Physicochemical and microbiological stability study of two new preservative-free methylprednisolone eye drops.

OBJECTIVE: To study the physicochemical and microbiological stability over 90 days of two preservative-free methylprednisolone sodium succinate (MTPSS) 1 and 10 mg/mL eye drops for use in ocular pathologies such as Sjögren's syndrome and dry eye syndrome. METHOD: The two eye drops were prepared from injectable MTPSS (Solu-moderin® and Urbason®), water for injection and normal saline solution. In accordance with ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) guidelines, they were then stored in triplicate under refrigerated conditions (5±3 °C), at room temperature (25±2 °C), and at 40 °C (±2 °C). In accordance with the USP (United States Pharmacopeia), physicochemical controls of the active ingredient content were carried out by HPLC-UV (High Performance Liquid Chromatography with Ultraviolet detection), together with controls of pH, osmolality, and visual examination. Microbiological sterility was also tested under refrigerated conditions up to 30 days in open containers and up to 90 days in closed ones. RESULTS: The eye drops stored at 5 °C were the most stable; in the 1 mg/mL eye drops, degradation of the drug fell below 90% from day 21, and in the 10 mg/mL eye drops, from day 42. pH change did not vary by ≥1 unit in formulations stored at 5 °C, unlike the other formulations. Changes in osmolality did not exceed 5% on day 90 in any storage conditions. Samples of non refrigerate eye drops at 10 mg/mL, presented a white precipitate from day 14 and 28, respectively. Non-refrigerated 1 mg/mL eye drops presented suspended particles on day 90. There were no color changes. Microbiological analysis showed that sterility was maintained for over 90 days in the closed containers, although microbial contamination was detected from day 21 in the open containers. CONCLUSIONS: 1 mg/mL MTPSS eye drops show physicochemical and microbiological stability for 21 days under refrigeration, compared to 42 days for 10 mg/mL eye drops stored under the same conditions. However, since they do not include preservatives in their composition, they should not be used for more than 7 days after opening.

Experiences of people with Long Covid with a digital physiotherapy intervention: A qualitative study.

PURPOSE: Long Covid syndrome is a multiorgan condition with multiple sequelae affecting quality of life, capacity to work and daily activities. The advantages that new technologies can offer are presented as an opportunity in the current healthcare framework. OBJECTIVE: This research aimed to explore people with Long Covid's experiences with a digital physiotherapy practice intervention, during four weeks. METHODS: Qualitative semistructured interviews were conducted by video call. Thirty-two Long Covid participants were invited to join an in-depth interview once the intervention was completed. Participants were queried on their intervention experiences and perceptions, as well as any lifestyle changes made, as a result of receiving digital physiotherapy practice. The interviews were transcribed and analysed using inductive qualitative content analysis. RESULTS: In-depth qualitative analysis has revealed four themes that reflect participants' perceptions of digital physiotherapy intervention. The helpfulness of the exercises, interaction with the physiotherapist, the domestic use of technology and the future of digital health practice were the topics highlighted by Long Covid participants. Some improvements have been suggested including video sounds and the need to introduce face-to-face sessions. Participants stated that interventions were helpful and superior to printed exercise sheets, mobile phone apps and usual care received. This intervention did not present major barriers, highlighting the importance of personalized care and continuity in the provision of health services. CONCLUSION: The digital physiotherapy practice is perceived by people with Long Covid as an appropriate method for the care of their health needs. Participants stated the need for this type of intervention in the public health system, where it would eliminate waiting lists, facilitate accessibility and improve existing care. PATIENT AND PUBLIC CONTRIBUTION: Participants contributed to the interpretation of the data acquired in the interview. CLINICAL TRIAL REGISTRATION: Trial registration NCT04742946.

Physicochemical and microbiological stability study of two new preservative-free methylprednisolone eye drops. / Estudio de estabilidad fisicoquímica y microbiológica de 2 nuevos colirios de metilprednisolona sin conservantes.

