Biomarkers of frailty.

Several biomarkers have been proposed to identify frailty, a multisystemic age-related syndrome. However, the complex pathophysiology and the absence of a consensus on a comprehensive and universal definition make it challenging to pinpoint a singular biomarker or set of biomarkers that conclusively characterize frailty. This review delves into the main laboratory biomarkers, placing special emphasis on those associated with various pathways closely tied to the frailty condition, such as inflammation, oxidative stress, mitochondrial dysfunction, metabolic and endocrine alterations and microRNA. Additionally, we provide a summary of different clinical biomarkers encompassing different tools that have been proposed to assess frailty. We further address various imaging biomarkers such as Dual Energy X-ray Absorptiometry, Bioelectrical Impedance analysis, Computed Tomography and Magnetic Resonance Imaging, Ultrasound and D3 Creatine dilution. Intervention to treat frailty, including non-pharmacological ones, especially those involving physical exercise and nutrition, and pharmacological interventions, that include those targeting specific mechanisms such as myostatin inhibitors, insulin sensitizer metformin and with special relevance for hormonal treatments are mentioned. We further address the levels of different biomarkers in monitoring the potential positive effects of some of these interventions. Despite the availability of numerous biomarkers, their performance and usefulness in the clinical arena are far from being satisfactory. Considering the multicausality of frailty, there is an increasing need to assess the role of sets of biomarkers and the combination between laboratory, clinical and image biomarkers, in terms of sensitivity, specificity and predictive values for the diagnosis and prognosis of the different outcomes of frailty to improve detection and monitoring of older people with frailty or at risk of developing it, being this a need in the everyday clinical practice.

Histoplasma capsulatum tenosynovitis: An unusual presentation in a kidney transplant recipient.

Histoplasmosis is an expected endemic mycosis in solid organ transplant recipients and occurs as a primary infection, reactivation, or, rarely, acquired from an infected allograft. Reactivation is favored by maintenance immunosuppression or anti-rejection therapy, which facilitates the appearance of disseminated forms as well as unusual presentations. We present the case of a 66-year-old woman with isolated tenosynovitis due to Histoplasma capsulatum 25 years after a kidney transplant.

Prognostic effect of systematic geriatric assessment on patients with acute heart failure.

AIMS: Frailty and dependence are frequent in patients admitted for acute heart failure (AHF), but their prognostic significance is unknown, especially in young adults. We aimed to study in adults admitted for AHF, regardless of age, the effect of frailty and dependence on the incidence of mortality and a combined event of mortality, readmissions for AHF, and visits to the emergency room (ER) for AHF at 1 and 6 months. METHODS AND RESULTS: We designed a prospective cohort study by including all the patients with AHF admitted in our Cardiology Department from July 2020 through May 2021. A multidimensional geriatric assessment was performed during the admission. We clinically followed up the patients 6 months after discharge. We enrolled 202 patients. The mean age was 73 ± 12.32 years, and 100 (49.5%) of the patients were elderly (>75 years). Just 78 patients (38.6%) were women, and 100 (49.5%) had previous HF. Frailty (FRAIL ≥ 3) was observed in 68 (33.7%) patients (mean FRAIL score: 1.88 ± 1.48). Dependence (Barthel < 100) was observed in 65 (32.2%) patients (mean Barthel index: 94.38 ± 11.21). Frailty and dependence showed a significant association with both prognostic events at 1 and 6 months. In the multivariable analysis, frailty was associated with higher mortality at 1 month [hazard ratio (HR) 12.61, 95% confidence interval (CI) 1.57-101.47, P = 0.017] but not at 6 months (HR 2.25, 95% CI 0.61-8.26, P = 0.224) or with the combined endpoint at neither 1 month (HR 1.64, 95% CI 0.54-5.03, P = 0.384) nor 6 months (HR 1.35, 95% CI 0.75-2.46, P = 0.320). Dependence was related to higher mortality at 1 month (HR 13.04, 95% CI 1.62-104.75, P = 0.016) and 6 months (HR 7.18, 95% CI 1.99-25.86, P = 0.003) and to higher incidence of the combined event at 1 month (HR 5.93, 95% CI 1.63-21.50, P = 0.007) and 6 months (HR 2.62, 95% CI 1.49-4.61, P = 0.001). CONCLUSIONS: In AHF patients, frailty and dependence implied a worse prognosis, rising mortality, readmissions, and ER visits for AHF.

Naphthoquinone Derivatives from Angustimassarina populi CF-097565 Display Anti-Tumour Activity in 3D Cultures of Breast Cancer Cells.

