins more often (23.5% vs. 9.1%; p<0.001) and initiated the use at younger ages (41.8 years [SD=6.3] vs. 45.9 years [3.1]; p<0.001) than control women. Also, LNG-IUD was inserted more frequently (p<0.001) in prior pre-eclamptic women (9.3%) than in controls (4.7%). Cyclic progestin or LNG-IUD use was accompanied by significant 37-90% elevations in future MHT use. Increased use of cyclic progestins and LNG-IUD in premenopausal women with a history of pre-eclamptic pregnancy can be seen as indirect evidence of earlier onset of ovulatory dysfunction. This may contribute to the elevated risk of endometrial cancer in these women. Our findings may indicate one additional late sequela of pre-eclamptic pregnancy.

The problem of ammonoid substantiation of the Artinskian–Kungurian boundary in Western Verkhoyanie

Kungurian ammonoids had high taxonomic diversity, but were distinguished by an extremely high level of endemism and sharp geographic differentiation. Therefore, outside the regions containing the most important conodont taxa, the Artinskian-Kungurian boundary based on ammonoids must be established through indirect evidence due to the lack of common species with potential global stratotypes of the lower boundary of the Kungurian. A long-term study of the reference sections of the Echian and Tumarian regional stages and their ammonoids made it possible to change the understanding of the bio- and lithostratigraphy of the Artinskian-Kungurian boundary deposits of the Kuranakh structural-facies zone of Western Verkhoyanie. Clarification of the upper boundary of the Khabakh Formation in the stratotype section led to the fact that the ammonoids previously belonging to this formation began to be considered in the lower part of the Orol formation. They characterize the Paratumaroceras? sp. nov. biostratigraphic beds of the lower part of the Tumarian Regional Stage. At the current level of knowledge, the ammonoid substantiation of the Artinskian–Kungurian boundary in Verkhoyanie is difficult due to the existing hiatus corresponding to the Khabakh formation and its age analogues. However, the appearance at the base of the Tumarian Regional Stage of the first paragastrioceratids with a ventral sinus in transverse sculpture (Paratumaroceras? sp. nov.) suggests that the boundary in question is located near the base of the indicated regional stage or even combined with it. For further clearer identification of the Kungurian lower boundary in Verkhoyanie, new studies of the Echian–Tumarian boundary deposits in typical sections, independent of paleontology, are necessary. Such research should primarily include isotope-stratigraphic subdivision and high-precision U-Pb dating.