OBJECTIVE: To study the physicochemical and microbiological stability over 90 days of two preservative-free methylprednisolone sodium succinate (MTPSS) 1 mg/ml and 10 mg/ml eye drops for use in ocular pathologies such as Sjögren's syndrome and dry eye syndrome. METHOD: The two eye drops were prepared from injectable MTPSS (Solu-moderin® and Urbason®), water for injection and normal saline solution. In accordance with ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines, they were then stored in triplicate under refrigerated conditions (5 ±3 °C), at room temperature (25 ± 2 °C), and at 40 °C (±2 °C). In accordance with the USP (United States Pharmacopeia), physicochemical controls of the active ingredient content were carried out by HPLC-UV (High Performance Liquid Chromatography with Ultraviolet detection), together with controls of pH, osmolality, and visual examination. Microbiological sterility was also tested under refrigerated conditions up to 30 days in open containers and up to 90 days in closed ones. RESULTS: The eye drops stored at 5 °C were the most stable; in the 1 mg/ml eye drops, degradation of the drug fell below 90% from day 21, and in the 10 mg/ml eye drops, from day 42. pH change did not vary by ≥1 unit in formulations stored at 5 °C, unlike the other formulations. Changes in osmolality did not exceed 5% on day 90 in any storage conditions. Samples of non refrigerate eye drops at 10 mg/ml, presented a white precipitate from day 14 and 28 respectively. Non-refrigerated 1 mg/ml eye drops presented suspended particles on day 90. There were no color changes. Microbiological analysis showed that sterility was maintained for over 90 days in the closed containers, although microbial contamination was detected from day 21 in the open containers. CONCLUSIONS: 1 mg/ml MTPSS eye drops show physicochemical and microbiological stability for 21 days under refrigeration, compared to 42 days for 10 mg/ml eye drops stored under the same conditions. However, since they do not include preservatives in their composition, they should not be used for more than 7 days after opening.

Clinicopathological and Genomic Identification of Breast Cancers with No Impact on Mortality.

BACKGROUND: Implementing mammogram screening means that clinicians are seeing many breast cancers that will never develop metastases. The purpose of this study was to identify subgroups of breast cancer patients who did not present events related to long-term breast cancer mortality, taking into account diagnosis at breast screening, absence of palpability and axillary involvement, and genomic analysis with PAM50. PATIENTS AND METHODS: To identify them, a retrospective observational study was carried out selecting patients without any palpable tumor and without axillary involvement, and a genomic analysis was performed with PAM50. RESULTS: The probability of distant metastasis-free interval (DMFI) of 337 patients was 0.92 (95% CI, 0.90-0.93) at 20 years and 0.96 (95% CI, 0.92-1.00) in 95 patients (28%) with available PAM50 tests. In 22 (23.15%) luminal A tumors and in 9 (9.47%) luminal B tumors smaller than 1 cm, and in HER2 and basal type tumors, there were no metastatic events (20-year DMFI of 1.00). CONCLUSION: Patients with nonpalpable breast cancer found at screening with negative nodes are at very low risk. It is possible to identify subgroups without metastatic events by determining the intrinsic subtype and tumor size less than 1 cm. Therefore, de-escalation of treatment should be considered.

Digital physiotherapy is a satisfactory and effective method to improve the quality of life in Long COVID patients.

