Perceptions of key informant neurologists before implementing anti-amyloid drugs in the Spanish departments of neurology.

BACKGROUND: A deep knowledge of the healthcare system and the organization of neurology departments is important for planning and optimizing changes to facilitate the successful implementation of anti-amyloid antibodies treatments. OBJECTIVE: We aimed to assess the necessary changes prior to introducing these therapies in our setting. METHODS: We conducted a key informant survey among heads of departments of neurology from 16 hospitals in Spain. The questionnaire comprised questions about changes in the organization and functioning of the departments of neurology with the introduction of anti-amyloid drugs, changes in diagnosis and patient care, use of diagnostic techniques, patients, families and public information, resources allocation, and research. RESULTS: Sixteen key informants completed the survey. They strongly agreed that the introduction of anti-amyloid drugs will impact the functioning of neurology services, especially in hospitals with dementia units. Consensus was reached regarding referring all Alzheimer's disease patients eligible for therapy to dementia units. There was also agreement on the need to expand the neurology services, day hospital units, extend visit durations, and hire more professionals, especially neurologists, neuropsychologists, and nuclear medicine physicians. Furthermore, consensus was achieved on increasing the use of MRI, amyloid PET, cerebrospinal fluid biomarkers, APOE genotyping, and the necessity of advancing blood biomarkers and tau tracers. CONCLUSIONS: Our study highlights the need for extensive changes within Spanish neurological departments to effectively integrate anti-amyloid antibodies. Implementing these changes is essential for the timely and equitable adoption of novel therapies.

Association of Cerebrovascular Reactivity With 1-Year Imaging and Clinical Outcomes in Small Vessel Disease: An Observational Cohort Study.

BACKGROUND AND OBJECTIVES: In patients with cerebral small vessel disease (SVD), impaired cerebrovascular reactivity (CVR) is related to worse concurrent SVD burden, but less is known about cerebrovascular reactivity and long-term SVD lesion progression and clinical outcomes. We investigated associations between cerebrovascular reactivity and 1-year progression of SVD features and clinical outcomes. METHODS: Between 2018 and 2021, we recruited patients from the Edinburgh/Lothian stroke services presenting with minor ischemic stroke and SVD features as part of the Mild Stroke Study 3, a prospective observational cohort study (ISRCTN 12113543). We acquired 3T brain MRI at baseline and 1 year. At baseline, we measured cerebrovascular reactivity to 6% inhaled CO2 in subcortical gray matter, normal-appearing white matter, and white matter hyperintensities (WMH). At baseline and 1 year, we quantified SVD MRI features, incident infarcts, assessed stroke severity (NIH Stroke Scale), recurrent stroke, functional outcome (modified Rankin Scale), and cognition (Montreal Cognitive Assessment). We performed linear and logistic regressions adjusted for age, sex, and vascular risk factors, reporting the regression coefficients and odds ratios with 95% CIs. RESULTS: We recruited 208 patients of whom 163 (mean age and SD: 65.8 ± 11.2 years, 32% female) had adequate baseline CVR and completed the follow-up structural MRI. The median increase in WMH volume was 0.32 mL with (Q1, Q3) = (-0.48, 1.78) mL; 29% had a recurrent stroke or incident infarct on MRI. At 1 year, patients with lower baseline cerebrovascular reactivity in normal-appearing tissues had increased WMH (regression coefficient: B = -1.14 [-2.13, -0.14] log10 (%ICV) per %/mm Hg) and perivascular space volumes (B = -1.90 [-3.21, -0.60] log10 (%ROIV) per %/mm Hg), with a similar trend in WMH. CVR was not associated with clinical outcomes at 1 year. DISCUSSION: Lower baseline cerebrovascular reactivity predicted an increase in WMH and perivascular space volumes after 1 year. CVR should be considered in SVD future research and intervention studies.

Unlocking Spanish pear genetic diversity: strategies for construction of a national core collection.