Cancer is one of the leading causes of death worldwide, with breast cancer being the second cause of cancer-related mortality among women. Natural Products (NPs) are one of the main sources for drug discovery. During a screening campaign focused on the identification of extracts from Fundación MEDINA's library inhibiting the proliferation of cancer cell lines, a significant bioactivity was observed in extracts from cultures of the fungus Angustimassarina populi CF-097565. Bioassay-guided fractionation of this extract led to the identification and isolation of herbarin (1), 1-hydroxydehydroherbarin (4) plus other three naphthoquinone derivatives of which 3 and 5 are new natural products and 2 is herein described from a natural source for the first time. Four of these compounds (1, 3, 4 and 5) confirmed a specific cytotoxic effect against the human breast cancer cell line MCF-7. To evaluate the therapeutic potential of the compounds isolated, their efficacy was validated in 3D cultures, a cancer model of higher functionality. Additionally, an in-depth study was carried out to test the effect of the compounds in terms of cell mortality, sphere disaggregation, shrinkage, and morphology. The cell profile of the compounds was also compared to that of known cytotoxic compounds with the aim to distinguish the drug mode of action (MoA). The profiles of 1, 3 and 4 showed more biosimilarity between them, different to 5, and even more different to other known cytotoxic agents, suggesting an alternative MoA responsible for their cytotoxicity in 3D cultures.

Invasive pulmonary aspergillosis following human metapneumovirus infection in solid-organ transplant recipients: Another virus to add to the list.

There is increasing recognition that respiratory viral infections such as influenza, respiratory syncytial virus, parainfluenza virus, adenovirus, and SARS-CoV-2 can promote the development of invasive fungal pulmonary coinfections, particularly invasive aspergillosis, both in immunocompetent and immunocompromised patients. To date, there are no case reports exploring the role of human metapneumovirus as a risk factor for fungal coinfection. Below, we describe the case of a 63-year-old woman who received a kidney transplant and developed invasive pulmonary aspergillosis after a human metapneumovirus infection and discuss the possible phenomena that could favor this association.

Validation of the 10-Item Unilateral Vocal Fold Paralysis-Handicap Index quality of life questionnaire.

OBJECTIVES: To validate and test the reliability of the 10-Item Unilateral Vocal Fold Paralysis-Voice Handicap Index (UVFP-HI-10) quality of life (QoL) questionnaire for patients with UVFP. DESIGN: Prospective describe study based on perceptive surveys. PARTICIPANTS: We recruited 61 patients with UVFP and 53 healthy individuals comprised the control group. MAIN OUTCOME MEASURES: Both the patients and controls completed the UVFP-HI-10 questionnaire. A statistical analysis was performed to assess the internal consistency and validity of the survey. In addition, maximum phonation time (MPT) was used to objectively measure patient QoL. RESULTS: Internal consistency was high (α = .914) and the correlation with MPT was significant (rs = -0.722). The estimated marginal mean in the discriminant validity study was around seven times higher in the UVFP group compared to the controls. The UVFP-HI-10 cut-off value was more than 0.9 and the sensitivity and specificity were more than 0.8. CONCLUSIONS: The UVFP-HI-10 is a self-administered patient-reported outcome questionnaire with a high reliability and excellent criterion-based validity. This questionnaire can be used to evaluate specific clinical complaints (e.g., vocalisation, swallowing, and breathing) in terms of their impact on QoL in patients with UVFP. Thus, its use is appropriate as a basic assessment tool as part of a specific UVFP treatment protocol.

How to assess eating disorder severity in males?The DSM-5 severity index versus severity based on drive for thinness.

Using a male eating disorder (ED) sample, this study assessed the clinical utility of the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) severity indices for males with anorexia nervosa (AN) and bulimia nervosa (BN) and compared it to an alternative transdiagnostic severity categorisation based on drive for thinness (DT). The participants included 143 males with an ED (60 [42.0%] AN and 83 [58.0%] BN) diagnosis, who were classified using these two severity classifications. The different severity categories were then compared based on ED symptoms, general psychopathology, and personality traits. Our results revealed that the DSM-5 "mild" and DT "low" severity categories were most prevalent in the AN and BN male patients. Clinically significant findings were strongest for the DT categorisation for both AN and BN. The current findings provide initial support for an alternative transdiagnostic DT severity classification for males that may be more clinically meaningful than the DSM-5 severity indices.

Identifying keystone connectivity spots under climate change: Implications to conservation and management of riparian systems.