Objective: This research aimed to explore Long COVID patient's quality of life, satisfaction and perception with an individualized and customizable digital physiotherapy intervention during a 4-week period. Methods: A pre-post clinical trial was conducted with 32 Long COVID patients. Quality of life was assessed using the 12-Item Short Form Survey and the European Quality of Life-5 Dimensions questionnaire (EuroQol-5D), while satisfaction and perception were measured using the Telemedicine Satisfaction Questionnaire. Optional open-ended questions were added as qualitative approach. A mixed design method was conducted. Results: After intervention, a statistically significant improvement (p < 0.05) was observed in quality of life. The SF-12 questionnaire showed an increase of 4.04 points in the physical component and 6.55 points in the mental component with a small/medium effect size. The EuroQoL-5D questionnaire demonstrated a medium effect size with an increase of 0.87 points. Patient perception indicated high rates of satisfaction and values above the minimal clinically important difference. The qualitative approach revealed several interesting findings. Conclusion: Participants found the digital intervention satisfactory and effective in improving their quality of life. Suggestions for improvement, such as the inclusion of face-to-face sessions, a chat for immediate contact, sound in breath exercises in the digital program, longer duration and continuity of intervention, were mentioned. Larger sample studies and in-deep qualitative methodologies are needed to draw extrapolable conclusions. Trial registration: NCT04742946.

Scanning Spin Probe Based on Magnonic Vortex Quantum Cavities.

Performing nanoscale scanning electron paramagnetic resonance (EPR) requires three essential ingredients: First, a static magnetic field together with field gradients to Zeeman split the electronic energy levels with spatial resolution; second, a radio frequency (rf) magnetic field capable of inducing spin transitions; finally, a sensitive detection method to quantify the energy absorbed by spins. This is usually achieved by combining externally applied magnetic fields with inductive coils or cavities, fluorescent defects, or scanning probes. Here, we theoretically propose the realization of an EPR scanning sensor merging all three characteristics into a single device: the vortex core stabilized in ferromagnetic thin-film discs. On one hand, the vortex ground state generates a significant static magnetic field and field gradients. On the other hand, the precessional motion of the vortex core around its equilibrium position produces a circularly polarized oscillating magnetic field, which is enough to produce spin transitions. Finally, the spin-magnon coupling broadens the vortex gyrotropic frequency, suggesting a direct measure of the presence of unpaired electrons. Moreover, the vortex core can be displaced by simply using external magnetic fields of a few mT, enabling EPR scanning microscopy with large spatial resolution. Our numerical simulations show that, by using low damping magnets, it is theoretically possible to detect single spins located on the disc's surface. Vortex nanocavities could also attain strong coupling to individual spin molecular qubits with potential applications to mediate qubit-qubit interactions or to implement qubit readout protocols.

Value of inflammatory response and oxidative damage in the diagnosis of infections in severe alcoholic hepatitis.

Severe alcoholic hepatitis is the most lethal complication in alcohol dependent patients. The concurrence of infections in these patients is very frequent. Both produce a systemic inflammatory response syndrome (SIRS), secondary to intense release of inflammatory cytokines, which can complicate the diagnosis. In our study, Interleukin (IL)-6 and IL-10 levels are higher in patients with SIRS (p<0.001 and p = 0.033, respectively). IL-4, IL-6, Interferon-gamma (IFNγ), Tumor necrosis factor alpha (TNFα) and IL-17 levels correlate with liver function, as estimated by MELD-Na (p = 0.018, p = 0.008, p = 0.009, p = 0.016 and p = 0.006, respectively). Malondialdehyde (MDA), a product of lipid peroxidation and marker of cell damage, also correlates with liver function (p = 0.002), but not with SIRS or infections. Only elevated IL-6 correlates independently with the presence of infections (RR=1.023 IC 95% 1.000-1.047), so it may be useful for the correct diagnosis in these patients. Values greater than 30 pg/mL have a sensitivity: 86.7% and specificity: 94.7% for the diagnosis of infections.

Caspase-3 cleaved tau impairs mitochondrial function through the opening of the mitochondrial permeability transition pore.