Spanish pear germplasm collections are crucial for preservation, research, and breeding efforts. However, genetic diversity and structure is unknown at national level. A coordinated national project analyzed 1251 accessions from 7 Spanish pear collections using an internationally recognized set of 14 SSRs to enhance the utilization of these collections. Key findings included the identification of 760 unique genotypes (490 diploids and 270 triploids). Notably, genotypes represented by a single accession accounted for 49% of the total, indicating high vulnerability of this material. Using a Bayesian clustering method revealed two main genetic groups, G1 containing most foreign cultivars and G2 retaining local Spanish cultivars, which were further divided into two other subgroups using a nested approach, revealing moderate but significant differentiation among them. The populations were renamed according to the origin of the reference samples assigned to each group as 'South' (G1.1), 'Western Europe-1' (G1.2), 'Western Europe-2' (G2.1) and 'No-Pyrus communis' (G2.2). The results led to the creation of a 'generalist' collection, aiming to maximize genetic diversity representativeness, starting with 68 genotypes but expanding to 111 to achieve better allele recovery. This core collection is a valuable resource for genetic studies and conservation, enhancing efforts to preserve pear biodiversity.

Myroides species, pathogenic spectrum and clinical microbiology sight in Mexican isolates.

INTRODUCTION: Myroides is a bacterial genus of opportunistic bacteria responsible for diverse infections including in the skin and soft tissues, urinary tract, cardiovascular system, and bacteremia, although the incidence of its reported infections is low, it is increasing, likely due the use of better bacterial identification methods, but also perhaps due an increase in its prevalence. In addition, their pathogenic role is limited in terms of reporting their microbial physiology, so the present work provides information in this regard in addition to the information that is available in the international literature. OBJECTIVE: To describe the microbiological and genetic characteristics of seven different Myroides spp. clinical strains and comment on their phylum, pathogenic and resistance characteristics. METHODS: Seven Myroides spp., strains associated with infections were included from 1/January/2012 to 1/January/20 and identified by miniaturized biochemistry and MALDI-ToF. Susceptibility tests were performed according to CLSI recommendations by broth microdilution. Whole genome sequencing was performed for each strain and bioinformatics analysis were performed. RESULTS: Strains were identified at genus level by two methodologies. Our results revealed that likely four strains belong to the species Myroides odoratimimus, while the other two may be undescribed ones. Remarkably, all isolates harbored several genes encoding antibiotic resistance determinants for ß-lactams, aminoglycosides and glycopeptides and in concordance, presented high levels of resistance, against these antibiotics (AK and GN both 100%, ATM, CAZ and FEP 100%, e.g.); moreover, the presences of carbapenemases were evidenced by meropenem (mCIM) and imipenem (CARBA NP) degrading activity in six isolates and two strains possessed plasmids harboring mainly ribosomal RNA genes, tRNAs and genes encoding proteins with unknown functions. CONCLUSIONS: Our study increases the knowledge about the biology of this understudied genus and highlights the potential of Myroides to emerge as a broader cause of recalcitrant opportunistic infections.

Retinal microvascular phenotypes can track small vessel disease burden and CPAP treatment effectiveness in obstructive sleep apnoea.

Optical coherence tomography angiography (OCT-A) retinal imaging enables in vivo visualization of the retinal microvasculature that is developmentally related to the brain and can offer insight on cerebrovascular health. We investigated retinal phenotypes and neuroimaging markers of small vessel disease (SVD) in individuals with obstructive sleep apnoea (OSA). We enrolled 44 participants (mean age 50.1 ± SD 9.1 years) and performed OCT-A imaging before and after continuous positive airway pressure (CPAP) therapy. Pre-treatment analyses using a generalized estimating equations model adjusted for relevant covariates, revealed perivascular spaces (PVS) volume in basal ganglia associated with greater foveal vessel density (fVD) (p-value < 0.001), and smaller foveal avascular zone area (p-value = 0.01), whereas PVS count in centrum semiovale associated with lower retinal vessel radius (p-value = 0.02) and higher vessel tortuosity (p-value = 0.01). A reduction in retinal vessel radius was also observed with increased OSA severity (p-value = 0.05). Post-treatment analyses showed greater CPAP usage was associated with a decrease in fVD (p-value = 0.02), and increased retinal vessel radius (p-value = 0.01). The findings demonstrate for the first time the potential use of OCT-A to monitor CPAP treatment and its possible impact on both retinal and brain vascular health.

Perivascular space enlargement accelerates in ageing and Alzheimer's disease pathology: evidence from a three-year longitudinal multicentre study.