12589 Two Systematic Reviews Of Treatment Efficacy On Patient Important Outcomes In Adult X-linked Hypophosphatemia

Abstract Disclosure: D.S. Ali: None. R. Mirza: None. F. Alsarraf: None. S. Hussein: None. N. Appelman-Dijkstra: Consulting Fee; Self; Amgen Inc, Kyowa Kirin, UCB. Grant Recipient; Self; Kyowa Kirin. S. Beck-Nielsen: Consulting Fee; Self; Kyowa Kirin, Inozymes, Novo Nordisk. Grant Recipient; Self; Kyowa Kirin. Speaker; Self; Kyowa Kirin. M. Biosse-Duplan: Advisory Board Member; Self; Alexion Pharmaceuticals, Inc.. Grant Recipient; Self; Kyowa Kirin. Speaker; Self; Kyowa Kirin, Alexion Pharmaceuticals, Inc. M. Brandi: Consulting Fee; Self; Alexion Pharmaceuticals, Inc., Aboca, Amolyt, Bruno Farmaceutici, Calcilytix, Kyowa Kirin. Speaker; Self; Alexion Pharmaceuticals, Inc., Amgen Inc, Eli Lilly &amp; Company, Takeda, Kyowa Kirin. C. Chaussain: Grant Recipient; Self; Kyowa Kirin. M. Cohen-Solal: Grant Recipient; Self; Kyowa Kirin. Speaker; Self; Kyowa Kirin. R.K. Crowley: Advisory Board Member; Self; UCB, Amgen Inc. Consulting Fee; Self; Kyowa Kirin. Speaker; Self; Kyowa Kirin. K. Dandurand: Speaker; Self; Amgen Inc, Kyowa Kirin. P.F. Florenzano: None. S. Fukumoto: Consulting Fee; Self; Kyowa Kirin. C. Gagnon: Grant Recipient; Self; Takeda, Ascendis Pharma. P. Goodyer: None. C. Grasemann: Speaker; Self; Kyowa Kirin. E.A. Imel: Consulting Fee; Self; Ultragenyx, Kyowa Kirin, Inozyme. Grant Recipient; Self; Ultragenyx, Kyowa Kirin, Amgen Inc. S.M. Jan De Beur: Consulting Fee; Self; Kyowa Kirin, Ultragenyx. E.M. Lewiecki: Consulting Fee; Self; Amgen Inc. Research Investigator; Self; Amgen Inc, Ultragenyx. Speaker; Self; Amgen Inc, Ascendis. E. Morgante: None. L. Ward: Other; Self; Tier 1 (Senior) Research Chair in Pediatric Bone Disorders from the University of Ottawa and the Children’s Hospital of Eastern Ontario Research Institute. A.A. Khan: Advisory Board Member; Self; Amgen Inc, Takeda, Alexion, Ascendis. Grant Recipient; Self; Takeda, Ascendis, Amolyt, Calcilytix. G. Guyatt: None. Objective: Our objective was to examine the highest certainty evidence addressing the management of X-linked hypophosphatemia in adults, aiming to inform treatment recommendations. Eligibility criteria: We searched Embase, MEDLINE, Web of Science, and Cochrane from inception to March 2023 and included RCTs and observational studies enrolling individuals ≥ 18 years diagnosed with XLH on clinical grounds or with a confirmed pathogenic variant in PHEX. Manuscripts evaluating the effectiveness of burosumab compared to either no treatment or conventional therapy (phosphate salts and active vitamin D) or evaluating conventional therapy compared to no treatment were selected. Methods: Two reviewers independently determined eligibility, conducted data extraction, and assessed the risk of bias (RoB). GRADE was used to assess certainty of evidence. Results: After removing duplicates from 7,043 citations, we assessed 254 full texts. Of those, one RCT proved eligible. The RCT of burosumab versus no treatment was at low RoB with certainty of evidence on individual outcomes ranging from high to very low. Burosumab probably improves pain inferred from fracture and pseudofracture healing (moderate certainty); however, burosumab probably has little or no impact on direct pain measures (moderate certainty). While burosumab may reduce the need for parathyroidectomy, indicated by lowered PTH levels (low certainty), it has little or no impact on fatigue (high certainty), stiffness (moderate certainty), and mobility (low certainty) over 24 weeks. Burosumab may also increase dental abscesses (low certainty). No formal comparisons of burosumab and conventional therapy exist; therefore, our low certainty evidence inferences regarding burosumab versus conventional therapy were based on indirect evidence from comparisons of burosumab versus no treatment and from conventional therapy versus no treatment. Observational studies proved at high RoB providing very low certainty of evidence regarding the impact of conventional therapy versus no treatment. This evidence pertained to the reduction in the risk of parathyroidectomy, as well as the reduction in the burden of symptoms caused by chronic hypophosphatemia. Conclusion: Burosumab when compared to no treatment may improve pain through fracture healing and may reduce the need for parathyroidectomy, but it could also increase the risk of dental abscess. However, when using direct measures of pain and function, burosumab demonstrated probably little or no impact on pain and stiffness, little or no impact on fatigue, and may have had little to no impact on mobility. Very low certainty exists regarding conventional therapy versus no treatment in adults. Overall, our review highlights the need for more data to better understand the long-term impact of burosumab and conventional therapy on patient-important outcomes. Presentation: 6/2/2024

First Observational Evidence That Dust‐Driven Cloud Phase Changes Cool the Surface Over Summertime Arctic Sea Ice

AbstractCloud phase has important impacts on Arctic surface temperatures, and circumstantial evidence suggests that dust aerosols have strong regional impacts on Arctic cloud phase. We used 7 years of satellite observations and model and reanalysis products to control for co‐varying meteorology, and to assess how dust and other aerosols impact cloud phase and cloud radiative effects over the summertime sea ice. We focus on clouds at 3 km, where dust modeling is most accurate. There is strong indication that dust aerosols caused about 4.5% of clouds below −15°C to change phase, with smaller effects at higher temperatures. Sulfate has a smaller impact on cloud phase. Dust is associated with cloud‐mediated surface cooling of up to a 6.3 W m−2 below single‐layer clouds at ∼3 km in June. This is the first observational study to constrain likely dust‐related cloud radiative effects over the summertime Arctic sea ice.