Mitochondrial dysfunction is a significant factor in the development of Alzheimer's disease (AD). Previous studies have demonstrated that the expression of tau cleaved at Asp421 by caspase-3 leads to mitochondrial abnormalities and bioenergetic impairment. However, the underlying mechanism behind these alterations and their impact on neuronal function remains unknown. To investigate the mechanism behind mitochondrial dysfunction caused by this tau form, we used transient transfection and pharmacological approaches in immortalized cortical neurons and mouse primary hippocampal neurons. We assessed mitochondrial morphology and bioenergetics function after expression of full-length tau and caspase-3-cleaved tau. We also evaluated the mitochondrial permeability transition pore (mPTP) opening and its conformation as a possible mechanism to explain mitochondrial impairment induced by caspase-3 cleaved tau. Our studies showed that pharmacological inhibition of mPTP by cyclosporine A (CsA) prevented all mitochondrial length and bioenergetics abnormalities in neuronal cells expressing caspase-3 cleaved tau. Neuronal cells expressing caspase-3-cleaved tau showed sustained mPTP opening which is mostly dependent on cyclophilin D (CypD) protein expression. Moreover, the impairment of mitochondrial length and bioenergetics induced by caspase-3-cleaved tau were prevented in hippocampal neurons obtained from CypD knock-out mice. Interestingly, previous studies using these mice showed a prevention of mPTP opening and a reduction of mitochondrial failure and neurodegeneration induced by AD. Therefore, our findings showed that caspase-3-cleaved tau negatively impacts mitochondrial bioenergetics through mPTP activation, highlighting the importance of this channel and its regulatory protein, CypD, in the neuronal damage induced by tau pathology in AD.

Civil liability for clinical misdiagnosis of suicidal intention: procedure and guidelines to minimize fatal diagnostic error / La responsabilidad civil por el diagnóstico clínico erróneo de la intención suicida: procedimiento y pautas para minimizar el error diagnóstico mortal

Background/Objectives: A fatal diagnostic error of suicidal intention, i.e., an error implying death or serious injuries (i.e., incapacitating, chronic injury) to the patient, may have civil liability (punishable error) for the clinician. The Scale for Suicidal Ideation (SSI) is the reference psychometric instrument used to measure suicidal intention. A meta-analytical review was designed with the aim of estimating the true reliability of the SSI in general and in different settings (moderators) with the aim of correcting unreliability raw scores. Method: A total of 90 primary studies reporting SSI's reliability (internal consistency) was found in the literature, yielding a total of 92 effect sizes. Bare-bones meta-analysis of correlation coefficients correcting effect by sampling error were run. Results: The results showed an overall mean true internal consistency of .8904, 95% CI [.8878, .8930], meaning that 42.6% of the population standard deviation is error and 18.11% of an individual's measure is error. Additional estimations (moderators) of SSI's reliability for gender (men: .8873, women: .8808) adaptation version (English: .9212, Korean: .9052, Chinese: .8402, Italian: .9163, Persian: .8612), and population (subclinical: .8769, general: .9230, mental illness: .9040) were obtained. All mean true estimations were under the desirable standard for applied settings where critical decisions are made, .95. Furthermore, for populations with risk of suicide, such as prison inmates and militaries, mean true reliability could not be computed as k was insufficient. Conclusion: Implications of true reliabilities obtained for the estimation of individuals' true scores and population standard deviations are discussed. Examples of computation of true scores to minimize fatal diagnosis errors were performed for both known reliability and unknown reliability settings (e.g., risk populations). (AU)