BACKGROUND: Perivascular space (PVS) enlargement in ageing and Alzheimer's disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD. METHODS: We studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; meanage = 70.78 ± 5.78) of the ongoing observational multicentre "DZNE Longitudinal Cognitive Impairment and Dementia Study" (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39). RESULTS: PVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p < 0.001; BG: B = 0.05 [0.03, 0.07], p < 0.001). PVS enlargement rates varied substantially across subjects and depended on the participant's age, white matter hyperintensities volumes, and amyloid and tau status. PVS volumes were higher across elderly participants, regardless of region of interest (CSO: B = 0.12 [0.02, 0.21], p = 0.017; BG: B = 0.19 [0.09, 0.28], p < 0.001). Faster BG-PVS enlargement related to lower baseline white matter hyperintensities volumes (ρspearman = -0.17, pFDR = 0.001) and was more pronounced in individuals who presented with combined amyloid and tau positivity versus negativity (A + T + > A-T-, pFDR = 0.004) or who were amyloid positive but tau negative (A + T + > A + T-, pFDR = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T + > A-T-, pFDR = 0.021). CONCLUSION: Our longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies. TRIAL REGISTRATION: German Clinical Trials Register DRKS00007966. Registered 04.05.2015 - retrospectively registered, https://drks.de/search/en/trial/DRKS00007966 .

Improving midwives' management of occiput-posterior fetal positions: a best practice implementation project.

INTRODUCTION: The occiput-posterior (OP) fetal position is the most frequent form of labor dystocia. This position has been associated with delaying the second stage of labor and adverse outcomes. OBJECTIVES: This project aimed to improve the quality of intrapartum care provided by midwives for OP fetal positions during the second stage of labor. METHODS: This best practice implementation project was conducted at the Río Hortega University Hospital in Valladolid, Spain. The project followed the JBI Evidence Implementation Framework, which is based on an audit, feedback, and re-audit process. Current practices were compared against best practices in a baseline audit using 13 audit criteria. Barriers to compliance with best practices were identified and improvement strategies were implemented. An initial follow-up audit was carried out after 4 months to avoid secondary bias. After another 4 months, a second follow-up audit was conducted. Data were collected and compared using the JBI Practical Application of Clinical Evidence System (JBI PACES). RESULTS: The results revealed an improvement in all structure criteria (1-3), five of the process criteria (4-6, 8, 10), and all results criteria (11-13). One process criterion (8) reached maximum compliance in all audits. A key finding was the inadequate recording of upright positions (criterion 7) and the interpretation of cardiotocography (criterion 9). CONCLUSIONS: Evidence-based interventions for managing OP labor improved the quality of care and underlined the importance of ongoing training for midwives. Additional studies are required on positions and fetal monitoring during labor. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A279.

[What do we know about craniopharyngioma? Updated review of the main advances and local experience.] / ¿Qué sabemos de craneofaringioma? Una revisión actualizada de los principales avances y la experiencia local.

Craniopharyngioma is a tumor of benign histology, although it can cause serious sequelae due to its location and growth in the sellar and suprasellar region. It is characterized by being aggressive due to its ability to invade locally, and by its high recurrence rate. Histologically, two distinct tumors have been acknowledged, which were previously considered subtypes. The adamantinomatous craniopharyngioma is the most frequent in children and is caused by an activating mutation of the CTNNB1 gene, which codes for a mutant form of ß-catenin. Whereas, papillary craniopharyngioma develops almost exclusively in adults, and it is associated with mutations in the BRAF oncogene and activation of the MAPK signaling pathway. The symptoms of both of these tumor types are secondary to hormonal deficits, hydrocephalus or visual disturbances. Treatment should be performed in centers with experience in them, achieving a balance between a wide resection and protection of hypothalamic function. Radiotherapy has proven to reduce tumor recurrence, with a current focus on the development of medical treatments based on molecular targets.

Prevalence and Clinical Implications of Hemosiderin Deposits in Recent Small Subcortical Infarcts.