Climate change has intensified the effects of habitat fragmentation in many ecosystems, particularly exacerbated in riparian habitats. Therefore, there is an urgent need to identify keystone connectivity spots to ensure long-term conservation and sustainable management of riparian systems as they play a crucial role for landscape connectivity. This paper aims to identify critical areas for connectivity under two contrasting climate change scenarios (RCP 4.5 and RCP 8.5 models) for the years 2030, 2050 and 2100 and to group these critical areas by similar connectivity in keystone spots for sustainable management. A set of analyses comprising climate analysis, drainage network analysis, configuration of potential riparian habitats, riparian habitat connectivity, data clustering, and statistical analysis within a Spanish river basin (NW Spain) were applied. The node and link connectivity would be reduced under the two climate change scenarios (≈2.5 % and 4.4 % reduction, respectively), intensifying riparian habitat fragmentation. Furthermore, 51 different clusters (critical areas) were obtained and classified in five classes (keystone spots) with similar connectivity across the different scenarios of climate change. Each keystone spot obtained by hierarchical classification was associated with one or more climate scenarios. One of these keystone spots was especially susceptible to the worst climate change scenario. Key riparian connectivity spots will be crucial for the management and restoration of highly threatened riparian systems and to ensure long-term biodiversity conservation.

Factors influencing xerostomia and oral health-related quality of life in polymedicated patients.

OBJECTIVES: To evaluate whether the severity of xerostomia in older polymedicated patients impacts oral health-related quality of life (OHRQoL). BACKGROUND: Medication-associated xerostomia is common in older people. Xerostomia may impair OHRQoL. MATERIALS AND METHODS: This cross-sectional study included older hypertensive patients from two health centres. We assessed the severity of xerostomia and OHRQoL using the Xerostomia Inventory (XI) tool, and the Oral Health Impact Profile-14 (OHIP-14) instrument, respectively. We measured unstimulated (UWS) and stimulated (SWS) salivary flows. Univariate and multiple linear regression analyses evaluated the associations of XI and OHIP-14 and different explanatory variables. RESULTS: Of the 218 patients enrolled, 51.8% had xerostomia, and 38.1% and 27.5% suffered from UWS and SWS hyposalivation, respectively. Patients with xerostomia, UWS, and SWS hyposalivation scored significantly higher on the XI. However, only those with xerostomia or UWS hyposalivation had significantly higher OHIP-14 scores. A moderate correlation was observed between XI and OHIP-14 scores. The multiple regression model showed that factors with the greatest impact on XI were the patient's complaint of xerostomia, UWS flow rate, age and sex. However, only the XI score was significantly associated with the OHIP-14 score. CONCLUSION: Xerostomia has a negative impact on OHRQoL in older polymedicated patients, but this impact is less than in other types of xerostomia. Longitudinal studies are needed to determine whether changes in the detected explanatory variables influence XI and OHIP scores in these patients.

Impulsivity and compulsivity in gambling disorder and bulimic spectrum eating disorders: Analysis of neuropsychological profiles and sex differences.

BACKGROUND: Gambling disorder (GD) and bulimic spectrum eating disorders (BSDs) not only share numerous psychopathological, neurobiological, and comorbidity features but also are distinguished by the presence of inappropriate behaviours related to impulsivity and compulsivity. This study aimed to emphasise the differences and similarities in the main impulsivity and compulsivity features between GD and BSD patients, and to analyse the potential influence of sex in these domains. METHODS: Using self-reported and neurocognitive measures, we assessed different impulsive-compulsive components in a sample of 218 female and male patients (59 with BSD and 159 with GD) and 150 healthy controls. RESULTS: We observed that GD and BSDs exhibited elevated levels of impulsivity and compulsivity in all the dimensions compared to healthy controls. Moreover, these disorders showed differences in several personality traits, such as high novelty seeking in GD, and low persistence and high harm avoidance in BSDs. In addition, patients with BSDs also displayed a trend towards greater impulsive choice than GD patients. Regarding sex effects, GD women presented higher overall impulsivity and compulsivity than GD men. Nevertheless, no sex differences were found in BSDs. CONCLUSIONS: Clinical interventions should consider these deficits to enhance their effectiveness, including adjunctive treatment to target these difficulties. Our findings also provide support to the relevance of sex in GD, which should also be considered in clinical interventions.

Acoustic droplet ejection facilitates cell-based high-throughput screenings using natural products.

Natural Products (NPs) are one of the main sources for drug discovery. Many clinical drugs are NPs or NP-inspired compounds, and recently discovered New Chemical Entities (NCEs) of NPs are emerging as promising new drugs. High-Throughput Screening (HTS) of large sample sets or libraries has grown to be vital for the drug discovery field. Industrial-scale HTS of NP libraries can be limited due to the difficulties entailed in working with tiny extract volumes and the variability in viscosity of NP extracts. For these reasons, the implementation of new technologies to miniaturize different reagent volumes grows to be fundamental. Since Acoustic Droplet Ejection (ADE) emerged as a helpful tool in HTS campaigns for the transference of compound libraries. The aim of this work was to test the effectiveness of ADE for the dispensation of NP extract libraries in cell-based HTS assays.