Antecedentes/Objetivo: Un error diagnóstico mortal de intención suicida, es decir, un error que implique la muerte o lesiones graves (es decir, incapacitantes, crónicas) para el paciente, puede tener responsabilidad civil (error punible) para el clínico. La Escala de Ideación Suicida (SSI) es el instrumento psicométrico de referencia utilizado para medir la intención suicida. En este estudio se diseñó una revisión metaanalítica para medir la fiabilidad real de la SSI en general y en diferentes ámbitos (moderadores), con el fin de corregir las puntuaciones brutas por la falta de fiabilidad de la medida. Método: En la búsqueda de estudios se encontró un total de 90 estudios primarios que trataban de la fiabilidad (consistencia interna) del SSI, lo que arrojó un total de 92 tamaños del efecto. Se ejecutaron meta-análisis del tipo bare-bone corrigiendo el efecto por el error de muestreo. Resultados: Se obtuvo una consistencia interna verdadera media global de .8904, IC 95% [.8878, .8930], es decir, el 42.6% de la desviación estándar de la población es error y el 18.11% de la medida de un sujeto es error. Se obtuvieron estimaciones adicionales (moderadores) de la fiabilidad del SSI para el género (hombres: .8873, mujeres: .8808), versión de adaptación (inglés: .9212, coreano: .9052, chino: .8402, italiano: .9163, persa: .8612) y población (subclínica: .8769, general: .9230, enfermedad mental: .9040). Todas las estimaciones verdaderas medias estaban por debajo del estándar deseable para entornos aplicados donde se toman decisiones críticas, .95. Además, para las poblaciones de riesgo de suicidio, como reclusos y militares, no se pudo calcular la fiabilidad media verdadera, ya que k era insuficiente. Conclusiones: Se discuten las implicaciones de la fiabilidad verdadera obtenida para la estimación de las puntuaciones verdaderas de los individuos y las desviaciones típicas de las poblaciones. ... (AU)

Cerebral Abscess Due to Nocardia beijingensis Associated With HIV: Case Report and Mini Review.

Brain abscesses are severe focal infections of the central nervous system. We report the case of a 37-year-old patient with a recent diagnosis of HIV, who presented with weakness in the left arm that progressed to left hemiplegia, ipsilateral paresthesia, holo cranial headache, fever accompanied by chills, and left tonic-clonic movements. A craniectomy and lesion resection were performed along with antimicrobial treatment. Subsequently, the patient persisted with left hemiplegia, which significantly improved after the procedure and gradually through physical physiotherapy. During the investigation, we complete medical history, physical examination, Image tests, laboratory tests, and cultures. After the finalization of the approach, the final diagnosis was a brain abscess due to Nocardia beijingensis associated with HIV. The patient was managed with anticonvulsants: levetiracetam, antimicrobials: ceftriaxone, trimethoprim/sulfamethoxazole, metronidazole, and vancomycin, Craniotomy plus resection of two brain abscesses, Steroidal anti-inflammatory: dexamethasone and antiretroviral therapy. With this, the patient was discharged successfully from the hospital.

Novel frameshift variants expand the map of the genetic defects in IRF2BP2.

Background: At present, the knowledge about disease-causing mutations in IRF2BP2 is very limited because only a few patients affected by this condition have been reported. As previous studies have described, the haploinsufficiency of this interferon transcriptional corepressors leads to the development of CVID. Very recently, a more accurate phenotype produced by truncating variants in this gene has been defined, manifesting CVID with gastrointestinal inflammatory symptoms and autoimmune manifestations. Methods: We analyzed 5 index cases with suspected primary immunodeficiency by high throughput sequencing. They were submitted for a genetic test with a panel of genes associated with immune system diseases, including IRF2BP2. The screening of SNVs, indels and CNVs fulfilling the criteria with very low allelic frequency and high protein impact, revealed five novel variants in IRF2BP2. In addition, we isolated both wild-type and mutated allele of the cDNA from one of the families. Results: In this study, we report five novel loss-of-function (LoF) mutations in IRF2BP2 that likely cause primary immunodeficiency, with CVID as more frequent phenotype, variable expression of inflammatory gastrointestinal features, and one patient with predisposition of viral infection. All identified variants were frameshift changes, and one of them was a large deletion located on chromosome 1q42, which includes the whole sequence of IRF2BP2, among other genes. Both de novo and dominant modes of inheritance were observed in the families here presented, as well as incomplete penetrance. Conclusions: We describe novel variants in a delimited low-complex region, which may be considered a hotspot in IRF2BP2. Moreover, this is the first time that a large CNV in IRF2BP2 has been reported to cause CVID. The distinct mechanisms than LoF in IRF2BP2 could cause different phenotype compared with the mainly described. Further investigations are necessary to comprehend the regulatory mechanisms of IRF2BP2, which could be under variable expression of the disease.