Особенности рассмотрения дел о взыскании алиментов с моряков на содержание несовершеннолетних детей

The article discusses the features of judicial review of claims for the recovery of alimony from seafarers. The analysis of the procedural procedure for the presentation of claims, the process of proof, the specifics of the evaluation of evidence is given. The question of the possibility of using indirect evidence in the consideration of this category of cases is raised.

Reductions in inpatient and outpatient mental health care in germany during the first year of the COVID-19 pandemic - What can we learn for a better crisis preparedness?

During the COVID-19 pandemic, reports from several European mental health care systems hinted at important changes in utilization. So far, no study examined changes in utilization in the German mental health care inpatient and outpatient mental health care system comprehensively. This longitudinal observational study used claims data from two major German statutory health insurances, AOK PLUS and BKK, covering 162,905 inpatients and 2,131,186 outpatients with mental disorders nationwide. We analyzed changes in inpatient and outpatient mental health service utilization over the course of the first two lockdown phases (LDPs) of the pandemic in 2020 compared to a pre-COVID-19 reference period dating from March 2019 to February 2020 using a time series forecast model. We observed significant decreases in the number of inpatient hospital admissions by 24-28% compared to the reference period. Day clinic admissions were even further reduced by 44-61%. Length of stay was significantly decreased for day clinic care but not for inpatient care. In the outpatient sector, the data showed a significant reduction in the number of incident outpatient diagnoses. Indirect evidence regarding the consequences of the reductions in both the inpatient and outpatient sector of care described in this study is ambiguous and direct evidence on treatment outcomes and quality of trans-sectoral mental healthcare is sparse. In line with WHO and OECD we propose a comprehensive mental health system surveillance to prepare for a better oversight and thereby a better resilience during future global major disruptions.

Hypoglycemic activity of Garcinia mangostana L. extracts on diabetes rodent models: A systematic review and network meta-analysis.

Diabetes mellitus is a significant global health issue, and alternative treatments from natural products like Garcinia mangostana L. [Clusiaceae] or GM are being explored for their potential benefits. This study focused on evaluating the hypoglycemic effects of GM on diabetic rodent models. A comprehensive search was conducted in PubMed, Scopus, and Embase for studies reporting blood glucose levels within 2weeks as the primary outcome and changes in total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) as secondary outcomes. A network meta-analysis (NMA) was performed to determine the pooled effectiveness of each intervention, estimating the weighted mean difference (WMD) and 95% confidence interval (CI) from both direct and indirect evidence. The surface under the cumulative ranking curve (SURCA) was used to rank the interventions. Ten articles were identified, with nine included for quantitative analysis. All GM extracts showed greater effectiveness than the control in decreasing blood glucose levels within 2weeks. GM at 200mg/kg (GM200) was the top-ranked extract for reducing glucose levels beyond 2weeks and increasing HDL-C levels. The ethanol extract of GM at 200mg/kg (GME200) was the most effective for blood glucose reduction within 2weeks and for TC and TG reductions. The methanol extract of GM at 200mg/kg (GMM200) was the top-ranked extract for LDL-C reductions. GM and its extracts demonstrated significant hypoglycemic activity and improvements in lipid profiles in diabetic rodent models, highlighting their potential as therapeutic agents for the prevention and treatment of diabetes mellitus. Further research in human trials is warranted to confirm these findings and establish clinical applications. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023426254.

Immunosuppression protocols for emerging oncological indications in liver transplantation: A systematic review and pooled analysis.