Pharmacokinetic and Exposure Response Analysis of the Double-Blind Randomized Study of Posaconazole and Voriconazole for Treatment of Invasive Aspergillosis.

BACKGROUND AND OBJECTIVE: A double-blind phase 3 study was conducted to compare posaconazole 300 mg intravenously (IV)/300 mg orally once daily (twice daily day 1) with voriconazole 4 mg/kg IV twice daily/200 mg orally twice daily (6 mg/kg day 1) for treatment of invasive aspergillosis. This analysis was conducted to summarize the pharmacokinetics and exposure-response relationships of posaconazole and voriconazole using plasma trough concentration (Ctrough) as a surrogate for exposure from the double-blind phase 3 study. METHODS: The pharmacokinetic evaluable population included all intention-to-treat (ITT) participants with at least one plasma concentration during the treatment period. Treatment blinding was maintained without therapeutic drug monitoring. Ctrough sampling occurred throughout treatment; efficacy and safety were evaluated using quartiles determined by mean Ctrough concentrations. Exposure efficacy variables included day 42 all-cause mortality (primary study endpoint) and global clinical response. Exposure safety variables included all adverse events and treatment-related adverse events. RESULTS: The pharmacokinetic analysis population included 506 of 575 ITT participants (437 with Ctrough concentrations: 228 posaconazole, 209 voriconazole). No trend was seen across quartiles of posaconazole Ctrough for the key efficacy endpoint of all-cause mortality through day 42. Participants in the highest quartile of voriconazole Ctrough had higher all-cause mortality through day 42 than participants in the lower three quartiles of voriconazole Ctrough. Similar findings were observed for global clinical response and Ctrough. No clear exposure safety trend by quartile was seen for posaconazole or voriconazole. CONCLUSIONS: A strong exposure-response relationship was not observed across the range of exposure from the administered doses and formulations for posaconazole or voriconazole. TRIAL REGISTRATION: NCT01782131; registered January 30, 2013.

Transfusion-associated adverse events incidence and severity after the implementation of an active hemovigilance program with 24 h follow-up. A prospective cohort study.

BACKGROUND: Hemovigilance (HV) is usually based on voluntary reports (passive HV). Our aim is to ascertain credible incidence, severity, and mortality of transfusion-associated adverse events (TAAEs) using an active HV program. STUDY DESIGN AND METHODS: Prospective cohort study to estimate transfusion risk after 46,488 transfusions in 5830 patients, using an active HV program with follow-up within the first 24 h after transfusion. We compared these results to those with the previously established passive HV program during the same 30 months of the study. We explored factors associated with the occurrence of TAAEs using generalized estimating equations models. RESULTS: With the active HV program TAAEs incidence was 57.3 (95% CI, 50.5-64.2) and mortality 1.1 (95% CI, 0.13-2.01) per 10,000 transfusions. Incidence with the new surveillance model was 14.0 times higher than with the passive. Most events occurred when transfusions had already finished (60.2%); especially pulmonary events (80.4%). Three out of five deaths and 50.3% of severe TAAEs were pulmonary. In the multivariate analysis surgical patients had half TAAEs risk when compared to medical patients (OR, 0.53; 95% CI, 0.34-0.78) and women had nearly twice the risk of a pulmonary event compared to men (OR, 1.84; 95% CI, 1.03-3.32). Patient's age, blood component type, or blood component shelf-life were unrelated to TAAEs risk. DISCUSSION: Active hemovigilance programs provide additional data which may lead to better recognition and understanding of TAAEs and their frequency and severity.

The enduring enigma of sporadic chorea: A single center case series.

Chorea can have a wide variety of causes including neurodegenerative, pharmacological, structural, metabolic, infectious, immunologic and paraneoplastic processes. We reviewed the clinical records of patients with apparently sporadic choreic movements and no relevant family history, who presented to our neurology department (Hospital Fundación Jimenez Diaz) between 1991 and 2022. We detected 38 cases of apparent sporadic chorea (ASC); Our analysis revealed 5 cases of genetic chorea (including 3 cases with Huntington's disease) while 6 cases were autoimmune/hematological; 6 drug-related chorea, 5 metabolic-vascular, 5 due to miscellaneous conditions and 4 were of mixed etiology. No clear etiology was identified in 8 cases. The differential diagnosis of ASC is extensive and challenging. Highlights: Chorea can have a wide variety of genetic and sporadic causesWe reviewed the clinical records of patients with apparently sporadic chorea (ASC), who presented to our neurology department over the last 30 yearsWe detected 38 cases of apparent ASC; Our analysis revealed a wide array of different sporadic conditions and 5 cases of genetic choreaThe differential diagnosis of ASC is extensive and challenging.