Virtual reality to improve low-back pain and pelvic pain during pregnancy: a pilot RCT for a multicenter randomized controlled trial.

A significant proportion of women experience low back and pelvic pain during and after pregnancy, which can negatively impact their daily lives. Various factors are attributed to these complaints, and many affected women do not receive adequate healthcare. However, there is evidence to support the use of different physiotherapeutic interventions to alleviate these conditions. Virtual reality is a promising complementary treatment to physiotherapy, particularly in improving pain perception and avoidance. The primary objective of this study is to evaluate the efficacy of a four-week program combining VR and physiotherapy compared to standard physiotherapy in pregnant women with low back and pelvic pain, in terms of improving pain avoidance, intensity, disability, and functional level. The study also aims to investigate patient satisfaction with the VR intervention. This research will be conducted through a multi-center randomized controlled clinical trial involving pregnant patients residing in the provinces of Seville and Malaga with a diagnosis of low back and pelvic pain during pregnancy. The alternative hypothesis is that the implementation of a Virtual Reality program in combination with standard physiotherapy will result in better clinical outcomes compared to the current standard intervention, which could lead to the development of new policies and interventions for these pathologies and their consequences. Clinical trial registration: clinicaltrials.gov, identifier NCT05571358.

Blood Flow Restriction in Oncological Patients: Advantages and Safety Considerations.

BACKGROUND: Cancer, being a highly widespread disease on a global scale, has prompted researchers to explore innovative treatment approaches. In this regard, blood flow restriction has emerged as a promising procedure utilized in diverse clinical populations with favorable results including improvements in muscle strength, cardiovascular function, and postoperative recovery. The aim of this systematic review was to assess the efficacy of blood flow restriction in cancer survivors. METHODS: An investigation was carried out using various databases until February 2023: PubMed, Scientific Electronic Library Online, Physiotherapy Evidence Database, Scopus, Web of Science, Cochrane Plus, SPORTDiscus, Physiotherapy and Podiatry of the Complutense University of Madrid, ScienceDirect, ProQuest, Research Library, Cumulative Index of Nursing and Allied Literature Complete Journal Storage, and the gray literature. To assess the methodological quality of the studies, the PEDro scale was utilized, and the Cochrane Collaboration tool was employed to evaluate the risk of bias. RESULTS: Five articles found that blood flow restriction was beneficial in improving several factors, including quality of life, physical function, strength, and lean mass, and in reducing postoperative complications and the length of hospital stay. CONCLUSION: Blood flow restriction can be a viable and effective treatment option. It is important to note that the caution with which one should interpret these results is due to the restricted quantity of articles and significant variation, and future research should concentrate on tailoring the application to individual patients, optimizing load progression, ensuring long-term follow-up, and enhancing the methodological rigor of studies, such as implementing sample blinding.

Effectiveness of Digital Physiotherapy Practice Compared to Usual Care in Long COVID Patients: A Systematic Review.

Long COVID syndrome has been recognized as a public health problem. Digital physiotherapy practice is an alternative that can better meet the needs of patients. The aim of this review was to synthesize the evidence of digital physiotherapy practice in Long COVID patients. A systematic review was carried out until December 2022. The review was complemented by an assessment of the risk of bias and methodological quality. A narrative synthesis of results was conducted, including subgroup analyses by intervention and clinical outcomes. Six articles, including 540 participants, were selected. Five articles were considered of high enough methodological quality. Parallel-group, single-blind, randomized controlled trials were the most commonly used research design. Tele-supervised home-based exercise training was the most commonly used intervention. Great heterogeneity in clinical outcomes and measurement tools was found. A subgroup analysis showed that digital physiotherapy is effective in improving clinical outcomes. Significant differences in favor of digital interventions over usual care were reported. Nevertheless, discrepancies regarding effectiveness were found. Improvements in clinical outcomes with digital physiotherapy were found to be at least non-inferior to usual care. This review provides new evidence that digital physiotherapy practice is an appropriate intervention for Long COVID patients, despite the inherent limitations of the review. Registration: CRD42022379004.