BACKGROUND AND OBJECTIVES: A quarter of ischemic strokes are of lacunar clinical subtype and have an underlying recent small subcortical infarct (RSSI), but their long-term outcomes remain poorly characterized. Hemosiderin deposits (HDs) have been noted in RSSIs at chronic stages and might mimic primary hemorrhage. We characterized HDs' morphology, frequency, and clinical relevance. METHODS: Participants with RSSIs were identified from a prospective longitudinal study and evaluated on 3T MRI including susceptibility-weighted imaging (SWI) from stroke diagnosis to 12 months. We categorized HDs in RSSIs on SWI at all available time points into 4 types (spots, smudge, rim, cluster) and assessed their associations with demographic factors, stroke-related factors, and image markers with adjusted logistic regression. RESULTS: HDs were observed in 43 (55.0%) of 108 participants within 3 months and 83 (76.9%) of 108 within 12 months after stroke onset. The mean time to first detection of HDs was 87 (interquartile range 53-164) days. A "rim" pattern (similar to late appearance of primary hemorrhage) occurred in at least 26.5% of RSSIs at all follow-up time points, mainly those located in the lentiform/internal capsule (50.0%) or thalamus (36.4%). Infarct volume (odds ratio [OR] 1.003, 95% CI 1.001-1.006; p = 0.004) and the total small vessel disease (SVD) score at baseline (OR 2.50, 95% CI 1.28-4.86, p = 0.007) independently predicted HDs at 12 months. HDs were positively associated with more lacunes (OR 1.60, 95% CI 1.13-2.26, p < 0.01), but not the Fazekas score, number of microbleeds, basal ganglia mineral deposit score, or clinical outcomes. DISCUSSION: HDs occur commonly in RSSIs and may be associated with infarct volume and SVD score. Hemosiderin "rim" is common in RSSIs, urging caution to avoid mistaking ischemic RSSI for primary hemorrhage in subacute and chronic stages.

Nursing Interventions Related to the Need for Oxygenation in Severe COVID-19 Disease in Hospitalized Adults: A Retrospective Study.

COVID-19 affects the respiratory system, reducing the oxygen saturation level, leading to hypoxemia and increasing the metabolic oxygenation need. OBJECTIVE: To describe the nursing interventions related to the need for oxygenation in hospitalized adults with severe COVID-19 disease in the Intensive Care Unit. METHOD: This was an observational, retrospective and descriptive study in a population of 2205 patients with a convenience sample of n = 430 and based on the North American Nursing Diagnosis Association (NANDA), the Nursing Interventions Classification (NIC) and the Nursing Outcomes Classification (NOC). The analysis was performed with a non-parametric test to determine the association between the nursing interventions and the need for oxygenation. RESULTS: The findings are aimed at improving nursing interventions with statistical associations as follow: oxygen therapy (p < 0.000), airway suctioning (p < 0.000), airway management (p = 0.029), invasive mechanical ventilation (p < 0.000) and non-invasive mechanical ventilation (p = 0.022). NOC taxonomy expected outcomes in ventilation, 34% (146), alteration in gas exchange, 33.7% (145), and respiratory status, 558.9% (253), were severely compromised. CONCLUSIONS: The nursing interventions to maintain the respiratory status are focused on airway care and oxygen therapy in order to increase the oxygen saturation level and decrease the severity of the need for oxygenation.

Vaccine effectiveness in patients admitted for influenza during the 2023-2024 season. / Efectividad vacunal en pacientes ingresados por gripe durante la temporada 2023-2024.

BACKGROUND AND GOAL: Vaccination against influenza is widespread worldwide, reducing complications associated with infection. However, the impact of vaccination on mortality/ICU admission in hospitalized patients has been little studied. MATERIAL AND METHODS: A retrospective observational study was conducted on 238 patients hospitalized for influenza from October 2023 to January 2024 to evaluate the vaccine's effectiveness in terms of the combined event of ICU admission/mortality during hospitalization. Additionally, the characteristics of vaccinated patients and the existence of bacterial superinfection were analyzed. Cox regression was performed using the SPSS program and the free «R¼ software. RESULTS: A total of 238 patients were included. Those vaccinated were older (78.2±8.8 vs 69.97±16.6years; P<.001) and were more likely to have hypertension (82.2% vs 56.2%; P<.001), cardiovascular disease (36.6% vs 24.1%; P=.05), chronic bronchopathy (25.7% vs 8.8%; P=.001), or chronic kidney disease (22.8% vs 8.8%; P=0.005). They had lower levels of CRP (8.39±9.55 vs 11.03±10.75mg/dl; P=.05), procalcitonin (0.62±1.74 vs 1.67±4.57ng/dl; P=.05), and SOFA scores (1.13±0.9 vs 1.39±0.97; P=0.033). 11 patients were admitted to ICU (4.6%) and 11 died (4.6%). Influenza vaccination was associated as a protective factor against ICU admission/mortality in the Cox regression (HR=0.216; 95%CI: 0.062-0.759, P=.017). The presence of bacterial superinfection was similar between vaccinated and unvaccinated patients (63.4% vs 67.9%; P=.556). CONCLUSIONS: Influenza vaccination may reduce the probability of ICU admission or death. This effect is likely due to better control of the immune response. We did not observe any relationship with the risk of presenting bacterial superinfection.