The evolving field of liver transplant (LT) oncology calls for tailored immunosuppression protocols to minimize the risk of tumor recurrence. We systematically reviewed the available evidence from inception to May 2023 regarding immunosuppression protocols used in patients undergoing LT for cholangiocarcinoma, neuroendocrine tumors (NET), hepatic-endothelial hemangioendothelioma (HEHE) and colorectal liver metastases (CRLM), to identify common practices and to evaluate their association with oncological outcomes. Studies not involving humans, case reports and short case series (i.e., n < 10) were excluded. Among 3,374 screened references, we included 117 studies involving 6,797 patients distributed as follows: cholangiocarcinoma (58.1%), NETs (18.8%), HEHE (7.7%), CRLM (6.8%), mixed neoplasms (6.8%) or others (1.7%). Only 41% of the studies disclosed details of the immunosuppression protocol, and 20.8% of studies provided drug trough concentrations during follow-up. The immunosuppression protocols described were heterogeneous and broadly mirrored routine practices for non-tumoral indications. The only exception was CRLM where tacrolimus minimization -or even withdrawal- in combination with inhibitors of the mammalian target of rapamycin (mTORi) were consistently reported. None of the studies evaluated the relationship between the immunosuppression protocol and oncological outcomes. In conclusion, based on low-quality and indirect scientific evidence, patients with tumoral indications for LT should receive the lowest tacrolimus level tolerated under close surveillance. The combination with mTORi titrated to achieve the top therapeutic range of trough concentrations could allow complete tacrolimus withdrawal. This approach may be particularly useful in patients with cholangiocarcinoma and CRLM, in whom tumor recurrence is the main cause of death. We propose a tool for reporting immunosuppression protocols which could be implemented in future transplant oncology studies.

Assessing the validity and limits of linear density models for predicting dissociation–association equilibria in supercritical water

A linear relationship between the logarithms of solute dissociation constants, log(K), and the density of water, log (ρH2O), has empirically been demonstrated for decades and raised hope for an universal formalism to describe solute thermodynamic properties over wide ranges of temperature and density at supercritical conditions. Yet, neither a theoretical foundation nor an assessment of the ranges of validity have been presented. Here, we use classical molecular dynamics (MD) simulations as a complementary tool to assess the validity of this linear relationship for the example of NaCl and reveal its limits at water densities below ca. 0.3gcm−3. The derivative ∂log(K)/∂log(ρH2O) is calculated based on the volume of reaction and water compressibility derived from the simulations performed in the isothermal–isobaric ensemble at 673K. Our results corroborate the linear dependence of log(K) vs. log(ρH2O) in the experimentally studied density range and suggest that the linear dependence also extends to higher densities. However, towards lower densities, log(K) decreases and takes on values that are lower than would be expected by simply extrapolating the linear behavior. This decrease is consistent with earlier theoretical predictions for the behavior of log(K) at vapor-like densities but questions the relevance of some indirect experimental evidence obtained at low temperatures. Although the function described by log(K) vs log(ρH2O) is non-linear in the low density range, it can be considered well-behaved even at near critical conditions.

A systematic review and network meta-analysis on the effectiveness of exercise-based interventions for reducing the injury incidence in youth team-sport players. Part 1: an analysis by classical training components

Objectives The primary purposes were (a) to estimate the pooled effects of injury prevention programs (IPPs) on reducing overall and some specific body regions (lower extremity, thigh, knee, and ankle) injury incidence rates (IIRs) and (b) to compare the effects of single- and multi-component IPPs on mitigating injury risk in youth team sport athletes. A secondary objective was to explore the individual effects of different components on these IIRs. Materials and methods Searches were performed up to 15 January 2024 in PubMed, Web of Science, SPORTDiscus, and Cochrane Library. Eligible criteria were: exercise-based interventions evaluated against a control group, overall IIRs were reported, and youth (≤19 years old) team sport players. Two reviewers extracted data and assessed trial quality using the Consolidated Standards of Reporting Trials (CONSORT) statement, the Physiotherapy Evidence Database Scale (PEDro), and a risk of bias tool (Cochrane Back and Neck Group). Pooled effects were calculated by Frequentist random effects pairwise and network meta-analyses. Results Twenty-one studies were included. IPPs reduced overall, lower extremities, thigh, knee, and ankle IIRs by an average of approximately 35%. Most of the IPPs demonstrated statistically significant risk mitigation effects for overall and lower extremity injuries compared to control group. Interventions comprised exclusively of strength ([IRR = 0.3 [95%CI = 0.10–0.93]) and flexibility (IRR = 0.49 [95%CI = 0.36–0.68]), as well as those including stability exercises, were the most effective measures for reducing injuries in youth team sports. Conclusions The implementation of current IPPs in training sessions for several weeks has shown to be an effective strategy for reducing the risk of injury in youth team sport athletes by one-third. Indirect evidence suggests that strength, flexibility, and stability might be exercise components with the highest risk mitigation effects; however, more research is crucial to confirm our estimates with direct evidence.