Clinical outcomes after CPX-351 in patients with high-risk acute myeloid leukemia: A comparison with a matched cohort from the Spanish PETHEMA registry.

BACKGROUND: CPX-351 is approved for the treatment of therapy related acute myeloid leukemia (t-AML) and AML with myelodysplastic related changes (MRC-AML). The benefits of this treatment over standard chemotherapy has not been addressed in well matched cohorts of real-life patients. METHODS: Retrospective analysis of AML patients treated with CPX-351 as per routine practice. A propensity score matching (PSM) was used to compare their main outcomes with those observed in a matched cohort among 765 historical patients receiving intensive chemotherapy (IC), all of them reported to the PETHEMA epidemiologic registry. RESULTS: Median age of 79 patients treated with CPX-351 was 67 years old (interquartile range 62-71), 53 were MRC-AML. The complete remission (CR) rate or CR without recovery (CRi) after 1 or 2 cycles of CPX-351 was 52%, 60-days mortality 18%, measurable residual disease <0.1% in 54% (12 out of 22) of them. Stem cell transplant (SCT) was performed in 27 patients (34%), median OS was 10.3 months, and 3-year relapse incidence was 50%. Using PSM, we obtained two comparable cohorts treated with CPX-351 (n = 52) or IC (n = 99), without significant differences in CR/CRi (60% vs. 54%) and median OS (10.3 months vs. 9.1 months), although more patients were bridged to SCT in the CPX-351 group (35% vs. 12%). The results were confirmed when only 3 + 7 patients were included in the historical cohort. In multivariable analyses, SCT was associated with better OS (HR 0.33 95% CI: 0.18-0.59), p < 0.001. CONCLUSION: Larger post-authorization studies may provide evidence of the clinical benefits of CPX-351 for AML in the real-life setting.

A quantum spin liquid candidate isolated in a two-dimensional CoIIRhIII bimetallic oxalate network.

A quantum spin liquid (QSL) is an elusive state of matter characterized by the absence of long-range magnetic order, even at zero temperature, and by the presence of exotic quasiparticle excitations. In spite of their relevance for quantum communication, topological quantum computation and the understanding of strongly correlated systems, like high-temperature superconductors, the unequivocal experimental identification of materials behaving as QSLs remains challenging. Here, we present a novel 2D heterometallic oxalate complex formed by high-spin Co(ii) ions alternating with diamagnetic Rh(iii) in a honeycomb lattice. This complex meets the key requirements to become a QSL: a spin ½ ground state for Co(ii), determined by spin-orbit coupling and crystal field, a magnetically-frustrated triangular lattice due to the presence of antiferromagnetic correlations, strongly suppressed direct exchange interactions and the presence of equivalent interfering superexchange paths between Co centres. A combination of electronic paramagnetic resonance, specific heat and ac magnetic susceptibility measurements in a wide range of frequencies and temperatures shows the presence of strong antiferromagnetic correlations concomitant with no signs of magnetic ordering down to 15 mK. These results show that bimetallic oxalates are appealing QSL candidates as well as versatile systems to chemically fine tune key aspects of a QSL, like magnetic frustration and superexchange path geometries.

Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.

Mutations in GBA1, the gene encoding the lysosomal enzyme ß-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.

New insights into the autophagy-NAD axis in brain disease.

Sun et al. demonstrate that defects in autophagy cause nicotinamide adenine dinucleotide (NAD) depletion and neurotoxicity.1 Restoring NAD levels rescues cytotoxicity in autophagy-deficient neurons, providing a potential therapy for neurodegenerative and lysosomal storage diseases associated with autophagy defects.