Pituitary stalk thickening in pediatric patients: an underrecognized diagnosis?

Objective: Pituitary stalk thickening (PST) is a rare condition in pediatric patients. Data on PST in Latin American pediatric populations are scarce. The aim of this study was to characterize a comprehensive cohort of pediatric patients diagnosed with PST in Chile between 2020 and 2022. Subjects and methods: Retrospective review of medical records from 2020 to 2022 of patients under 18 years old diagnosed with PST, defined as a pituitary stalk width ≥ 3 mm at the pituitary insertion and/or ≥ 4 mm at the optic chiasm. A literature review was also performed to compare the identified cases with previously published ones. Results: Nine patients with PST were identified. Their mean age at diagnosis was 10.36 years (range 2.4-17 years). The patients' main manifestations were polydipsia and polyuria (100%) and poor growth (77.8%). Eight patients had germ cell tumors, while one patient had Langerhans cell histiocytosis. At the time of diagnosis, all patients had arginine vasopressin (AVP) deficiency, along with a deficiency in at least one anterior pituitary hormone. Germ cell tumor markers were negative in all patients. A biopsy-confirmed diagnosis was obtained in all cases. Four patients required a second biopsy. The frequency of PST due to germ cell tumors was four patients/year during the study period, which is twice the expected frequency in Chile. Conclusion: This study, characterizing the largest cohort of pediatric patients with PST in Latin America, found germ cell tumors to be the main etiology of this condition. It is important to focus diagnostic procedures on obtaining a correct diagnosis and promptly initiating appropriate treatment in patients with PST. Regional cooperation is essential for gathering data from larger cohorts to enhance our understanding of pediatric PST and improve patient outcomes.

Retrospective study assessing the role of the androgen receptor in clear cell renal cell cancer patients treated with VEGFR inhibitors in monotherapy.

BACKGROUND AND PURPOSE: Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions. PATIENTS AND METHODS: We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis. RESULTS: Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC. CONCLUSIONS: AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

Definitions of white matter hyperintensity change: impact on estimates of progression and regression.

BACKGROUND: White matter hyperintensity (WMH) progression is well documented; WMH regression is more contentious, which might reflect differences in defining WMH change. We compared four existing WMH change definitions in one population to determine the effect of definition on WMH regression. METHODS: We recruited patients with minor non-disabling ischaemic stroke who underwent MRI 1-3 months after stroke and 1 year later. We assessed WMH volume (in absolute mL and % intracranial volume) and applied four different definitions, including two thresholds (based on SD or mL), percentile and quintile approaches. RESULTS: In 198 participants, mean age 65.5 (SD=11.13), baseline WMH volume was 15.46 mL (SD=19.2), the mean net WMH volume change was 0.98 mL (SD=2.84), range -7.98 to +12.84 mL. Proportion regressing/stable/progressing WMH were threshold 1 (SD), 29.8%/55.6%/14.6%; threshold 2(mL), 29.8%/16.7%/53.5%; percentile approach, 28.3%/21.2%/50.5%. The quintile approach includes five groups with quintile 3 reflecting no change (N=40), quintiles 1 and 2 any WMH decrease (N=80) and quintiles 4 and 5 any WMH increase (N=78). CONCLUSIONS: Different WMH change definitions cause big differences in how participants are categorised; additionally, non-normal WMH distribution precludes use of some definitions. Consistent use of an appropriate definition would facilitate data comparisons, particularly in clinical trials of potential WMH treatments.

Probing the orthogonality and robustness of the mammalian RNA-binding protein Musashi-1 in Escherichia coli.

RNA recognition motifs (RRMs) are widespread RNA-binding protein domains in eukaryotes, which represent promising synthetic biology tools due to their compact structure and efficient activity. Yet, their use in prokaryotes is limited and their functionality poorly characterized. Recently, we repurposed a mammalian Musashi protein containing two RRMs as a translation regulator in Escherichia coli. Here, employing high-throughput RNA sequencing, we explored the impact of Musashi expression on the transcriptomic and translatomic profiles of E. coli, revealing certain metabolic interference, induction of post-transcriptional regulatory processes, and spurious protein-RNA interactions. Engineered Musashi protein mutants displayed compromised regulatory activity, emphasizing the importance of both RRMs for specific and sensitive RNA binding. We found that a mutation known to impede allosteric regulation led to similar translation control activity. Evolutionary experiments disclosed a loss of function of the synthetic circuit in about 40 generations, with the gene coding for the Musashi protein showing a stability comparable to other heterologous genes. Overall, this work expands our understanding of RRMs for post-transcriptional regulation in prokaryotes and highlight their potential for biotechnological and biomedical applications.