Sclerostin, vascular risk factors, and brain atrophy in excessive drinkers.

Objective: Heavy alcohol consumption causes several organic complications, including vessel wall calcification. Vascular damage may be involved in the development of brain atrophy and cognitive impairment. Recently, sclerostin (whose levels may be altered in alcoholics) has emerged as a major vascular risk factor. The objective of the present study is to analyze the prevalence of vascular calcifications in alcoholics, and the relationships of these lesions with brain atrophy, as well as the role of sclerostin on these alterations. Patients and methods: A total of 299 heavy drinkers and 32 controls were included. Patients underwent cranial computed tomography, and several indices related to brain atrophy were calculated. In addition, patients and controls underwent plain radiography and were evaluated for the presence or absence of vascular calcium deposits, cardiovascular risk factors, liver function, alcohol intake, serum sclerostin, and routine laboratory variables. Results: A total of 145 (48.47%) patients showed vascular calcium deposits, a proportion significantly higher than that observed in controls (χ2 = 16.31; p < 0.001). Vascular calcium deposits were associated with age (t = 6.57; p < 0.001), hypertension (t = 5.49; p < 0.001), daily ethanol ingestion (Z = 2.18; p = 0.029), duration of alcohol consumption (Z = 3.03; p = 0.002), obesity (χ2 = 4.65; p = 0.031), total cholesterol (Z = 2.04; p = 0.041), triglycerides (Z = 2.05; p = 0.04), and sclerostin levels (Z = 2.64; p = 0.008). Calcium deposits were significantly related to Bifrontal index (Z = 2.20; p = 0.028) and Evans index (Z = 2.25; p = 0.025). Serum sclerostin levels were related to subcortical brain atrophy, assessed by cella media index (Z = 2.43; p = 0.015) and Huckmann index (ρ = 0.204; p = 0.024). Logistic regression analyses disclosed that sclerostin was the only variable independently related to brain atrophy assessed by altered cella media index. Sclerostin was also related to the presence of vascular calcifications, although this relationship was displaced by age if this variable was also included. Conclusion: Prevalence of vascular calcification in alcoholics is very high. Vascular calcium deposits are related to brain atrophy. Serum sclerostin is strongly related to brain shrinkage and also shows a significant relationship with vascular calcifications, only displaced by advanced age.

The cost-effectiveness of a uniform versus age-based threshold for one-off screening for prevention of cardiovascular disease.

The objective of this article was to assess the cost-effectiveness of screening strategies for cardiovascular diseases (CVD). A decision analytic model was constructed to estimate the costs and benefits of one-off screening strategies differentiated by screening age, sex and the threshold for initiating statin therapy ("uniform" or "age-adjusted") from the Spanish NHS perspective. The age-adjusted thresholds were configured so that the same number of people at high risk would be treated as under the uniform threshold. Health benefit was measured in quality-adjusted life years (QALY). Transition rates were estimated from the European Prospective Investigation into Cancer and Nutrition (EPIC-CVD), a large multicentre nested case-cohort study with 12 years of follow-up. Unit costs of primary care, hospitalizations and CVD care were taken from the Spanish health system. Univariate and probabilistic sensitivity analyses were employed. The comparator was no systematic screening program. The base case model showed that the most efficient one-off strategy is to screen both men and women at 40 years old using a uniform risk threshold for initiating statin treatment (Incremental Cost-Effectiveness Ratio of €3,274/QALY and €6,085/QALY for men and women, respectively). Re-allocating statin treatment towards younger individuals at high risk for their age and sex would not offset the benefit obtained using those same resources to treat older individuals. Results are sensitive to assumptions about CVD incidence rates. To conclude, one-off screening for CVD using a uniform risk threshold appears cost-effective compared with no systematic screening. These results should be evaluated in clinical studies.