Efficacy of a High-Protein Diet to Lower Glycemic Levels in Type 2 Diabetes Mellitus: A Systematic Review.

Diabetes is a metabolic disease with a high worldwide prevalence and an important factor in mortality and disability in the population. Complications can be reduced or prevented with lifestyle changes in physical activity, dietary habits, and smoking cessation. High-protein diets (HPDs, >30% or >1.0 g/Kg/day) decrease hyperglycemia in part due to their content of branched-chain amino acids (BCAAs), mainly leucine. Leucine (and other BCAAs) improve glucose metabolism by directly signaling in the medio-basal hypothalamus (MBH), increasing liver insulin sensitivity. To determine the effectiveness of an HPD to lower hyperglycemia, we analyzed the results of published clinical studies focusing on the levels of fasting plasma glucose and/or glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM). We carried out a systematic search for clinical studies using HPDs. We searched five databases (Scopus, Web of Science, PubMed, Epistemonikos, and Cochrane), collecting 179 articles and finally selecting 8 articles to analyze their results. In conclusion, HPDs are an effective alternative to reduce hyperglycemia in patients with T2DM, especially so-called Paleolithic diets, due to their higher-quality protein from animal and vegetal sources and their exclusion of grains, dairy products, salt, refined fats, and added sugars.

Intraoperative marking of pulmonary nodules in a hybrid operating room: electromagnetic navigation bronchoscopy versus percutaneous marking.

Background: Intraoperative identification of subsolid or small pulmonary nodules during minimally invasive procedures is challenging. Recent localization techniques show varying success and complications. Hybrid operating rooms (HORs), equipped with radiological tools, facilitate intraoperative imaging. This study compares the accuracy and safety of marking pulmonary nodules using electromagnetic navigation bronchoscopy (ENB) combined with Cone Beam Computed Tomography (CBCT) vs. CBCT-guided percutaneous marking (PM). Methods: This retrospective cohort study included patients with pulmonary nodules scheduled for minimally invasive resection in a HOR. Marking techniques included ENB assisted by CBCT and PM guided by CBCT. The study compared the success rate, procedure time, intraoperative complications and radiation dose of both techniques. Results: A total of 104 patients with 114 nodules were included (October 2021-July 2024). Thirty nodules were marked using ENB, and 84 with PM. One case used both techniques due to ENB failure. No differences among groups were found in nodule characteristics. Success rates were similar (93.3% in ENB group vs. 91.7% in PM group, p = 1). Marking took significantly longer time in the ENB group (median 40 min) compared to PM group (25 min, p = 0.007). Five (6%) patients in the PM group experienced intraoperative complications compared to none in the ENB (p = 0.323). Radiation dose was significantly higher in the ENB group (p = 0.002). Conclusions: ENB assisted by CBCT is a safe and effective technique, with success rates comparable to CBCT-guided PM, though it may result in longer procedural times and higher radiation doses.

Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein kinase 1.

Casein kinase 1δ (CK1δ) controls essential biological processes including circadian rhythms and wingless-related integration site (Wnt) signaling, but how its activity is regulated is not well understood. CK1δ is inhibited by autophosphorylation of its intrinsically disordered C-terminal tail. Two CK1 splice variants, δ1 and δ2, are known to have very different effects on circadian rhythms. These variants differ only in the last 16 residues of the tail, referred to as the extreme C termini (XCT), but with marked changes in potential phosphorylation sites. Here, we test whether the XCT of these variants have different effects in autoinhibition of the kinase. Using NMR and hydrogen/deuterium exchange mass spectrometry, we show that the δ1 XCT is preferentially phosphorylated by the kinase and the δ1 tail makes more extensive interactions across the kinase domain. Mutation of δ1-specific XCT phosphorylation sites increases kinase activity both in vitro and in cells and leads to changes in the circadian period, similar to what is reported in vivo. Mechanistically, loss of the phosphorylation sites in XCT disrupts tail interaction with the kinase domain. δ1 autoinhibition relies on conserved anion-binding sites around the CK1 active site, demonstrating a common mode of product inhibition of CK1δ. These findings demonstrate how a phosphorylation cycle controls the activity of this essential kinase.